I read this paper with great interest and congratulate the authors on consideration of tetanus in this case. I would point out that the EEG in Figure 1 was recorded with a low pass filter of 30 Hz, which could make EMG artifact look like the fast activity labeled as wicket spikes. If the raw EEG data are still available, examination at a low pass filter of 70 Hz would resolve the issue.
Tetanus does not in and of itself alter consciousness, so one might infer that she had suffered hypoxia during her spasms to cause her coma on presentation, which likely led to the idea that this was status epilepticus. Her eventual cognitive recovery attests to the skill and persistence of her medial team.
Culturing C. tetanii from a wound does not prove the diagnosis of tetanus, as the spores are ubiquitous, and only antitetanus antibodies from vaccination prevent the disease. However, I have no doubt about the diagnosis on clinical grounds. Did she receive tetanus toxoid in addition to human tetanus immune globulin? There are unfortunately cases of recurrent tetanus if active immunization is not pursued.
Ref: Birch TB, Bleck TP. Tetanus (Clostridium tetani). In Bennett JE, Dolin R, Blaser MJ (eds), Mandell, Douglas, and Bennett’s Principles and practice of infectious diseases (ed 9). Philadelphia: Elsevier, 2020, pp. 2948 – 2953.
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an
individual may have a different disorder responsible for ataxia apart from being a carrier for Fr...
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an
individual may have a different disorder responsible for ataxia apart from being a carrier for Friedreich ataxia. [1] Nevertheless, investigators should look for an FXN loss-of-function mutation in heterozygosity with the GAA repeat expansion whenever possible, both by sequencing the FXN coding exons and the adjoining intronic sequences and by gene-dosage determination to rule out significant deletions. [1] These types of facilities are only available in the research faculties which are not available in our case, the same has been accepted as a limitation of our case. Sharma P et al. studied the carrier frequency estimation in a sample of 790 healthy study subjects across India. They reported the prevalence of “carrier state” to be 0.63% i.e. 5 in 790. They reported an approximately 19% prevalence of long-normal alleles (>12 alleles) with the longest repeats being 28. [2] The estimated prevalence of FRDA is 1/1,00,000 based on carrier frequency in the Indian population. [2]
We believe that due to the low prevalence of Friedreich ataxia carriers in India, we should investigate for mutations on other alleles even in heterozygous pre-mutated states, where FRDA has a high clinical likelihood. Even so, Sharma P et al. and the paper by Mukerji M et al. lack the data on the frequency of permutated alleles in the Indian population. [2,3] This underlines the lack of data on pre-mutated alleles in India. A study by Sharma R et al. shows that somatic instability of borderline alleles, which are not generally thought to cause disease, imparts a risk for clinical disease development. [4] Individual somatic cells in different organs may have dramatically varying allele sizes, implying that traditional DNA testing may be insufficient for phenotypic prediction in persons with borderline alleles. [4] In FRDA, the allele size at the lower end of the pathogenic allele range is not clearly entrenched. Although the actual frequency of borderline alleles has not been determined, they account for less than 1% of FXN alleles. As per Cook A et al. “In terms of genetics of FRDA, till date important clarifications still need to be made, particularly with regards to the specific chromatin modifiers responsible for silencing the FXN gene and the extent of this heterochromatization, and the epigenetic basis of FRDA”. [5] As more and more literature is published, FRDA is being studied and reported as an gene silencing disorder with epigenetic basis. [5]
In our case, clinical presentation along with radiological investigations pointed us towards the possibility of the FRDA despite the borderline pre-mutated heterozygous state. We already accepted the limitation in our case was the inability to perform the full genome sequencing or exome sequencing which could have predicted the point mutation or deletion.
In our case, we barely aggravated any of our findings (radiological and clinical), and a most likely diagnosis of FRDA was considered. Nowhere, we tried to manipulate or exaggerate our findings. During the care of this patient, we took opinions from our neurology department, but we did not mention them in the acknowledgment as they were not involved in the writing of the case report. Furthermore, a patient hospitalized in an internal medicine department is routinely checked and advised by the neurology department at our tertiary care hospital.
As per the respected reader, interpretation of genetic tests needs subspecialty expertise provided by medical geneticists, genetic counselors, or neurogeneticists. However, these kinds of facilities are not available at our institute, and the case was managed in resource-limited settings.
According to the esteemed reader, errors of overinterpreting genetic test results and, even more so, erroneous interpretation can be harmful to patients and their relatives. In the present clinical setting, we tried to explain the intricacies of genetic tests to the patient and their relatives. We explained the disease's degenerative nature and the clinical likelihood of the FRDA. However, in the absence of a thorough genetic workup, we left this to the patient's next of kin, whether or not to further go for a workup. Clinically his next of kin (his son) was normal. We believe that, from an ethical point of view, as a physician, we managed the patient with the best of our abilities, clinical acumen, and available resources.
In our settings, it is not always possible to contact a neurogeneticist or other such professional due to the relative non - availability of such practitioners or the patient's inability to pay for such services (here in this case the annual income of the patient was below USD 1250 [no insurance]). Though we have a neurology department, it is not possible to do NCS testing (most of the time machines are in a non-working state), or many facilities are yet unavailable. With great efforts, we were able to convince the relatives for the costly triplet primed PCR assay. For even making an MRI or any radiological scan, the patient’s affordability is an issue that we felt at every stage of treatment. In India (or any other Low-middle income country), such types of cases are handled by Internal medicine physicians (internists) primarily with neurological opinions from neurology consultants, which has happened in our case. These other factors must also be considered in the context of this case report.
We don't want to rule out completely the possibility that this might be a pre-mutated carrier state of FRDA; neither we want to mislead the scientific community. Irrespective of the genetics and diagnosis, the diagnostic dilemma we faced, and the clinical course of the patient are indeed was interesting and worth reporting. We already have accepted our limitations in the published version that we did not have access to advanced investigations required to certainly diagnose these kinds of borderline cases.
The reader is a renowned neurogeneticist and neurologist, as well as considering his vast experience in the said field, we will be more than happy to connect, discuss and collaborate with the esteemed professor on this topic.
REFERENCES:
1 Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 2009;5:222–34. doi:10.1038/nrneurol.2009.26
2 Sharma P, Sonakar AK, Tyagi N, et al. Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool. Genet Genomics Next 2022;3:n/a. doi:10.1002/ggn2.202100078
3 Mukerji M, Choudhry S, Saleem Q, et al. Molecular analysis of Friedreich’s ataxia locus in the Indian population: Friedreich’s ataxia in India. Acta Neurol Scand 2000;102:227–9. doi:10.1034/j.1600-0404.2000.102004227.x
4 Sharma R, De Biase I, Gómez M, et al. Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Ann Neurol 2004;56:898–901. doi:10.1002/ana.20333
5 Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull 2017;124:19–30. doi:10.1093/bmb/ldx034
Maes et al suggest that the burden of organdonation related issues in organdonation after euthanasia (ODE) patients is well tolerable or may even be neglegible. They present two cases with untreatable psychiatric disorders who requested for euthanasia and expressed their deathwish to combine with postmortal organdonation. The burden relates to the patient, his family and the professionals involved in euthanasia. They propose that all psychiatric patients whom euthanasia is granted should be informed about the possibility of postmortal organ donation(1).
First, we state that the burden can even be minimized further: it is not necessary for the patient to have his euthanasia performed in the hospital. These patients can be given the sense of dying at home and transported thereafter using an anesthesia bridge to the hospital, as we have shown to be feasible(2).
Second, it is not fair to use the experience of these two evident highly for ODE motivated psychiatric patients and their families as a reference for comparable euthanasia patients who are unaware of the option of post mortal organdonation.
But third, of perimount importance, we criticize the opinion that the amount of burden for ODE patients may reach a point to be neglegible. In our opinion this burden should not be minimized, but excluded. The suggestions of Maes et al are motivated by utilistic ethical considerations and the existence of waitinglists for transplantation. The act of organdonation h...
Maes et al suggest that the burden of organdonation related issues in organdonation after euthanasia (ODE) patients is well tolerable or may even be neglegible. They present two cases with untreatable psychiatric disorders who requested for euthanasia and expressed their deathwish to combine with postmortal organdonation. The burden relates to the patient, his family and the professionals involved in euthanasia. They propose that all psychiatric patients whom euthanasia is granted should be informed about the possibility of postmortal organ donation(1).
First, we state that the burden can even be minimized further: it is not necessary for the patient to have his euthanasia performed in the hospital. These patients can be given the sense of dying at home and transported thereafter using an anesthesia bridge to the hospital, as we have shown to be feasible(2).
Second, it is not fair to use the experience of these two evident highly for ODE motivated psychiatric patients and their families as a reference for comparable euthanasia patients who are unaware of the option of post mortal organdonation.
But third, of perimount importance, we criticize the opinion that the amount of burden for ODE patients may reach a point to be neglegible. In our opinion this burden should not be minimized, but excluded. The suggestions of Maes et al are motivated by utilistic ethical considerations and the existence of waitinglists for transplantation. The act of organdonation however is a pure altruistic one, and in the face of the ultimate choice to end one’s life incompatible with any utilistic view.
Any suggestion of organdonation to an euthanasia patient, irrespective of the underlying disorder making him to choose his own death, compromises his freedom of an eventually irrevocable and irreversible choice to end his life.
Also the treating physician should be free of any coercion during the whole project of ODE and moral pressure beyond the relationship with the (euthanasia) patient; this excludes even the suggestion for a potential organdonation.
From the first international round table conference on ODE, we became aware of the moral conflicts of healthcare providers experienced in Canada in their practice to ask euthanasia patients to consider organdonation who were not aware of this possibility, which appeared far from a neglegible burden(3). We also know from the practice in the Netherlands that healthcare professionals at the ICU experience an increasing personal burden after multiple ODEs, especially in cases of psychiatric patients.
Using the donor registry as an opportunity to bring up the issue of organ donation in case of euthanasia does not resolve the intertwinement. It is of note that the donor registry has never been designed to be used in the context of ODE. ‘Shared decision making’ also does not mean that interests of transplant recipients need to be considered by euthanasia patients.
We conclude that the altruistic deed of an ODE patient should be safeguarded against any external driven interests and coercion, while at the same time healthcare providers shape the conditions that the wish to donate will be fulfilled.
The awareness of ODE will gradually grow via social media, internet and patient platforms. There is no alternative. Most important is the separation of interests to be hold. In the extremely vulnerability of ODE, society should have no doubts that healthcare professionals, as founded in constitutional legislation, first of all seek anyone’s integrity of life, mind and person. This priority should never be compromised by any interests of others. Intertwinement of these interests may eventually further harm the challenges in ODE and post mortal organdonation in general, than it may help to reduce waitinglists for transplantation.
1. Maes G, Oude Voshaar R, Bollen J, Marijnissen R. Burden of organ donation after euthanasia in patients with psychiatric disorder. BMJ Case Rep. 2022 Jul 4;15(7):e246754. doi: 10.1136/bcr-2021-246754. PMID: 35787499.
2. Mulder J, Sonneveld JPC. Organ donation after medical assistance in dying at home. CMAJ. 2018 Nov 5;190(44):E1305-E1306. doi: 10.1503/cmaj.170517. PMID: 30397157; PMCID: PMC6217602.
3. Mulder J, Sonneveld H, Healey A, Van Raemdonck D. The first international roundtable on "organ donation after circulatory death by medical assistance in dying" demonstrates increasing incidence of successful patient-driven procedure. Am J Transplant. 2022 Mar;22(3):999-1000. doi: 10.1111/ajt.16879. Epub 2021 Nov 6. PMID: 34706144.
Answer by Marijnissen et al,
We thank Sonneveld and Mulder for their thoughtful comments and an opportunity to provide additional explanation to our paper 1. Sonneveld and Mulder argue that the burden of ODE should be fully excluded instead of being reduced as much as possible. In our opinion, however, excluding the patient burden completely in these delicate situations is impossible.
Nevertheless, somewhat paradoxically, the authors suggest that the burden of ODE can be reduced based on the possibility of letting people say goodbye to loved ones at home, after which they are transported to the hospital under anaesthesia. This assumption that saying goodbye at home will reduce burden however does not apply automatically for all patients and their loved ones. For example, the described opportunity has been openly discussed with the first patient some weeks prior to the ODE was performed and afterwards with the family of the second patient. However, they considered the burden of performing this procedure at home higher than saying goodbye in the hospital, as they preferred to accompany their loved ones to the ODE procedure in the hospital as well as when they actually die. This reflects, however, very personal views, which should always be considered and why in our opinion shared decision making is so important.
Sonneveld and Mulder also nuance our conclusion ‘that the burden can be minimal after ODE’ is based on two patients highly motivated for ODE’. Case-reports present by definition highly selective cases, but are important for the discovery of new ideas, for education in rare diagnoses or exceptional situations, and, as in our case, to challenge widespread believes.3 We wanted to inform other health care professionals about the possibility of organ donation after euthanasia in these patients, and its positive consequences – arguing that ODE is not necessarily or merely a burden to every patient.
We are a bit surprised that these authors feel it is better that patients are informed about ODE through social media than by their physician, who knows them best and who can provide correct and nuanced information. The report of the limited round table conference only advertises ODE with anesthesia initiated at home (ODEH) and talks about a ‘patient ‐driven process’, but how can this be patient-driven if the patient is not aware of the possibility of this procedure? Furthermore, by only focusing on avoiding an act in the interest of the transplant waiting list (which is not the way we see ODE), the authors forget to act in the interest of the dying patient by ignoring potential altruistic motives. Physicians are responsible to provide information about all possibilities a patient has, making shared decision possible – only then we can speak of an “irrevocable and irreversible choice to end his life” and “integrity of life, mind and person”. We however do not challenge that informing a patient about ODE is a very sensitive matter, because of which the registration as an organ donor might be a good starting point for this patient-physician discussion. Recently, a Dutch medical disciplinary committee judged that informed consent is also necessary when physicians decide not to perform a surgery, which demonstrates that withholding a medical act causes a burden for both patients and relatives. In other words, irrespective of whether patients chose for ODE or not, the burden of ODE can never be fully excluded. Nonetheless, more research is needed on the best way to introduce and implement ODE, probably especially in a patient with a psychiatric disorder, to minimize the burden.
Our case report on the burden of organ donation after euthanasia in patients with a psychiatric disorder was not aimed to state that the burden of ODE is low in general. Instead, it was meant to give the perspective that a doctor may do the patients short when he or she avoids discussing ODE based on the assumption that it may be too burdensome for them. Nonetheless, we fully agree that the burden for professionals working at the ICU can be substantial and this burden also involves professionals informing patients about the possibility of organ donation during a trajectory for euthanasia 4. We fully agree with the authors that patients should always be prevented from feeling pressure to donate their organs. To this end, our protocols (and laws) state that both procedures should independently be performed by different teams. The best way and timing of discussing all possibilities with patients is probably highly personal and require further study how to optimize the procedures of ODE from both a patient and doctors’ perspective beyond expert opinion.
References
1. Maes G, Oude Voshaar R, Bollen J, Marijnissen R. Burden of organ donation after euthanasia in patients with psychiatric disorder. BMJ Case Rep. 2022 Jul 4;15(7):e246754. doi: 10.1136/bcr-2021-246754. PMID: 35787499; PMCID: PMC9255367.
2. https://www.ama-assn.org/delivering-care/ethics/withholding-information-...
3. Vandenbroucke JP. Observational research, randomised trials, and two views of medical science. PLoS Med. 2008 Mar 11;5(3):e67. doi: 10.1371/journal.pmed.0050067.
4. Mulder J, Sonneveld H, Healey A, Van Raemdonck D. The first international roundtable on "organ donation after circulatory death by medical assistance in dying" demonstrates increasing incidence of successful patient-driven procedure. Am J Transplant. 2022 Mar;22(3):999-1000. doi: 10.1111/ajt.16879. Epub 2021 Nov 6. PMID: 34706144.
Response from Tushar Vidhale, MD (Dated: July 8th, 2022)
Respected Editor and Dr. Pulst,
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder respon...
Response from Tushar Vidhale, MD (Dated: July 8th, 2022)
Respected Editor and Dr. Pulst,
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder responsible for ataxia apart from being a carrier for Friedreich ataxia. [1] Nevertheless, investigators should look for an FXN loss-of-function mutation in heterozygosity with the GAA repeat expansion whenever possible, both by sequencing the FXN coding exons and the adjoining intronic sequences and by gene-dosage determination to rule out significant deletions. [1] These types of facilities are only available in the research faculties which are not available in our case, the same has been accepted as a limitation of our case. Sharma P et al. studied the carrier frequency estimation in a sample of 790 healthy study subjects across India. They reported the prevalence of “carrier state” to be 0.63% i.e. 5 in 790. They reported an approximately 19% prevalence of long-normal alleles (>12 alleles) with the longest repeats being 28. [2] The estimated prevalence of FRDA is 1/1,00,000 based on carrier frequency in the Indian population. [2] We believe that due to the low prevalence of Friedreich ataxia carriers in India, we should investigate for mutations on other alleles even in heterozygous pre-mutated states, where FRDA has a high clinical likelihood. Even so, Sharma P et al. and the paper by Mukerji M et al. lack the data on the frequency of permutated alleles in the Indian population. [2,3] This underlines the lack of data on pre-mutated alleles in India. A study by Sharma R et al. shows that somatic instability of borderline alleles, which are not generally thought to cause disease, imparts a risk for clinical disease development. [4] Individual somatic cells in different organs may have dramatically varying allele sizes, implying that traditional DNA testing may be insufficient for phenotypic prediction in persons with borderline alleles. [4] In FRDA, the allele size at the lower end of the pathogenic allele range is not clearly entrenched. Although the actual frequency of borderline alleles has not been determined, they account for less than 1% of FXN alleles. As per Cook A et al. “In terms of genetics of FRDA, till date important clarifications still need to be made, particularly with regards to the specific
chromatin modifiers responsible for silencing the FXN gene and the extent of this heterochromatization, and the epigenetic basis of FRDA”. [5] As more and more literature is published, FRDA is being studied and reported as an gene silencing disorder with epigenetic basis. [5]
In our case, clinical presentation along with radiological investigations pointed us towards the possibility of the FRDA despite the borderline pre-mutated heterozygous state. We already accepted the limitation in our case was the inability to perform the full genome sequencing or exome sequencing which could have predicted the point mutation or deletion.
In our case, we barely aggravated any of our findings (radiological and clinical), and a most likely diagnosis of FRDA was considered. Nowhere, we tried to manipulate or exaggerate our findings. During the care of this patient, we took opinions from our neurology department, but we did not mention them in the acknowledgment as they were not involved in the writing of the case report. Furthermore, a patient hospitalized in an internal medicine department is routinely checked and advised by the neurology department at our tertiary care hospital.
As per the respected reader, interpretation of genetic tests needs subspecialty expertise provided by medical geneticists, genetic counselors, or neurogeneticists. However, these kinds of facilities are not available at our institute, and the case was managed in resource-limited settings.
According to the esteemed reader, errors of overinterpreting genetic test results and, even more so, erroneous interpretation can be harmful to patients and their relatives. In the present clinical setting, we tried to explain the intricacies of genetic tests to the patient and their relatives. We explained the disease's degenerative nature and the clinical likelihood of the FRDA. However, in the absence of a thorough genetic workup, we left this to the patient's next of kin, whether or not to further go for a workup. Clinically his next of kin (his son) was normal. We believe that, from an ethical point of view, as a physician, we managed the patient with the best of our abilities, clinical acumen, and available resources.
In our settings, it is not always possible to contact a neurogeneticist or other such professional due to the relative non - availability of such practitioners or the patient's inability to pay for such services (here in this case the annual income of the patient was below USD 1250 [no insurance]). Though we have a neurology department, it is not possible to do NCS testing (most of the time machines are in a non-working state), or many facilities are yet unavailable. With great efforts, we were able to convince the relatives for the costly triplet primed PCR assay. For even making an MRI or any radiological scan, the patient’s affordability is an issue that we felt at every stage of treatment. In India (or any other Low-middle income country), such types of cases are handled by Internal medicine physicians (internists) primarily with neurological opinions from neurology consultants, which has happened in our case. These other factors must also be considered in the context of this case report.
We don't want to rule out completely the possibility that this might be a pre-mutated carrier state of FRDA; neither we want to mislead the scientific community. Irrespective of the genetics and diagnosis, the diagnostic dilemma we faced, and the clinical course of the patient are indeed was interesting and worth reporting. We already have accepted our limitations in the published version that we did not have access to advanced investigations required to certainly diagnose these kinds of borderline cases.
The reader is a renowned neurogeneticist and neurologist, as well as considering his vast experience in the said field, we will be more than happy to connect, discuss and collaborate with the esteemed professor on this topic.
REFERENCES:
1 Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 2009;5:222–34. doi:10.1038/nrneurol.2009.26
2 Sharma P, Sonakar AK, Tyagi N, et al. Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool. Genet Genomics Next 2022;3:n/a.doi:10.1002/ggn2.202100078
3 Mukerji M, Choudhry S, Saleem Q, et al. Molecular analysis of Friedreich’s ataxia locus in the Indian population: Friedreich’s ataxia in India. Acta Neurol Scand 2000;102:227–9.doi:10.1034/j.1600-0404.2000.102004227.x
4 Sharma R, De Biase I, Gómez M, et al. Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Ann Neurol 2004;56:898–901. doi:10.1002/ana.20333
5 Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull 2017;124:19–30. doi:10.1093/bmb/ldx034
Dear Editor:
We have read with interest this case, but we do not agree with the authors about considering this case as a visceral leishmaniasis (VL). This is a typical case of localized leishmanial Lymphadenopathy (LLL), as we and others described in several series of cases (1,2). This not-well known form of presentation of leishmaniasis is more common in Middle-East region, caused by dermatotropic strains like L. tropica or L. major, but isolated cases are described in Mediterranean region caused by L. infantum, as probably this case.
In last decade, we suffered in Southern urban cities of Madrid, mainly Fuenlabrada, an important outbreak of leishmaniasis. More than 1000 cases of leishmaniasis were reported, and we could describe several cases of LLL (2).
LLL is a form of presentation of leishmaniasis in patients without cellular immunosuppression, which presented with lymphadenopathy as the only form of presentation, and without systemic manifestations (no fever, no splenomegaly, no kytopenias, and normal acute phase reactants). Some LLL patients can refer lesions of cutaneous leishmaniasis (CL) near the adenopathy that had been previously spontaneously resolved or not, showing adenopathies as a local inflammatory rather than a systemic disease. Median duration of the adenopathy was 3 months in our patients. None of these patients, some of them without treatment, progressed to VL.
We think it is important to distinguish LLL from VL because of crit...
Dear Editor:
We have read with interest this case, but we do not agree with the authors about considering this case as a visceral leishmaniasis (VL). This is a typical case of localized leishmanial Lymphadenopathy (LLL), as we and others described in several series of cases (1,2). This not-well known form of presentation of leishmaniasis is more common in Middle-East region, caused by dermatotropic strains like L. tropica or L. major, but isolated cases are described in Mediterranean region caused by L. infantum, as probably this case.
In last decade, we suffered in Southern urban cities of Madrid, mainly Fuenlabrada, an important outbreak of leishmaniasis. More than 1000 cases of leishmaniasis were reported, and we could describe several cases of LLL (2).
LLL is a form of presentation of leishmaniasis in patients without cellular immunosuppression, which presented with lymphadenopathy as the only form of presentation, and without systemic manifestations (no fever, no splenomegaly, no kytopenias, and normal acute phase reactants). Some LLL patients can refer lesions of cutaneous leishmaniasis (CL) near the adenopathy that had been previously spontaneously resolved or not, showing adenopathies as a local inflammatory rather than a systemic disease. Median duration of the adenopathy was 3 months in our patients. None of these patients, some of them without treatment, progressed to VL.
We think it is important to distinguish LLL from VL because of critical outcome differences. VL is an incurable and potential mortal disease without treatment. LLL is a benign localized disease, similar to CL, which can be treated with systemic treatment for a faster resolution of the adenopathy, but that it is possible to resolve with lower doses of Liposomal Amphotericin B, avoiding toxicity, or even monitoring without treatment (2).
1.Ignatius R, Loddenkemper C, Woitzik J, Schneider T, Harms G. Localized leishmanial lymphadenopathy: an unusual manifestation of leishmaniasis in a traveler in southern Europe. Vector Borne Zoonotic Dis. 2011 Aug;11(8):1213-5. doi: 10.1089/vbz.2011.0642. Epub 2011 May 25. PMID: 21612538.
2.Horrillo L, San Martín JV, Molina L, Madroñal E, Matía B, Castro A, García-Martínez J, Barrios A, Cabello N, Arata IG, Casas JM, Ruiz Giardin JM. Atypical presentation in adults in the largest community outbreak of leishmaniasis in Europe (Fuenlabrada, Spain). Clin Microbiol Infect. 2015 Mar;21(3):269-73. doi: 10.1016/j.cmi.2014.10.017. Epub 2014 Oct 29. PMID: 25658537.
Jiang presents a very interesting and unique case of bilateral corneal decompensation in a patient with COVID pneumonitis. We would like to offer a similar case to support their hypothesis of viral endotheliitis. These cases demonstrate an ocular manifestation of COVID-19 infection which was previously unknown. This manifestation is important to be aware of as the subsequent visual impairment may be profound, though likely amenable to treatment.
Jiang pointed out the unclear onset for their case and possible delayed presentation from 34 days of ventilation. While we cannot assume the onset time of Jiang’s patient, our patient provides an interesting comparison. Our case describes a male patient who developed significant and painless overnight vision loss. He had gone to bed with only cough as a symptom of COVID infection and awoke to find himself only able to perceive light and gross motion. This patient presented to our local accident and emergency department with this sudden and profound bilateral loss of vision. He required admission due to his inability to self-care.
On examination the patient was found to have significant bilateral corneal oedema. Both eyes were white with no evidence of local infection, inflammation, or ocular surface trauma. There was no epithelial uptake with fluorescein in either eye. Intraocular pressure was within normal limits and symmetrical. No corneal dystrophy could be seen with biomicroscopy. The patient was started on topi...
Jiang presents a very interesting and unique case of bilateral corneal decompensation in a patient with COVID pneumonitis. We would like to offer a similar case to support their hypothesis of viral endotheliitis. These cases demonstrate an ocular manifestation of COVID-19 infection which was previously unknown. This manifestation is important to be aware of as the subsequent visual impairment may be profound, though likely amenable to treatment.
Jiang pointed out the unclear onset for their case and possible delayed presentation from 34 days of ventilation. While we cannot assume the onset time of Jiang’s patient, our patient provides an interesting comparison. Our case describes a male patient who developed significant and painless overnight vision loss. He had gone to bed with only cough as a symptom of COVID infection and awoke to find himself only able to perceive light and gross motion. This patient presented to our local accident and emergency department with this sudden and profound bilateral loss of vision. He required admission due to his inability to self-care.
On examination the patient was found to have significant bilateral corneal oedema. Both eyes were white with no evidence of local infection, inflammation, or ocular surface trauma. There was no epithelial uptake with fluorescein in either eye. Intraocular pressure was within normal limits and symmetrical. No corneal dystrophy could be seen with biomicroscopy. The patient was started on topical Predforte drops which were administered 2 hourly to both eye. He was also given topical lubrication in the form of celluvisc 0.5% four times a day to both eyes. Notably, viral eye swabs taken from the conjunctival sac were positive for COVID and negative for HSV and VZV. Viral eye swabs as a diagnostic tool for aetiology of ocular pathology is of unknown specificity, though has been widely suggested in the literature (1).
This gentleman was rather comorbid with, notably, diabetes, hypertension, obesity and stable sarcoidosis. He had no ophthalmic history or family history of note. Though he suffered from polypharmacy, he was not on any medication known to cause corneal decompensation and no significant medication changes had been made within 12 months of his admission. His chest x-ray on admission showed only air space shadowing consistent with COVID pneumonitis. Therefore, there were no other obvious causes of corneal decompensation (2).
Systemically our gentleman was also found at admission to have an acute kidney injury and hypoglycaemia. This was thought to be secondary to his inability to feed himself with his acutely deteriorated eyesight. Hypoglycaemia was treated by the paramedics, but his kidney injury worsened and ultimately, sadly, resulted in death at 72 hours after admission. The patient was reviewed daily and interestingly, as his kidney function continued to deteriorate his corneal oedema began to improve. His vision improved to counting fingers in each eye. As noted by Jiang, this systemic upset is unlikely to be the cause of corneal decompensation which is usually due to a more local insult. Hence the most likely cause and perhaps supported by the positive swab is viral endotheliitis secondary to COVID-19 infection.
Supporting Jiang’s case, we, similarly have a case of profound bilateral corneal decompensation for which all differentials for cause had been ruled out and leaving viral endotheliitis secondary to COVID infection the most likely cause. In comparison to Jiang’s case, our gentleman shows that acute deterioration is possible, and importantly, this manifestation of disease may occur throughout the range of the severity of COVID pneumonitis. Reassuringly, both patients have shown good initial responses to topical treatment with steroids. The literature continues to grow with profound manifestations of COVID pneumonitis, it remains of utmost importance to be aware of these presentations especially when they may present across the range of COVID severity.
(A note to the editor: we have submitted this letter with the purpose outlined above. If consent from this patient’s relatives is required, please let us know. Many thanks for reading this letter.)
References:
1. Kaur P, Sehgal G, Shailpreet, Singh K, Singh B. Evaluation and comparison of conjunctival swab polymerase chain reaction results in SARS-CoV-2 patients with and without ocular manifestations. 2021.
2. Moshirfar M, Murri M, Shah T, Skanchy D, Tuckfield J, Ronquillo Y et al. A Review of Corneal Endotheliitis and Endotheliopathy: Differential Diagnosis, Evaluation, and Treatment. 2021.
Summary:
A supporting case from Dr Evelyn Qian, Lothian describes similar ocular manifestation and positive conjunctival swab PCR relating to severe COVID pneumonitis, in support of our hypothesis of SARS-CoV-2 viral endotheliitis which was previously unknown.
Qian describes a case of acute bilateral corneal oedema in the presence of severe COVID-19. Conjunctival swabs were positive for SARS-CoV-2 by rRT-PCR assay, and negative for HSV and VZV. His ocular condition was treated with topical steroid drops which demonstrated clinical improvement before he passed away from acute kidney injury at 72 hours after admission.
Thanks for your interest in our case report and the literature review on CeAD and spinal manipulation, which is the most important element of patient care.
All clinicians would like to have a positive outcome for their patients using evidence-based practice.
Unfortunately, the patient in this case had a near fatal outcome by a chiropractor practising in a major metropolitan region of China. The chiropractor is a graduate of a traditional Chinese medical university. The patient could only recall heavy massage and possibly using an equipment (activator? we did not put in the paper because of the uncertainty).
The side effect with this mode of chiropractor treatment is extremely rare as what we have reviewed. This mode of treatment can certainly be the risk factors for the outcome (we ruled out most of the other risk factors presented in our case). We are sharing this case purely for education purpose without the intention of criticising any individual and the chiropractor profession. We did not want to see any more similar cases with an almost fatal outcome. We do appreciate that the whole profession of chiropractors constantly reviews their practice to ensure the delivery of evidence-based practice for treatment effectiveness of various aches and pain (shoulder girdle and neck pain in our case), which all health professionals should practice routinely.
Thanks for your interest in our case report and the literature review on CeAD and spinal manipulation, which is the most important element of patient care.
All clinicians would like to have a positive outcome for their patients using evidence-based practice.
Unfortunately, the patient in this case had a near fatal outcome by a chiropractor practising in a major metropolitan region of China. The chiropractor is a graduate of a traditional Chinese medical university. The patient could only recall heavy massage and possibly using an equipment (activator? we did not put in the paper because of the uncertainty).
The side effect with this mode of chiropractor treatment is extremely rare as what we have reviewed. This mode of treatment can certainly be the risk factors for the outcome (we ruled out most of the other risk factors presented in our case). We are sharing this case purely for education purpose without the intention of criticising any individual and the chiropractor profession. We did not want to see any more similar cases with an almost fatal outcome. We do appreciate that the whole profession of chiropractors constantly reviews their practice to ensure the delivery of evidence-based practice for treatment effectiveness of various aches and pain (shoulder girdle and neck pain in our case), which all health professionals should practice routinely.
Hope the response helps to clarify the queries.
kind regards
Daniel
Dr Daniel Xu
MBBS, PhD, FRACGP
Academic Coordinators, General Practice Research & International Health
Curtin Medical School
Visiting Professor
The First Affiliated Hospital, Sun Yat-Sen University
Guangzhou, China
Senior Research Fellow
CCRE, School of Public Health
Faculty of Health Sciences
Curtin University
Location Building 408, Level 3, Room 3516
Postal Address |GPO Box U1987, Perth, Western Australia, 6845 | AUSTRALIA
Tel | +61 (0)8 9266 1740
Mobile | +61 (0)415288896
Email |daniel.xu@curtin.edu.au
Sindgikar et al. report a severe paradoxical reaction in a 15-year-old HIV-uninfected patient with stage III tuberculous meningitis, during her fifth month of treatment. After improving with re-initiation of corticosteroids, the paradoxical reaction worsened after the prednisolone was weaned over 8 weeks. The patient continued 4 months of corticosteroids in addition to 13 months anti-TB treatment (ATT) with significant morbidity at one year follow up, including permanent disability.
Whilst corticosteroids are the mainstay of treatment for paradoxical reactions, their effectiveness for this difficult-to-treat complication has not been assessed in randomised controlled trials (RCT)(1). TNF-alpha is a key cytokine implicated in the exaggerated inflammatory response underlying paradoxical reactions (2,3). We have used infliximab, a monoclonal antibody targeting TNF-alpha, in the management of severe paradoxical reactions in paediatric central nervous system TB with positive outcomes (4,5). Anti-TNFα monoclonal antibodies, including infliximab, have also been used with encouraging results in adults for this indication (6,7). Thalidomide, another anti-TNF-alpha therapy was evaluated in an RCT of children with stage II and III tuberculous meningitis (8), however, this trial was ceased early due to increased deaths and adverse outcomes with a thalidomide dose of 24 mg/kg/day. A subsequent case series of 38 children treated with low-dose thalidomide (3-5 mg/kg) with life-th...
Sindgikar et al. report a severe paradoxical reaction in a 15-year-old HIV-uninfected patient with stage III tuberculous meningitis, during her fifth month of treatment. After improving with re-initiation of corticosteroids, the paradoxical reaction worsened after the prednisolone was weaned over 8 weeks. The patient continued 4 months of corticosteroids in addition to 13 months anti-TB treatment (ATT) with significant morbidity at one year follow up, including permanent disability.
Whilst corticosteroids are the mainstay of treatment for paradoxical reactions, their effectiveness for this difficult-to-treat complication has not been assessed in randomised controlled trials (RCT)(1). TNF-alpha is a key cytokine implicated in the exaggerated inflammatory response underlying paradoxical reactions (2,3). We have used infliximab, a monoclonal antibody targeting TNF-alpha, in the management of severe paradoxical reactions in paediatric central nervous system TB with positive outcomes (4,5). Anti-TNFα monoclonal antibodies, including infliximab, have also been used with encouraging results in adults for this indication (6,7). Thalidomide, another anti-TNF-alpha therapy was evaluated in an RCT of children with stage II and III tuberculous meningitis (8), however, this trial was ceased early due to increased deaths and adverse outcomes with a thalidomide dose of 24 mg/kg/day. A subsequent case series of 38 children treated with low-dose thalidomide (3-5 mg/kg) with life-threatening TB mass lesions despite drug-susceptible anti-TB treatment and corticosteroids reported encouraging results (9), further supporting the role of anti-TNF-alpha agents in the treatment of paradoxical tuberculous reactions.
Future carefully designed trials are needed to evaluate the effectiveness of anti-TNF agents for paradoxical reactions. They could also establish risk factors and biomarkers to help determine which patients are likely to develop paradoxical reactions, and which would potentially benefit from anti-TNF-alpha therapy shortly after ATT initiation to prevent the long-term morbidity associated with this potentially devastating complication.
1. Marais S, Van Toorn R, Chow FC, et al. Management of intracranial tuberculous mass lesions: how long should we treat for? Wellcome Open Res. 2019;4:158.
2. Tsenova L, Sokol K, Freedman VH, Kaplan G. A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death. J Infect Dis. 1998;177(6):1563-1572.
3. Donald PR, Schoeman JF, Beyers N, et al. Concentrations of interferon gamma, tumor necrosis factor alpha, and interleukin-1 beta in the cerebrospinal fluid of children treated for tuberculous meningitis. Clin Infect Dis. 1995;21(4):924-929.
4. Abo YN, Curtis N, Butters C, Rozen TH, Marais BJ, Gwee A. Successful Treatment of a Severe Vision-Threatening Paradoxical Tuberculous Reaction with Infliximab: First Pediatric Use. Pediatr Infect Dis J. 2020;39(4):e42-e45.
5. Abo YN, Curtis N, Osowicki J, et al. Iin press). Infliximab for paradoxical reactions in pediatric central nervous system tuberculosis. Journal of the Pediatric Infectious Diseases Societ. 2021.
6. Santin M, Escrich C, Majòs C, Llaberia M, Grijota MD, Grau I. Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis: Case report and review. Medicine. 2020;99(43):e22626-e22626.
7. Marais BJ, Cheong E, Fernando S, et al. Use of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions. Open Forum Infect Dis. 2021;8(1):ofaa604.
8. Schoeman JF, Springer P, van Rensburg AJ, et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J Child Neurol. 2004;19(4):250-257.
9. van Toorn R, Solomons RS, Seddon JA, Schoeman JF. Thalidomide Use for Complicated Central Nervous System Tuberculosis in Children: Insights From an Observational Cohort. Clin Infect Dis. 2021;72(5):e136-e145.
We read, with interest, “Obstetric rectal laceration in the absence of an anal sphincter injury” by Awomolo et al in your journal [1]. We commend the authors on reviewing this rare injury.
We appreciate your detailed case report and were pleased to read that your patient recovered well from her injury. We agree that these rare injuries require careful repair with experience, good surgical technique and detailed knowledge of perineal anatomy. Your extensive literature review found other similar cases, many of which we included in our most comprehensive case series [2], but we were surprised to see that our case series was not included in your paper. Although rectal buttonhole tears are rare they are now defined in many National guidelines in the world [3]. What our paper also adds is a standardised approach for repair of isolated rectal tears and follow up, with a video demonstration on a porcine specimen. In addition, we have highlighted that rectal button hole tears can occur concomitantly with a third or 4th degree tear when there is intact bridge of anorectal mucosa between the two injuries.
We appreciated the insufficiencies in training regarding classification, diagnosis and repair of obstetric anal sphincter injuries (OASIS) over 20 years ago and began the first hands-on course in 2000 (www.perineum.net). We have also introduced the Prevention and Repair Of perineal Trauma Episiotomy through Co...
We read, with interest, “Obstetric rectal laceration in the absence of an anal sphincter injury” by Awomolo et al in your journal [1]. We commend the authors on reviewing this rare injury.
We appreciate your detailed case report and were pleased to read that your patient recovered well from her injury. We agree that these rare injuries require careful repair with experience, good surgical technique and detailed knowledge of perineal anatomy. Your extensive literature review found other similar cases, many of which we included in our most comprehensive case series [2], but we were surprised to see that our case series was not included in your paper. Although rectal buttonhole tears are rare they are now defined in many National guidelines in the world [3]. What our paper also adds is a standardised approach for repair of isolated rectal tears and follow up, with a video demonstration on a porcine specimen. In addition, we have highlighted that rectal button hole tears can occur concomitantly with a third or 4th degree tear when there is intact bridge of anorectal mucosa between the two injuries.
We appreciated the insufficiencies in training regarding classification, diagnosis and repair of obstetric anal sphincter injuries (OASIS) over 20 years ago and began the first hands-on course in 2000 (www.perineum.net). We have also introduced the Prevention and Repair Of perineal Trauma Episiotomy through Coordinated Training (PROTECT) course certified by the International Urogynecological Association (www.IUGA.org). We are currently appraising OASIS diagnosis and repair training for doctors and midwives in the UK, through online surveys and evaluation of training courses. We hope to publish our data in the coming year, making recommendations about content and frequency of training.
Yours sincerely,
Joanna C. Roper MRCOG
Ranee Thakar MD FRCOG
Abdul H. Sultan MD FRCOG
References:
1. Awomolo A, Hardman D, Louis-Jacques A (2021) Obstetric rectal laceration in the absence of an anal sphincter injury. BMJ Case Rep 14:e243296. https://doi.org/10.1136/bcr-2021-243296
2. Roper JC, Thakar R, Sultan AH (2020) Isolated rectal buttonhole tears in obstetrics: case series and review of the literature. Int Urogynecol J. https://doi.org/10.1007/s00192-020-04502-2
3. Roper JC, Amber N, Wan OYK, et al (2020) Review of available national guidelines for obstetric anal sphincter injury. Int Urogynecol J 31:2247–2259. https://doi.org/10.1007/s00192-020-04464-5
We read with interest the case report by Yap et al regarding “A near-fatal consequence of chiropractor massage: massive stroke from carotid arterial dissection and vertebral arterial oedema,”(1) which describes a 35-year-old man with a massive stroke purportedly caused by massage. Cerebrovascular disease is an invested topic for manual therapists, considering such providers are responsible for recognizing emergent signs/symptoms of a cervical artery dissection (CeAD) and referring accordingly,(2) however, we are concerned about appropriate and accurate reporting of details of the case including several inconsistencies and evident biases.
We believe this case report likely misclassifies the treating provider as a chiropractor. The report does not specify the credentials of the person providing massage during the business trip. As pointed out by the authors, there is limited regulation and licensing of chiropractic in China.(3) Furthermore, spinal manipulation is by far the most common treatment intervention provided by chiropractors(4) but the authors did not mention its use in the case presentation.
We request the authors clarify the credentials of the massage provider, and elaborate on treatment interventions, specifically if cervical spinal manipulation was performed. Previous case reports have misrepresented the treating provider as a chiropractor when describing potential adverse events.(5) This practice is spurious and adds to over-reporting of adverse...
We read with interest the case report by Yap et al regarding “A near-fatal consequence of chiropractor massage: massive stroke from carotid arterial dissection and vertebral arterial oedema,”(1) which describes a 35-year-old man with a massive stroke purportedly caused by massage. Cerebrovascular disease is an invested topic for manual therapists, considering such providers are responsible for recognizing emergent signs/symptoms of a cervical artery dissection (CeAD) and referring accordingly,(2) however, we are concerned about appropriate and accurate reporting of details of the case including several inconsistencies and evident biases.
We believe this case report likely misclassifies the treating provider as a chiropractor. The report does not specify the credentials of the person providing massage during the business trip. As pointed out by the authors, there is limited regulation and licensing of chiropractic in China.(3) Furthermore, spinal manipulation is by far the most common treatment intervention provided by chiropractors(4) but the authors did not mention its use in the case presentation.
We request the authors clarify the credentials of the massage provider, and elaborate on treatment interventions, specifically if cervical spinal manipulation was performed. Previous case reports have misrepresented the treating provider as a chiropractor when describing potential adverse events.(5) This practice is spurious and adds to over-reporting of adverse events incorrectly linked to the chiropractic profession.(5)
The authors also conflate “massage” with “chiropractic manipulation” which are two distinct forms of treatment. Spinal manipulation performed by a chiropractor typically involves a thrust or impulse directed to the spine, while massage does not.(6) While the case presentation states massage was the treatment rendered, the title, the discussion, and learning points all highlight chiropractic cervical spine manipulation—which by definition, is not massage. The authors’ literature review included the search term “chiropractic manipulation” which is inappropriate to introduce, as their case pertains to massage.
The authors’ discussion references case reports only, missing seminal studies relevant to manipulation and CeAD, and their conclusions regarding “chiropractic massage” being a “fatal practice” is not supported by the literature. A systematic review of several large observational studies including more than 100 million person-years of data did not identify evidence of a causal association between chiropractic spinal manipulation and CeAD.(7) This is supported by a systematic review of 47 prospective trials that did not identify any incidents of CeAD in recipients of spinal manipulation.(8) Further, to our knowledge there is no epidemiologic evidence linking massage and stroke, and only one case report describing a potential relationship.(9)
Protopathic bias, or confounding by indication, have been proposed as explanations for rare instances in which a stroke is preceded by chiropractic spinal manipulation. In both models, neck pain or headache, common prodromal symptoms of CeAD, prompt a patient to seek care from a chiropractor when the dissection is already in progress.(7, 10-14) This hypothesis is supported by case reports describing such patients presenting to chiropractors with evolving CeAD and referring appropriately.(15-18)
The current case is potentially another example of a dissection-in-progress considering the patient sought massage for neck, shoulder girdle, and upper back pain. The details of initial presentation and physical examination (if performed) for this “chiropractor massage” are not reported, which may have led to a different outcome if the case was managed by a qualified/licensed chiropractor.
The authors’ report of symptom onset coinciding solely with this “chiropractor massage” is not supported in the literature. We propose alternative explanations to the authors regarding the mechanism and resulting conclusions for the case report. Cervical artery dissections are often spontaneous without a known cause.(19) However, there are hypothesized triggers of CeAD which the authors did not mention and could have played a role in the current case such as airplane travel20 and/or viral infection such as mild case of COVID-19 given the timing of this report.(21,22)
In summary, the authors’ conclusions regarding a correlation between chiropractic spinal manipulation and carotid artery dissection and are superseded by higher levels of epidemiologic evidence that has not identified such a causal link. Additionally, the postulated causal relationship between carotid artery dissection and massage exceeds the available data. The patient’s stroke could have been precipitated by a spontaneous CeAD and was treated with massage therapy rather than emergency care. This case should not deter health care providers from referring to, or patients from seeking care from, qualified chiropractors.
References
1. Yap T, Feng L, Xu D, Zhang J. A near-fatal consequence of chiropractor massage: massive stroke from carotid arterial dissection and bilateral vertebral arterial oedema. BMJ Case Rep. 2021 Aug 6;14(8):e243976. doi: 10.1136/bcr-2021-243976. PMID: 34362754; PMCID: PMC8351484.
2. Chaibi A, Russell MB. A risk-benefit assessment strategy to exclude cervical artery dissection in spinal manual-therapy: a comprehensive review. Ann Med. 2019 Mar;51(2):118-127. doi: 10.1080/07853890.2019.1590627. Epub 2019 Apr 6. PMID: 30889367; PMCID: PMC7857472.
3. World Federation of Chiropractic: Legal Status of Chiropractic by Country. (Accessed August 23, 2021) https://www.wfc.org/website/index.php?option=com_content&view=article&id...
4. Beliveau PJH, Wong JJ, Sutton DA, Simon NB, Bussières AE, Mior SA, French SD. The chiropractic profession: a scoping review of utilization rates, reasons for seeking care, patient profiles, and care provided. Chiropr Man Therap. 2017 Nov 22;25:35. doi: 10.1186/s12998-017-0165-8. PMID: 29201346; PMCID: PMC5698931.
5. Wenban AB. Inappropriate use of the title 'chiropractor' and term 'chiropractic manipulation' in the peer-reviewed biomedical literature. Chiropr Osteopat. 2006 Aug 22;14:16. doi: 10.1186/1746-1340-14-16. PMID: 16925822; PMCID: PMC1570468.
6. Hurwitz EL. Epidemiology: Spinal manipulation utilization. J Electromyogr Kinesiol. 2012;22(5):648-654. doi:10.1016/j.jelekin.2012.01.006
7. Church EW, Sieg EP, Zalatimo O, Hussain NS, Glantz M, Harbaugh RE. (2016). Systematic Review and Meta-analysis of Chiropractic Care and Cervical Artery Dissection: No Evidence for Causation. Cureus. 2016;8(2):e498.
8. Coulter ID, Crawford C, Vernon H, Hurtwitz L, Khorsan R, et al. Manipulation and mobilization for treating chronic nonspecific neck pain: a systematic review and meta-analysis for an appropriateness panel. Pain Physician 2019;22(2):E55-E70.
9. Birkett W, Pouryahya P, Meyer ADM. Bilateral vertebral artery dissection and cerebellar stroke: a rare complication of massage. N Z Med J. 2020 Apr 3;133(1512):88-92. PMID: 32242183.
10. Cassidy JD, Bronfort G, Hartvigsen J. Should we abandon cervical spine manipulation for mechanical neck pain? No. BMJ. 2012;344:e3680. doi:10.1136/bmj.e3680
11. Hutting N, Kerry R, Coppieters MW, Scholten-Peeters GG. Considerations to improve the safety of cervical spine manual therapy. Musculoskelet Sci Pract. 2018;33:41-45.
12. Perle SM, Jung H, Ham J, Choi H. Letter to the Editor: A Case of Posterior Inferior Cerebellar Artery Infarction after Cervical Chiropractic Manipulation (Korean J Neurotrauma 2018; 14: 159–163). Korean J Neurotrauma. 2019;15(1):72-73.
13. Murphy DR, Schneider MJ, Perle SM, Bise CG, Timko M, Haas M. Does case misclassification threaten the validity of studies investigating the relationship between neck manipulation and vertebral artery dissection stroke? No. Chiropr Man Ther. 2016;24(1):43. doi:10.1186/s12998-016-0124-9
14. Bronson MA, Perle SM, Tuchin P. Issues with vertebral artery dissections. Interv Neuroradiol. 2017;23(2):154-155. doi:10.1177/1591019916680111
15. Michaud TC. Uneventful upper cervical manipulation in the presence of a damaged vertebral artery. Journal of Manipulative and Physiological Therapeutics. 2002;25(7):472-483.
16. Tarola G, Phillips RB. Chiropractic response to a spontaneous vertebral artery dissection. Journal of Chiropractic Medicine 2015;14(3):183-190.
17. Futch D, et al. Vertebral artery dissection in evolution found during chiropractic examination. BMJ Case Reports. 2015: bcr2015212568.
18. Mosby JS, Duray SM. Vertebral artery dissection in a patient practicing self-manipulation of the neck. Journal of Chiropractic Medicine. 2011;10(4):283-287.
19. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med. 2001 Mar 22;344(12):898-906. doi: 10.1056/NEJM200103223441206. PMID: 11259724.
20. Humaidan H, et al. Airplane stroke syndrome. Journal of Clinical Neuroscience. 2016;29:77-80.
21. Morassi M, et al. Bilateral carotid artery dissection in a SARS-CoV-2 infected patient: causality or coincidence? Journal of Neurology. 2020.;267(10):2812-2814.
22. Gencler OS, Meltem RE, Aydın A. Unilateral common carotid artery dissection in a patient with recent COVID-19: An association or a coincidence? Journal of Clinical Neuroscience. 2021;87: 26-28.
I read this paper with great interest and congratulate the authors on consideration of tetanus in this case. I would point out that the EEG in Figure 1 was recorded with a low pass filter of 30 Hz, which could make EMG artifact look like the fast activity labeled as wicket spikes. If the raw EEG data are still available, examination at a low pass filter of 70 Hz would resolve the issue.
Tetanus does not in and of itself alter consciousness, so one might infer that she had suffered hypoxia during her spasms to cause her coma on presentation, which likely led to the idea that this was status epilepticus. Her eventual cognitive recovery attests to the skill and persistence of her medial team.
Culturing C. tetanii from a wound does not prove the diagnosis of tetanus, as the spores are ubiquitous, and only antitetanus antibodies from vaccination prevent the disease. However, I have no doubt about the diagnosis on clinical grounds. Did she receive tetanus toxoid in addition to human tetanus immune globulin? There are unfortunately cases of recurrent tetanus if active immunization is not pursued.
Ref: Birch TB, Bleck TP. Tetanus (Clostridium tetani). In Bennett JE, Dolin R, Blaser MJ (eds), Mandell, Douglas, and Bennett’s Principles and practice of infectious diseases (ed 9). Philadelphia: Elsevier, 2020, pp. 2948 – 2953.
Respected Editor and Dr. Pulst,
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an
Show Moreindividual may have a different disorder responsible for ataxia apart from being a carrier for Fr...
Maes et al suggest that the burden of organdonation related issues in organdonation after euthanasia (ODE) patients is well tolerable or may even be neglegible. They present two cases with untreatable psychiatric disorders who requested for euthanasia and expressed their deathwish to combine with postmortal organdonation. The burden relates to the patient, his family and the professionals involved in euthanasia. They propose that all psychiatric patients whom euthanasia is granted should be informed about the possibility of postmortal organ donation(1).
Show MoreFirst, we state that the burden can even be minimized further: it is not necessary for the patient to have his euthanasia performed in the hospital. These patients can be given the sense of dying at home and transported thereafter using an anesthesia bridge to the hospital, as we have shown to be feasible(2).
Second, it is not fair to use the experience of these two evident highly for ODE motivated psychiatric patients and their families as a reference for comparable euthanasia patients who are unaware of the option of post mortal organdonation.
But third, of perimount importance, we criticize the opinion that the amount of burden for ODE patients may reach a point to be neglegible. In our opinion this burden should not be minimized, but excluded. The suggestions of Maes et al are motivated by utilistic ethical considerations and the existence of waitinglists for transplantation. The act of organdonation h...
Response from Tushar Vidhale, MD (Dated: July 8th, 2022)
Respected Editor and Dr. Pulst,
Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.
Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder respon...
Show MoreDear Editor:
Show MoreWe have read with interest this case, but we do not agree with the authors about considering this case as a visceral leishmaniasis (VL). This is a typical case of localized leishmanial Lymphadenopathy (LLL), as we and others described in several series of cases (1,2). This not-well known form of presentation of leishmaniasis is more common in Middle-East region, caused by dermatotropic strains like L. tropica or L. major, but isolated cases are described in Mediterranean region caused by L. infantum, as probably this case.
In last decade, we suffered in Southern urban cities of Madrid, mainly Fuenlabrada, an important outbreak of leishmaniasis. More than 1000 cases of leishmaniasis were reported, and we could describe several cases of LLL (2).
LLL is a form of presentation of leishmaniasis in patients without cellular immunosuppression, which presented with lymphadenopathy as the only form of presentation, and without systemic manifestations (no fever, no splenomegaly, no kytopenias, and normal acute phase reactants). Some LLL patients can refer lesions of cutaneous leishmaniasis (CL) near the adenopathy that had been previously spontaneously resolved or not, showing adenopathies as a local inflammatory rather than a systemic disease. Median duration of the adenopathy was 3 months in our patients. None of these patients, some of them without treatment, progressed to VL.
We think it is important to distinguish LLL from VL because of crit...
Jiang presents a very interesting and unique case of bilateral corneal decompensation in a patient with COVID pneumonitis. We would like to offer a similar case to support their hypothesis of viral endotheliitis. These cases demonstrate an ocular manifestation of COVID-19 infection which was previously unknown. This manifestation is important to be aware of as the subsequent visual impairment may be profound, though likely amenable to treatment.
Jiang pointed out the unclear onset for their case and possible delayed presentation from 34 days of ventilation. While we cannot assume the onset time of Jiang’s patient, our patient provides an interesting comparison. Our case describes a male patient who developed significant and painless overnight vision loss. He had gone to bed with only cough as a symptom of COVID infection and awoke to find himself only able to perceive light and gross motion. This patient presented to our local accident and emergency department with this sudden and profound bilateral loss of vision. He required admission due to his inability to self-care.
On examination the patient was found to have significant bilateral corneal oedema. Both eyes were white with no evidence of local infection, inflammation, or ocular surface trauma. There was no epithelial uptake with fluorescein in either eye. Intraocular pressure was within normal limits and symmetrical. No corneal dystrophy could be seen with biomicroscopy. The patient was started on topi...
Show MoreDear Sir/Madam.
Thanks for your interest in our case report and the literature review on CeAD and spinal manipulation, which is the most important element of patient care.
All clinicians would like to have a positive outcome for their patients using evidence-based practice.
Unfortunately, the patient in this case had a near fatal outcome by a chiropractor practising in a major metropolitan region of China. The chiropractor is a graduate of a traditional Chinese medical university. The patient could only recall heavy massage and possibly using an equipment (activator? we did not put in the paper because of the uncertainty).
The side effect with this mode of chiropractor treatment is extremely rare as what we have reviewed. This mode of treatment can certainly be the risk factors for the outcome (we ruled out most of the other risk factors presented in our case). We are sharing this case purely for education purpose without the intention of criticising any individual and the chiropractor profession. We did not want to see any more similar cases with an almost fatal outcome. We do appreciate that the whole profession of chiropractors constantly reviews their practice to ensure the delivery of evidence-based practice for treatment effectiveness of various aches and pain (shoulder girdle and neck pain in our case), which all health professionals should practice routinely.
Hope the response helps to clarify the queries.
kind regards
...
Show MoreSindgikar et al. report a severe paradoxical reaction in a 15-year-old HIV-uninfected patient with stage III tuberculous meningitis, during her fifth month of treatment. After improving with re-initiation of corticosteroids, the paradoxical reaction worsened after the prednisolone was weaned over 8 weeks. The patient continued 4 months of corticosteroids in addition to 13 months anti-TB treatment (ATT) with significant morbidity at one year follow up, including permanent disability.
Whilst corticosteroids are the mainstay of treatment for paradoxical reactions, their effectiveness for this difficult-to-treat complication has not been assessed in randomised controlled trials (RCT)(1). TNF-alpha is a key cytokine implicated in the exaggerated inflammatory response underlying paradoxical reactions (2,3). We have used infliximab, a monoclonal antibody targeting TNF-alpha, in the management of severe paradoxical reactions in paediatric central nervous system TB with positive outcomes (4,5). Anti-TNFα monoclonal antibodies, including infliximab, have also been used with encouraging results in adults for this indication (6,7). Thalidomide, another anti-TNF-alpha therapy was evaluated in an RCT of children with stage II and III tuberculous meningitis (8), however, this trial was ceased early due to increased deaths and adverse outcomes with a thalidomide dose of 24 mg/kg/day. A subsequent case series of 38 children treated with low-dose thalidomide (3-5 mg/kg) with life-th...
Show MoreDear Editor,
We read, with interest, “Obstetric rectal laceration in the absence of an anal sphincter injury” by Awomolo et al in your journal [1]. We commend the authors on reviewing this rare injury.
We appreciate your detailed case report and were pleased to read that your patient recovered well from her injury. We agree that these rare injuries require careful repair with experience, good surgical technique and detailed knowledge of perineal anatomy. Your extensive literature review found other similar cases, many of which we included in our most comprehensive case series [2], but we were surprised to see that our case series was not included in your paper. Although rectal buttonhole tears are rare they are now defined in many National guidelines in the world [3]. What our paper also adds is a standardised approach for repair of isolated rectal tears and follow up, with a video demonstration on a porcine specimen. In addition, we have highlighted that rectal button hole tears can occur concomitantly with a third or 4th degree tear when there is intact bridge of anorectal mucosa between the two injuries.
We appreciated the insufficiencies in training regarding classification, diagnosis and repair of obstetric anal sphincter injuries (OASIS) over 20 years ago and began the first hands-on course in 2000 (www.perineum.net). We have also introduced the Prevention and Repair Of perineal Trauma Episiotomy through Co...
Show MoreWe read with interest the case report by Yap et al regarding “A near-fatal consequence of chiropractor massage: massive stroke from carotid arterial dissection and vertebral arterial oedema,”(1) which describes a 35-year-old man with a massive stroke purportedly caused by massage. Cerebrovascular disease is an invested topic for manual therapists, considering such providers are responsible for recognizing emergent signs/symptoms of a cervical artery dissection (CeAD) and referring accordingly,(2) however, we are concerned about appropriate and accurate reporting of details of the case including several inconsistencies and evident biases.
We believe this case report likely misclassifies the treating provider as a chiropractor. The report does not specify the credentials of the person providing massage during the business trip. As pointed out by the authors, there is limited regulation and licensing of chiropractic in China.(3) Furthermore, spinal manipulation is by far the most common treatment intervention provided by chiropractors(4) but the authors did not mention its use in the case presentation.
We request the authors clarify the credentials of the massage provider, and elaborate on treatment interventions, specifically if cervical spinal manipulation was performed. Previous case reports have misrepresented the treating provider as a chiropractor when describing potential adverse events.(5) This practice is spurious and adds to over-reporting of adverse...
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