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.  However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder respon...
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.  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.  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.  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.  The estimated prevalence of FRDA is 1/1,00,000 based on carrier frequency in the Indian population.  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.  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.  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”.  As more and more literature is published, FRDA is being studied and reported as an gene silencing disorder with epigenetic basis. 
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.
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
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...
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.)
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.
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.
Hope the response helps to clarify the queries.
Dr Daniel Xu
MBBS, PhD, FRACGP
Academic Coordinators, General Practice Research & International Health
Curtin Medical School
The First Affiliated Hospital, Sun Yat-Sen University
Senior Research Fellow
CCRE, School of Public Health
Faculty of Health Sciences
Location Building 408, Level 3, Room 3516
Postal Address |GPO Box U1987, Perth, Western Australia, 6845 | AUSTRALIA
Tel | +61 (0)8 9266 1740
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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...
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 . 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 , 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 . 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 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.
Joanna C. Roper MRCOG
Ranee Thakar MD FRCOG
Abdul H. Sultan MD FRCOG
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 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.
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.
We read with great interest the article by Vidhale and colleagues.1 They provide a detailed description of a man presenting with a relatively rapidly progressing neurodegenerative disease including his neuroimaging findings.
After testing for a few DNA repeat expansion diseases, the authors arrived at the conclusion that their patient’s diagnosis was Friedreich ataxia (FRDA). FRDA is a recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene. Their patient had 5 and 37 GAA repeats. The lower limit for full penetrance alleles is > 66 GAA repeats.2 Thus, it is not apparent how their patient meets diagnostic criteria for FRDA.
The 37 GAA repeat allele falls at the lower end of premutation alleles (range 34-65), so named as these alleles do not cause disease, but can rarely expand to the disease range during meiosis. In rare cases, somatic expansion of pre-mutations in cell populations has been postulated to cause disease, but this occurs only in the setting of the 2nd allele in the clear pathogenic range of expansion.
The authors alternatively postulate that the patient could represent a compound heterozygous state based on his clinical presentation. Comparison with cases of very late-onset FRDA (vLOFA), however, clearly shows that the patient’s course is too rapid and severe for vLOFA. Even if the patient were to carry a pathogenic point mutation in one of the allel...
The authors alternatively postulate that the patient could represent a compound heterozygous state based on his clinical presentation. Comparison with cases of very late-onset FRDA (vLOFA), however, clearly shows that the patient’s course is too rapid and severe for vLOFA. Even if the patient were to carry a pathogenic point mutation in one of the alleles, the second allele would still not be pathogenic at 37 GAA repeats.
In summary, the case report points to the fact that interpretation of genetic tests needs subspecialty expertise provided by medical geneticists, genetic counsellors or neurogeneticists. The neurologist can play an important role in classifying the neurologic phenotype and guide further evaluations. I sincerely doubt that the official report of the genetic testing laboratory suggested a diagnosis of FRDA. Errors of overinterpreting genetic test results and, even more so, erroneous interpretation can be harmful to patients and their relatives.
1. Vidhale TA, Gupta HR, Pj R, Gandhi C. Very late-onset Friedreich's ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type. BMJ Case Rep. 2021 Jul 23;14(7):e242073. doi: 10.1136/bcr-2021-242073.
2. Bidichandani SI, MBBS, PhD and Martin B Delatycki, MBBS, FRACP, PhD.Friedreich ataxia. https://www.ncbi.nlm.nih.gov/books/NBK1281/2017 (accessed August 11 2021)
Stefan-M. Pulst, MD Dr med
University of Utah
A taser is a weapon used by police in order to provide a safe means of subduing an uncooperative person via an “electric shock”. This handheld device features two small barbed darts designed to puncture the skin. These darts are connected via copper wires to a main unit which delivers an electric current to the individual causing neuromuscular incapacitation by disrupting the voluntary control of muscles(1). A number of studies have raised concern over the health risks of tasers, including ventricular arrhythmias and cardiac arrest(2). Something I have come across during my training was a case of complete heart block provoked by a taser discharge. This phenomenon is not frequently described in the literature.
The patient in question had cardiac arrest immediately after receiving a discharge from a taser during an altercation with police. Thankfully, he was given bystander CPR and had return of spontaneous circulation after 3 minutes. On presentation to the Emergency Department the patient was found to be in complete heart block. He was admitted acutely to the coronary care unit for monitoring and had a permanent pacemaker inserted three days later.
The taser is considered a non-lethal weapon but can it truly be considered such?
Since it is not thought of as a firearm, taser use is not regulated by the Bureau of Alcohol, Tobacco, Firearms and Explosives. The main objective of this article is not to comment on the propriety of taser...
Since it is not thought of as a firearm, taser use is not regulated by the Bureau of Alcohol, Tobacco, Firearms and Explosives. The main objective of this article is not to comment on the propriety of tasers, since it is the law enforcement authorities who must make a judgement call on that. However, I do believe that authorities should be judicious in its application. It is my opinion that a taser should be given equal consideration to a firearm since the consequences of discharging a taser can indeed be lethal.
1. Ideker RE, Dosdall DJ. Can the direct cardiac effects of the electric pulses generated by the TASER X26 cause immediate or delayed sudden cardiac arrest in normal adults?. The American journal of forensic medicine and pathology. 2007 Sep 1;28(3):195-201.
2. Zipes DP. Sudden cardiac arrest and death following application of shocks from a TASER electronic control device. Circulation. 2012 May 22;125(20):2417-22.
Active TB globally affects over 10 million people each year and accounts for approximately 1.6 million deaths. Since publishing this case report we since have learned that IGRA blood tests are not entirely useful in diagnosing active TB, as IGRA will also pick up cases of latent TB.
Presently, the most useful microbiological method of diagnosis is now widely recognised as the Gene Xpert or Gene Xpert MTB/RIF Ultra, a rapid molecular test for Mycobacterium tuberculosis and rifampicin resistance which can be performed on sputum, pleural fluid or CSF. Access to this technology has been widely scaled up in recent years as part of the WHO End TB Strategy and most countries are switching from traditional AFB smears to rapid molecular testing due to reduced costs and demand on laboratory facilities. However, the COVID-19 pandemic has also redirected human, diagnostic and financial resources elsewhere and modelling predicts a regression in TB control and increase in mortality from 13% in 2020 to 20% in 2025.
Thank you very much for your letter on our published case report of a pregnant woman that was diagnosed with a left parietal glioma in the 28th gestational week after a first generalised seizure, and for your opinion and thorough review of the literature.
In our patient we performed a two-stage approach with first a tumour resection under general anaesthesia and preservation of the pregnancy and after caesarean section performed in the 37th gestational week an awake craniotomy for resection of residual tumour under neuropsychological monitoring and mapping.
We decided to do a two-stage approach after a round table where obstetricians, neurosurgeons, anesthetists, neonatologists, and midwives were involved and after several long conversations with the patient and her husband. For the patient clearly the health of her unborn child was the most important aspect of her treatment and therefore she wanted to prolong the pregnancy until term. The tumor of our patient was located with a broad base to the surface and seemed to have a plane to the underlying white matter. There was no, in this location possible eloquent, unaffected cortex overlying the tumor. Moreover, our patient was already in the 28th gestational week of her pregnancy, the uterine fundus was high and the abdomen extended. The use of cortical or subcortical electric stimulation does increase the seizure risk1-4. Because of all these reasons we decided aga...
We decided to do a two-stage approach after a round table where obstetricians, neurosurgeons, anesthetists, neonatologists, and midwives were involved and after several long conversations with the patient and her husband. For the patient clearly the health of her unborn child was the most important aspect of her treatment and therefore she wanted to prolong the pregnancy until term. The tumor of our patient was located with a broad base to the surface and seemed to have a plane to the underlying white matter. There was no, in this location possible eloquent, unaffected cortex overlying the tumor. Moreover, our patient was already in the 28th gestational week of her pregnancy, the uterine fundus was high and the abdomen extended. The use of cortical or subcortical electric stimulation does increase the seizure risk1-4. Because of all these reasons we decided against an awake craniotomy and an operation under general anesthesia was performed. During the first procedure we did not use electrophysiological monitoring or functional mapping at all to keep the seizure risk as low as possible.
We acknowledge that there are reports in the literature emerging that awake craniotomy during pregnancy seem to be a safe and feasible option and the authors of this letter provide a well-managed example from their own experience5. However, their patient was having a glioma with clear high-grade features present, leaving less time for multi staged procedures as these are aggressive tumors with limited prognosis. The tumor of our patient did radiologically not have high grade features, although preoperative imaging was obtained without administration of contrast. Histology of the tumor did show diffuse IDH-mutant astrocytoma classified between WHO grade II and III. The tumor exhibited methylation of the O-6 methylguanine DNA methyltransferase (MGMT) promotor and no complete deletion of cyclin-dependent kinase inhibitor 2a/b (CDKN2a/b) that are both positive prognostic and IDH mutation is a positive predictive marker. Morphologically it did show some anaplastic features and that is why it was finally treated like an anaplastic tumor.
5-aminolevulenic acid (5-ALA) in glioma surgery permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon to reach a complete resection of the contrast-enhancing tumor. Some studies show a potential risk for the fetus if 5-ALA has been given together with irradiation in the first trimester6. To this date, there is no evidence about a possible teratogenic effect of 5-ALA in the third trimester7-9.
In our clinic we do not use the drug Gliolan® but a pharmaceutic product containing 5-ALA that is completely manufactured by our hospital pharmacy. Before application of this drug in our pregnant patient we had extensive consultation with our clinical pharmacologists and pharmacists. This counseling did not identify a risk to the pregnancy of our patient who was in the third trimester and therefore application was officially allowed. Before application of this medication we had a shared decision making conversation with the patient, where we informed her openly about studies showing possible risks for the fetus in the first trimester6 but that there was no evidence for risk to her pregnancy in the current stage. She then agreed to the use of 5-ALA for her surgery.
In the retrospect, we agree that administration of 5-ALA may not have been necessary since we considered a possible second operation already initially.
The authors of the e-letter took the statement that propofol would not be appropriate from two cases described from Sethuraman et al. where after very long procedures (11 and 10 hours respectively) the use propofol caused maternal mild metabolic acidosis10.
As our procedure did not last that long, the use of propofol during pregnancy in this case was reasonable as also confirmed by Wang et al. 11
Furthermore, during surgery we regularly performed ABGs in order to monitor the pH and avoid acidosis.
It will remain challenging to define standards of care for glioma patients in pregnancy. However, we agree with the authors of this letter that the single-stage strategy with awake craniotomy is a considerable alternative to our proposed strategy and that multidisciplinary discussion and careful perioperative planning are of upmost importance for these patients.
1. Jasper H. Electrocorticography. In. Boston: Little Brown1954:p. 692 - 738.
2. Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol. 2004;115(4):982-989.
3. Karakis I, Leeman-Markowski BA, Leveroni CL, et al. Intra-stimulation discharges: an overlooked cortical electrographic entity triggered by direct electrical stimulation. Clin Neurophysiol. 2015;126(5):882-888.
4. PINSKY C, BURNS BD. Production of epileptiform afterdischarges in cat's cerebral cortex. J Neurophysiol. 1962;25:359-379.
5. Kamata K, Fukushima R, Nomura M, Ozaki M. A case of left frontal high-grade glioma diagnosed during pregnancy. JA Clin Rep. 2017;3(1):18.
6. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401.
7. Hadjipanayis CG, Widhalm G, Stummer W. What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas? Neurosurgery. 2015;77(5):663-673.
8. Yang JZ, Van Vugt DA, Melchior MF, Hahn PM, Reid RL. Photodynamic ablation of early pregnancy in the rat with 5-aminolevulinic acid: a potential new therapy for tubal ectopic pregnancy in the human. Fertil Steril. 1994;62(5):1060-1065.
9. Olzowy B, Hundt CS, Stocker S, Bise K, Reulen HJ, Stummer W. Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid. J Neurosurg. 2002;97(4):970-976.
10. Sethuraman M, Neema PK, Rathod RC. Prolonged propofol infusion in pregnant neurosurgical patients. J Neurosurg Anesthesiol. 2007;19:67-8.
11. Wang, Lars Peter MD (Cph), FANZCA*; Paech, Michael James MBBS, DRCOG, FRCA, FANZCA, FFPMANZCA, FRANZCOG (Hon), DM† Neuroanesthesia for the Pregnant Woman, Anesthesia & Analgesia: July 2008 - Volume 107 - Issue 1 - p 193-200