The history of celiac disease (CD) is very long. The cultivation of grains, developed in the Neolithic period after the last ice age, particularly in the “Fertile Crescent” of the Near East including the Tigris, the Euphrates and the Upper Nile. With the development of cooking, agriculture came into its own and wheat became a main support of the vast growth in population in succe...
The history of celiac disease (CD) is very long. The cultivation of grains, developed in the Neolithic period after the last ice age, particularly in the “Fertile Crescent” of the Near East including the Tigris, the Euphrates and the Upper Nile. With the development of cooking, agriculture came into its own and wheat became a main support of the vast growth in population in successive millennia. Thus arose the possibility of development of syndromes, including CD, reflecting intolerance of wheat. In this context is interesting that the generally accepted earliest description of CD, is attributed to “Aretaeus the Cappadocian” (I-II century A.D.), and Cappadocia is a region in the eastern part of Turkey near to the ‘Fertile Crescent’. Further descriptions, which may have been of CD followed, by the Dutch physician Vincent Ketelaer, William Hillary of Yorkshire, England, and others.
The origin of the modern history of CD is ascribed to Samuel Gee in a lecture in 1887 followed by his written account in the Saint Bartholomew’s Hospital Reports in 1888. He termed the condition ‘the Celiac Affection’ after the translation by Francis Adams, in 1856, of the description by Aretaeus. In a notably description, Gee refers to the appearance of the stools, the onset of the condition, the muscular weakness, the abdominal distension and the chronic course of the disease.
Subsequent to the suggestion by Samuel Gee there were various attempts at dietary management which bore some relation to the eventual recognition of cereal grains as being responsible.
Herter in 1908 suggested that fats were better tolerated than carbohydrates, Still in 1918 drew attention to the poor tolerance of bread, Howland in 1921 recognised intolerance to carbohydrates and Haas in 1924 suggested a banana diet which, even though it contains carbohydrates, excludes the damaging cereals.
The great breakthrough was by Wim Dicke of The Juliana Children's Hospital in The Hague. In his doctoral thesis of 1950 to the University of Utrecht he showed that exclusion of wheat, rye and oats from the diet led to dramatic improvement in the general condition of the child and marked reduction in the fatty diarrhoea. Wheat starch did not have the same damaging effect. There are descriptions of how Dicke came across this association. During wartime the gruel supplied to children in hospital might, at different times, have contained wheat or other plant products, depending on what was available, which would have provided the clue. Confirmation came with Dicke's laboratory colleagues Weijers and Van de Kamer. With the chemical measurement of stool fat, it became possible to diagnose less severe cases showing that excluding wheat, rye, barley and oats led to reduction in the fat content of the stool and improvement in the clinical condition of the patient. French, showed that similar changes occurred in adults with otherwise unexplained steatorrhoea. Faecal fat is rarely estimated now because of the requirements for accurate diet and prolonged collection of stools, and the associated expense.
Since wheat starch did not produce the effect, attention was drawn to the protein components of the relevant cereals, referred to as gluten since the work of Jacopo Bartolomeo Beccari in Bologna in 1745. At present the etiology and pathogenesis of these disorders is uncertain.
In the recent years, same relevant studies concerning CD, are performed by Professor Giovanni Gasbarrini, Director to the Institute of Internal Medicine, Catholic University of Rome, and my chief. The research Group to Professor Gasbarrini, have been described pathophysiology mechanisms and clinical manifestations of CD and published more than 140 articles, on this topic, available in pub-med. In the May issue, Dr Grossman highlighted the relationship between CD and neurological disorders (1). Our group reported, a case of brain perfusion abnormalities, assessed by single photon emission computed tomography (SPECT) examination, in a 33-year-old CD patient with schizophrenia; regression of both cerebral hypoperfusion and schizophrenic symptoms was observed after 6 months of a gluten free diet (GFD) (2). On the basis of this case we performed a SPECT study evaluating regional cerebral perfusion in untreated CD adult patients (age: 37±9 years), comparing them with CD patients on GFD, and with healthy controls (3). The study showed the presence of regional cerebral hypoperfusion in 73% of the untreated CD patients, compared with only 7% of CD patients on GFD and none of the controls. An overall multivariate test showed a significant difference in cerebral perfusion among the three groups of subjects (p=0.01).
Considering each single region, a significant lower cerebral perfusion was found in untreated celiac patients compared to controls in seven of the 26 cerebral regions evaluated. Perfusion defects were predominant in the superior and anterior areas of the frontal cortex with the involvement of the adjacent anterior cingulated cortex. We have been reported similar cerebral blood flow changes, in patients suffering from different neurological and psychiatric disorders (4,5). In according to the author, I suggest to early investigate the presence of CD in patients with neurological abnormalities.
To conclude I want to give my gratitude to Professor Giovanni Gasbarrini, for his scientific commitment and to be a guide for us young researchers.
References:
1. Grossman G. Neurological complications of coeliac disease: what is the evidence? Pract Neurol. 2008; 8:77-89.
2. De Santis A, Addolorato G, Romito A, et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997; 242: 421-23.
3. Addolorato G, Di Giuda D, De Rossi G, et al. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004; 116: 312-17.
4. Gabrielli M, Cremonini F, Fiore G, et al. Association between migraine and celiac disease. Am J Gastroenterol 2003; 98: 625-29
5. Addolorato G, Leggio L, D'Angelo C, et al. Affective and psychiatric disorders in celiac disease. Dig Dis. 2008; 26: 140-48.
Dear Editor,
In conversations and correspondences with colleagues, we are often still asked if our pre-pandemic call to “stop testing for VGKC antibodies” (1, 2), as echoed by others (3-5), has stood the test of time. Recent articles have raised public health and patient safety concerns, particularly around neurology temporally associated with COVID infections, prompting us to continue to strongly advocate for this stance and avoid misinterpreting positive neurologic antibody results (6-15).
Indeed, the misinterpretation of double negative VGKC-antibodies (dnVGKC; samples with VGKC-complex immunoprecipitation but no LGI1 or CASPR2 reactivity) remains a leading cause of AE misdiagnosis, a problem which now appears to overwhelm the rates of accurate AE diagnosis (16, 17). Patients given this misdiagnosis often experience adverse effects from immunotherapies, and suffer from a misdirected clinical journey (14) given most harbour an alternative, non-immunological underlying diagnosis.
An important explanation has been independently demonstrated in large-cohort studies: dnVGKC antibodies have a high false positive rate at approximately five percent in healthy and other neurological disorder control populations (1, 4). This rate is likely a conservative estimate, as many labs utilize a more liberal cut-off, further exacerbating the irrelevance of dnVGKC antibodies (18). If interpreted as a surrogate of disease incidence, one could conservatively diagnose AE in...
Dear Editor,
In conversations and correspondences with colleagues, we are often still asked if our pre-pandemic call to “stop testing for VGKC antibodies” (1, 2), as echoed by others (3-5), has stood the test of time. Recent articles have raised public health and patient safety concerns, particularly around neurology temporally associated with COVID infections, prompting us to continue to strongly advocate for this stance and avoid misinterpreting positive neurologic antibody results (6-15).
Indeed, the misinterpretation of double negative VGKC-antibodies (dnVGKC; samples with VGKC-complex immunoprecipitation but no LGI1 or CASPR2 reactivity) remains a leading cause of AE misdiagnosis, a problem which now appears to overwhelm the rates of accurate AE diagnosis (16, 17). Patients given this misdiagnosis often experience adverse effects from immunotherapies, and suffer from a misdirected clinical journey (14) given most harbour an alternative, non-immunological underlying diagnosis.
An important explanation has been independently demonstrated in large-cohort studies: dnVGKC antibodies have a high false positive rate at approximately five percent in healthy and other neurological disorder control populations (1, 4). This rate is likely a conservative estimate, as many labs utilize a more liberal cut-off, further exacerbating the irrelevance of dnVGKC antibodies (18). If interpreted as a surrogate of disease incidence, one could conservatively diagnose AE in up to 5 of every 100 people, without respect to their clinical picture. This massive overinflation constitutes a dangerous disservice to many patients, with consequent overexposure to toxic immunotherapies. At a ~20% adverse effect rate, this creates a huge potential for iatrogenic harm and can dangerously delay more appropriate treatments (16). Furthermore, the intracellular, and even non-mammalian, targets of these antibodies add weight to the argument of their clinical irrelevance (2).
Two large studies analysing neuronal autoantibody positivity rates during the COVID-19 pandemic did not find any attributable increase of known or novel encephalitis mediated by autoantibodies (19, 20) consistent with broader testing (21). An autoimmune referral center’s experience (22) and several case reviews (8, 10, 13, 15) further describe only classic clinical presentations for bona fide antibody-mediated AE coinciding with COVID-19. In the context of COVID-19 seroprevalance reaching as high as 99% in the United States (23), the reported infectious associations are very likely coincidental (24).
Thus, clinical practice should adhere to well-described standards of evaluation and treatment in AE (25-27). Indeed, autoimmune neurological diagnosis remains foremost clinical, utilising autoantibodies as an adjunct. The same is true for genetic neurological diagnosis, where polymorphisms are not considered pathogenic if observed in conjunction with incongruent clinical phenotypes. We continue to advocate that ‘clinically irrelevant’ or ‘false positive’ antibody results are the correct interpretation when they do not align with the clinical diagnosis. In our referral clinic, we commonly see an incorrect clinical diagnosis of AE arising from misinterpreting the temporal progression, the presence of vague or incongruent encephalopathy symptoms not limited to COVID-19 (28), sometimes in combination with overreliance on a single, low titer antibody test. These errors appear perpetuated within the COVID-19 literature not just with dnVGKC, but also for other common self-antigens including GAD65 and TPO (6-8, 10-15, 29-32).
We agree with the need to openly report clinical experience, but urge caution in overinterpreting significance in the above scenarios, as it is paramount to reduce the risks of patient misinformation and mistreatment (33). In the authors’ experiences, this can cause misdirection, danger, and frustration to patients misdiagnosed with AE. More broadly, discussing the potential for false positive neuronal antibody results in case reports and case series is important to maintain the highest standards of patient care in this rapidly evolving field.
References
1. Michael S, Waters P, Irani SR. Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Pract Neurol. 2020;20(5):377-84.
2. Lang B, Makuch M, Moloney T, Dettmann I, Mindorf S, Probst C, et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry. 2017;88(4):353-61.
3. Graus F, Gorman MP. Voltage-gated potassium channel antibodies: Game over. Neurology. 2016;86(18):1657-8.
4. van Sonderen A, Schreurs MW, de Bruijn MA, Boukhrissi S, Nagtzaam MM, Hulsenboom ES, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-9.
5. López-Chiriboga AS, Klein C, Zekeridou A, McKeon A, Dubey D, Flanagan EP, et al. LGI1 and CASPR2 neurological autoimmunity in children. Ann Neurol. 2018;84(3):473-80.
6. Dulanto J, Chu D, Saffari P, Abdelshahid M, Xu P, Hauser J, et al. Three Patients With Chorea and Positive Voltage-Gated Potassium Channel Antibody: Is This the Link Between Hyperkinetic von Economo Disease and COVID-19? Cureus. 2023;15(3):e35666.
7. Hasan SF, Lutfi L, Shukur M, Alemam S, Esmaeel H, Nawaz F. Psychiatric Manifestations in an Adolescent With Voltage-Gated Potassium Channels (VGKC) Autoimmune Encephalitis: A Case Report. Cureus. 2023;15(6):e39960.
8. Islam MA, Cavestro C, Alam SS, Kundu S, Kamal MA, Reza F. Encephalitis in Patients with COVID-19: A Systematic Evidence-Based Analysis. Cells. 2022;11(16):2575.
9. Mansour K, Chadli Z, Ghachem I, Fredj NB, Romdhane HB, Fadhel NB, et al. Seronegative acute encephalitis following COVID-19 vaccines: a case series of an overlooked diagnosis with literature review. European Journal of Clinical Pharmacology. 2023;79(7):975-87.
10. Nabizadeh F, Balabandian M, Sodeifian F, Rezaei N, Rostami MR, Naser Moghadasi A. Autoimmune encephalitis associated with COVID-19: A systematic review. Multiple Sclerosis and Related Disorders. 2022;62:103795.
11. Novoselova V, Kumar V, Singh NN, Lacasse A. A case of anti-VGKC antibody encephalitis and prolonged encephalopathy despite spontaneous resolution of imaging abnormalities. Journal of Community Hospital Internal Medicine Perspectives. 2020;10(6):591-3.
12. Saffari P, Aliakbar R, Haritounian A, Mughnetsyan R, Do C, Jacobs J, et al. A Sharp Rise in Autoimmune Encephalitis in the COVID-19 Era: A Case Series. Cureus. 2023;15(2):e34658.
13. Stoian A, Stoian M, Bajko Z, Maier S, Andone S, Cioflinc RA, et al. Autoimmune Encephalitis in COVID-19 Infection: Our Experience and Systematic Review of the Literature. Biomedicines. 2022;10(4).
14. Vu P, Nia S, Saffari P, Peng D, Liu A. Increased cases of VGKC-complex observed during current COVID-19 pandemic - In response to an article in 2018 "Distinction between anti-VGKC-complex seropositive patients with and without anti-LGI1/CASPR2 antibodies" by Yeo et al. J Neurol Sci. 2024;456:122842.
15. Xue H, Zeng L, He H, Xu D, Ren K. Autoimmune encephalitis in COVID-19 patients: a systematic review of case reports and case series. Frontiers in Neurology. 2023;14.
16. Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, Blackburn KM, Turaga S, Binks S, et al. Autoimmune Encephalitis Misdiagnosis in Adults. JAMA Neurology. 2023;80(1):30-9.
17. Van Steenhoven RW, de Vries JM, Bruijstens AL, Paunovic M, Nagtzaam MM, Franken SC, et al. Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria. Neurol Neuroimmunol Neuroinflamm. 2023;10(6).
18. ARUP Laboratories Test Directory: Autoimmune Neurologic Disease Panel with Reflex Serum. Accessed September 18, 2023 [Available from: https://ltd.aruplab.com/Tests/Pub/3006051.
19. Ariño H, Ruiz García R, Rioseras B, Naranjo L, Martinez-Hernandez E, Saiz A, et al. Frequency and Referral Patterns of Neural Antibody Studies During the COVID-19 Pandemic: Experience From an Autoimmune Neurology Center. Neurol Neuroimmunol Neuroinflamm. 2023;10(4).
20. Handel AE, Palace J, Bateman E, Waters P, Irani SR. Changes in the Rate of Leucine-Rich Glioma-Inactivated 1 Seropositivity During the COVID-19 Lockdown. JAMA Neurology. 2023;80(4):419-20.
21. Van Regemorter E, Zorzi G, Scohy A, Gruson D, Morelle J. Impact of the COVID-19 pandemic on temporal trends of biological indicators of autoimmunity. Journal of Translational Autoimmunity. 2023;7:100222.
22. Valencia Sanchez C, Theel E, Binnicker M, Toledano M, McKeon A. Autoimmune Encephalitis After SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes. Neurology. 2021;97(23):e2262-e8.
23. Prevention CfDCa. COVID-19 SeroHub 2023 [Available from: https://covid19serohub.nih.gov/.
24. Vasilevska V, Guest PC, Szardenings M, Benros ME, Steiner J. Possible temporal relationship between SARS-CoV-2 infection and anti-NMDA receptor encephalitis: a meta-analysis. Translational Psychiatry. 2024;14(1):139.
25. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
26. Uy CE, Binks S, Irani SR. Autoimmune encephalitis: clinical spectrum and management. Practical Neurology. 2021;21(5):412-23.
27. Budhram A, Irani SR, Flanagan EP. Looking Beyond Syndrome-Based Criteria for Autoimmune Encephalitis-The Need for Complementary Neural Antibody-Based Diagnostic Criteria. JAMA Neurol. 2024;81(3):227-8.
28. Benedict D. Michael, Ph.D., M.R.C.P. ,, Dean Walton, M.B.B.Ch., B.Sc. ,, Erica Westenberg, M.Sc. ,, David García-Azorín, M.D., Ph.D. ,, Bhagteshwar Singh, M.R.C.P. ,, Arina A. Tamborska, M.R.C.P. ,, et al. Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients. The Journal of Neuropsychiatry and Clinical Neurosciences. 2023;35(1):12-27.
29. Deniz Ç, Altunan B, Ünal A. Anti-GAD Encephalitis Following COVID-19 Vaccination: A Case Report. Noro Psikiyatr Ars. 2023;60(3):283-7.
30. Salari M, Zaker Harofteh B, Etemadifar M. Autoimmune meningoencephalitis associated with anti-glutamic acid decarboxylase antibody following COVID-19 infection: A case report. Clinical Case Reports. 2022;10(12):e6597.
31. Shahab MA, Zhao K, Pal S. COVID-19 Related Hashimoto’s and VGKC Encephalitis (P7-9.004). Neurology. 2022;98(18_supplement):3271.
32. Viscasillas Sancho M, Moreno Loscertales C, García Rubio S, Sagarra Mur D. Hashimoto encephalopathy after vaccination against SARS-CoV-2. Neurologia (Engl Ed). 2023;38(8):601-2.
33. Encephalitis: Rare Pre-COVID But… A Rise in Autoimmune Encephalitis [Available from: https://www.brainweek.org/encephalitis-rare-pre-covid/.
I enjoyed this article on this important area of non-traumatic non-aneurysmal convexity SAH. The authors seems to have not recognised the literature that points to convexity/Sulcal subarachnoid haemorrhage in the context of ipsilateral carotid artery stenosis, which in some case series make up a significant proprtion of the cases (10-50%, references below). Also I would be cautious about having dichotomoised age as a rule, but better as a guide. In the case of carotid artery stenosis this is seen in the under 60s sometimes.
Geraldes et al J Stroke Cereb Dis 23:e23-30, 2014.
Zhao et al J Int Med Res 2017 45:1870.
Renou et al 2012 Cerebrovasc Dis. 2012;34(2):147-52.
Forman et al; J Stroke Cerebrovasc Dis. 2019;28(12):104473.
I read the article by Alvar Paris et al. with great interest. The consumption of nitrous oxide (N2O) has recently surfaced as an exponentially growing form of recreational abuse, particularly among students, due to its euphoric effects and accessibility. The European Monitoring Centre for Drugs and Drug Addiction has expressed concern in a recent report about the recreational use of N2O in Europe. 1
The most common neurological complications associated with N2O consumption are toxic polyneuropathy and subacute combined degeneration of the spinal cord (N2O-SACD), which may occur concurrently— a critical aspect that should not be overlooked. Initial clinical descriptions of N2O-SACD were reported in 2015 and complicated episodic use mediated through canisters. 2 Recently, the market for N2O distribution has expanded with diverse consumption accessories. The introduction of larger cylinders facilitates the consumption of significant amounts of N2O, posing younger individuals at an elevated risk of early and severe Vitamin B12 deficiency along with systemic complications. Consequently, new complications associated with N2O intoxication have been described, and their wide-ranging effects are regularly emphasized in the literature.
Beyond psychiatric symptoms like hallucinations, cognitive impairments including Gayet-Wernicke's encephalopathy have been recently reported. 3 These deficiencies are mediated by Vitamin B1 levels, suggesting a risk of broader deficie...
I read the article by Alvar Paris et al. with great interest. The consumption of nitrous oxide (N2O) has recently surfaced as an exponentially growing form of recreational abuse, particularly among students, due to its euphoric effects and accessibility. The European Monitoring Centre for Drugs and Drug Addiction has expressed concern in a recent report about the recreational use of N2O in Europe. 1
The most common neurological complications associated with N2O consumption are toxic polyneuropathy and subacute combined degeneration of the spinal cord (N2O-SACD), which may occur concurrently— a critical aspect that should not be overlooked. Initial clinical descriptions of N2O-SACD were reported in 2015 and complicated episodic use mediated through canisters. 2 Recently, the market for N2O distribution has expanded with diverse consumption accessories. The introduction of larger cylinders facilitates the consumption of significant amounts of N2O, posing younger individuals at an elevated risk of early and severe Vitamin B12 deficiency along with systemic complications. Consequently, new complications associated with N2O intoxication have been described, and their wide-ranging effects are regularly emphasized in the literature.
Beyond psychiatric symptoms like hallucinations, cognitive impairments including Gayet-Wernicke's encephalopathy have been recently reported. 3 These deficiencies are mediated by Vitamin B1 levels, suggesting a risk of broader deficiencies beyond Vitamin B12. Physicians should be vigilant about potential cognitive and psycho-behavioral deficiencies. Neuropsychological assessments and proactive identification of cognitive sequelae are crucial.
To physical health risks, one must also consider the risks of co-addiction to psychoactive substances, as well as psychosocial risks like anxiety and depression that may complicate N2O consumption. The risk of road accidents should also be highlighted.
Radiologically, the described MRI findings appear to be related to a higher density of myelinated fibers in the fasciculus gracilis in the cervical area. This can explain the patients' sensory disorders like numbness and ataxia. However, muscle weakness and pyramidal signs often accompany these sensory disorders, pointing to a close association with pyramidal tract fibers. Frequent signal abnormalities in the lateral corticospinal tracts on axial MRI series have been noted. This emerging neuroradiological pattern aligns with recent descriptions of frequent motor disorders and warrants further analysis.
Physicians must be aware of the evolving spectrum of neurological complications associated with N2O intoxication, as well as their radiological characteristics. A surge in case incidence is anticipated due to its rapidly growing utilization.
References
1. https://www.emcdda.europa.eu/publications/rapid-communication/recreation...
2. Ernst LD et al. Longitudinally Extensive Myelopathy With Novel Radiographics Features. JAMA Neurology. 2015 Nov;72(11):1370-1
3. Amir Garakani et Al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Addict. 2016 Aug;25(5):358-69.
The authors of this article would like to apologise for omitting a reference to The Northwick Park Integrated Care Pathway (ICP) for Management of Hemiplegic Shoulder Pain. Further information about the pathway, its tools and ongoing development, may be found here (https://www.kcl.ac.uk/cicelysaunders/resources/management-of-hemiplegic-...) and in the following 2 citations:
D. Jackson, L. Turner-Stokes, A. Khatoon, H. Stern, L. Knight & A. O'Connell (2002). Development of an integrated care pathway for the management of hemiplegic shoulder pain, Disability and Rehabilitation, 24:7, 390-398,
Jackson D, Turner-Stokes L, Williams H, Das-Gupta R. Use of an integrated care pathway: a third-round audit of the management of shoulder pain in neurological conditions. J Rehabil Med. 2003 Nov;35(6):265-70.
I was interested to read the article by Andrew Larner in Practical Neurology suggesting that listening for orbital bruits is “useful for impressing students but is not very rewarding”.
I had not heard of Charles Warlow’s challenge before.
My mentor as a trainee, Bernard Gilligan, would routinely listen to carotids and orbits and often femoral arteries as well - we saw a lot of large vessel arterial disease in those days – and I got into the habit of auscultating at least carotids and orbits.
It paid off at least once: I enclose extracts from a letter I wrote in 2001.
Thank you for referring this most interesting 30 year old lady. She has had migraines from her early twenties. Initially they were quite occasional but severe when they occurred. They tended to be triggered by exams or stress.
She moved to Australia about 3 years ago and since then has had unusual episodes of bouts of migraine. In the first of these she had migraine every day for a week or so. Since then the attacks seem to be becoming more frequent and more prolonged so that the most recent one which finished about 2 weeks ago had lasted for 3 weeks or more.
Typically at the start of a bout she will have aura symptoms consisting of numbness of the left finger, arm and face and blurred vision in the left visual field. In the early days of a bout there may be no headache following this. However then a pattern establishes with headache occurring on a virtually...
I was interested to read the article by Andrew Larner in Practical Neurology suggesting that listening for orbital bruits is “useful for impressing students but is not very rewarding”.
I had not heard of Charles Warlow’s challenge before.
My mentor as a trainee, Bernard Gilligan, would routinely listen to carotids and orbits and often femoral arteries as well - we saw a lot of large vessel arterial disease in those days – and I got into the habit of auscultating at least carotids and orbits.
It paid off at least once: I enclose extracts from a letter I wrote in 2001.
Thank you for referring this most interesting 30 year old lady. She has had migraines from her early twenties. Initially they were quite occasional but severe when they occurred. They tended to be triggered by exams or stress.
She moved to Australia about 3 years ago and since then has had unusual episodes of bouts of migraine. In the first of these she had migraine every day for a week or so. Since then the attacks seem to be becoming more frequent and more prolonged so that the most recent one which finished about 2 weeks ago had lasted for 3 weeks or more.
Typically at the start of a bout she will have aura symptoms consisting of numbness of the left finger, arm and face and blurred vision in the left visual field. In the early days of a bout there may be no headache following this. However then a pattern establishes with headache occurring on a virtually daily basis. For example in the middle of a bout typically an attack will start with visual blurring in the left field. This has a shimmering quality and would stay there for 30 to 60 minutes. The headache then comes on while the vision is still abnormal. It would be right sided always involving forehead, temple and neck. She uses Panadol and Naramig and the headache usually settles within 4 hours. Sleeping helps. After that she can function but the headache will come back again in 12 to 24 hours. Towards the end of the bout the headaches become milder but the visual episodes may still occur for a few days until they also settle.
She has been taking Inderal during the bouts but it is not clear whether this is helping at all.
She has had no other illness. In the family her mother gets migraine every week or two but there is no aura.
Blood pressure was 120/70. There was a long loud right carotid bruit which extended into diastole. There was probably in addition a soft right orbital bruit. Fundi, cranial nerves and neurological examination were normal.
The history is certainly unusual. Migraine usually doesn’t occur in bouts like this. The finding of the prominent right carotid bruit made me concerned that she may have a right cerebral arterio-venous malformation and I thought because of the crescendo nature of her episodes we ought to get this clarified quickly. I have therefore arranged for her to have an MRI brain and MRA later this afternoon.
MRI and MRA did indeed demonstrate an AVM in the right occipital lobe and this was successfully excised. The patient still gets migraines and still comes to see me.
A couple of other patients with AVMs have had orbital bruits but this was recognised after they had been diagnosed already. They also had long carotid bruits and I think that hearing a carotid bruit extending into diastole might be a reasonable basis for spending 10 seconds on listening for an orbital bruit. However, I recognise that carotid auscultation is now also going out of favour.
In their review on vision loss in giant cell arteritis (GCA), the authors point out that anterior arteritic ischaemic optic neuropathy is the most common ophthalmic manifestation of the disease, followed by central retinal artery or cilioretinal artery occlusion and posterior ischaemic optic neuropathy. We do agree that these ocular findings must be quickly diagnosed to prevent devastating visual consequences. When diagnosed, however, not much can be done to restore the visual function. We rather believe that more emphasis should be given to other ophthalmic features that can occur as the initial manifestation of GCA and, when unrecognized, can result in an unfortunate late diagnosis. These include amaurosis fugax, uveitis, anterior or posterior scleritis and ocular pain. Awareness of these uncommon ocular conditions as the presenting signs of impending visual loss in GCA should prompt clinicians to consider this diagnosis in any elderly patient presenting with ophthalmic manifestations other than permanent visual loss, especially if other signs of GCA are detectable.
I read with great interest the excellent paper by Kumta and colleagues1 and the accompanying editorial2 concerning a patient with severe Guillain-Barré syndrome (GBS) requiring mechanical ventilation, who provided his experiences during the 31-day period of locked-in syndrome. I wish to open up some insights on the reported pain.
Physical therapy, in particular the passive stretching of calf and masseter muscles, provoked him intense pain, the patient’s description being very impressive: “It felt like they were trying to tear the muscles off the bone … I’ve never known pain like it” 1. Pain due to peripheral nerve damage is basically divided into two major types: dysesthetic pain and nerve trunk pain, the distinction between them being based upon clinical observation and experience3. Reported aching characteristics in the current patient (excruciating, deep, and provoked by nerve stretch) points to nerve trunk pain.
Pain is an integral manifestation of GBS. In a series of 55 consecutive GBS patients, Moulin and colleagues analysed pain features4, which could be summarised as follows: i/ 49 (89%) patients described pain during the course of their illness; ii/ in around half of them, it was described as excruciating; and iii/ pain preceded weakness by a mean of 5.3 days in 14, and both symptoms appeared simultaneously in seven. Furthermore, in “pure” motor GBS syndromes, usually classified as acute motor axonal neuropathy (AMAN), nerve trunk pain may occur in a h...
I read with great interest the excellent paper by Kumta and colleagues1 and the accompanying editorial2 concerning a patient with severe Guillain-Barré syndrome (GBS) requiring mechanical ventilation, who provided his experiences during the 31-day period of locked-in syndrome. I wish to open up some insights on the reported pain.
Physical therapy, in particular the passive stretching of calf and masseter muscles, provoked him intense pain, the patient’s description being very impressive: “It felt like they were trying to tear the muscles off the bone … I’ve never known pain like it” 1. Pain due to peripheral nerve damage is basically divided into two major types: dysesthetic pain and nerve trunk pain, the distinction between them being based upon clinical observation and experience3. Reported aching characteristics in the current patient (excruciating, deep, and provoked by nerve stretch) points to nerve trunk pain.
Pain is an integral manifestation of GBS. In a series of 55 consecutive GBS patients, Moulin and colleagues analysed pain features4, which could be summarised as follows: i/ 49 (89%) patients described pain during the course of their illness; ii/ in around half of them, it was described as excruciating; and iii/ pain preceded weakness by a mean of 5.3 days in 14, and both symptoms appeared simultaneously in seven. Furthermore, in “pure” motor GBS syndromes, usually classified as acute motor axonal neuropathy (AMAN), nerve trunk pain may occur in a high proportion of patients5, 6. In this regard, it is worth recalling that pain was an outstanding feature in the original AMAN description7: “many patients had neck and back stiffness and pain, one father said his son seemed as though he had a rod up his spine”. The corollary is that in any locked-in GBS, each healthcare assistant should assume the high likelihood of being confronted with a patient that may be suffering from nerve trunk pain, either spontaneous or provoked.
The mechanism of pain in early stages of GBS (≤ 10 days after onset) is controversial4, 5; I shall offer a brief explanation. Pathological changes in early GBS mainly consist of inflammatory oedema predominating in the region where motor and sensory roots join to form spinal nerves8-10. Such lesional predominance is correlated with less efficient blood-nerve barrier of proximal nerve trunks9. Spinal roots traverse the subarachnoid space surrounded by an elastic multicellular root sheath derived from the arachnoid and penetrate the subarachnoid angle; external to this angle, the newly formed spinal nerves possess epi-perineurium and endoneurium as in the peripheral nerve trunks (see figure 3 in reference 9). The absence of epi-perineurium in the spinal roots probably prevents their having an increase of endoneurial fluid pressure (EFP) and ischemic injury despite inflammatory changes. Perineurium is relatively inelastic and has only a limited ability to expand9. Small increases of EFP, caused by endoneurial inflammation, can be accommodated, but any increase beyond these limits, as presumably occurs in early GBS, will produce an increase in EFP leading to compromise of transperineurial microcirculation and endoneurial ischemia, which causes proximal nerve conduction failure and eventually nerve trunk pain. In other words, in early severe GBS widespread inflammation of spinal nerves might account for neuropathic pain, indistinguishable from that associated with multilevel spinal root compression. In AMAN extension of ventral root inflammatory oedema into ventral rami of spinal nerves could involve abutting dorsal rami, thus causing nerve trunk pain referred to their innervation territories, from neck to buttocks, eventually accompanied by neck and back stiffness (masterfully illustrated in figure 1 of reference 7).
Treatment of nerve trunk pain in GBS may be challenging, given that in addition to conventional non-steroidal anti-inflammatory drugs or simple analgesics, up to 74% of cases require opioids analgesics or even parental morphine9. The pathogenic role of inflammatory oedema in early GBS is the rationale for using short courses of intravenous corticosteroids; in fact, there have been at least 13 well-documented GBS patients with severe backache, unresponsive to analgesics, who exhibited rapid response to steroids9.
The touching story of the current patient teaches us how distressing may be painful sensation in a patient suffering from locked-in GBS. As timely indicated by the authors, this calls for several approaches to minimize the “living nightmare”1. Concerning nerve trunk pain such approach should comprise the following measures: i/ optimal analgesic regimens including the potential use of short courses of intravenous corticosteroids; ii/ if the patient is not completely sedated, nerve traction maneuvers should be avoided during physical therapy; and iii/ whenever possible, approach the patient asking about pain.
References
1. Kumta N, Carter A, Schuller P, et al. Locked-in Guillain-Barré syndrome: 'my living nightmare'. Pract Neurol. Epub ahead of print: 2021 Oct 29:practneurol-2021-003110. doi: 10.1136/practneurol-2021-003110.
2. Law D, Morgan M Listening to patients in intensive care. Epub ahead of print: Pract Neurol. 2021 Nov 29:practneurol-2021-003255. doi: 10.1136/practneurol-2021-003255.
3. Asbury AK, Fields HL. Pain due to peripheral nerve damage: an hypothesis. Neurology 1984; 34: 1587-90.
4. Moulin DE, Hagen N, Feasby TE, et al. Pain in Guillain-Barré syndrome. Neurology 1997; 48: 328-31.
5. Ruts L, Rico R, van Koningsveld R, et al. Pain accompanies pure motor Guillain-Barré syndrome. J Peripher Nerv Syst 2008; 13: 305-6.
6. Zhao F, Wang J, Zhang J, et al. Pain in acute motor axonal neuropathy. Muscle Nerve 2021; 64:739-43.
7. McKhann GM, Cornblath DR, Ho T, et al. Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China. Lancet 1991; 338: 593-7.
8. Haymaker WE, Kernohan JW. The Landry-Guillain-Barré syndrome; a clinicopathologic report of 50 fatal cases and a critique of the literature. Medicine (Baltimore) 1949; 28: 59-141.
9. Berciano J, Sedano MJ, Pelayo-Negro AL, et al. Proximal nerve lesions in early Guillain-Barré syndrome: implications for pathogenesis and disease classification. J Neurol 2017; 264: 221-36.
10. Berciano J. Axonal degeneration in Guillain-Barré syndrome: a reappraisal. J Neurol 2021; 268: 3728-43.
Your artclce mentions phenytoin as a treatment that has been tried in open label studies. When I began as a neurologist I'd not heard of its use but was put on to it by a senior colleague. I do use carbamazepine as first line but have found phenytoin far superior to other second line agents. I draw the interested reader to the excellent article by Hellelink and Schatman (J Pain Res. 2017; 10: 1663-6 doi: 10.2147/JPR.S141896) which puts a case for phenytoin being considered first line.
Dear Editor
The history of celiac disease (CD) is very long. The cultivation of grains, developed in the Neolithic period after the last ice age, particularly in the “Fertile Crescent” of the Near East including the Tigris, the Euphrates and the Upper Nile. With the development of cooking, agriculture came into its own and wheat became a main support of the vast growth in population in succe...
Dear Editor,
Show MoreIn conversations and correspondences with colleagues, we are often still asked if our pre-pandemic call to “stop testing for VGKC antibodies” (1, 2), as echoed by others (3-5), has stood the test of time. Recent articles have raised public health and patient safety concerns, particularly around neurology temporally associated with COVID infections, prompting us to continue to strongly advocate for this stance and avoid misinterpreting positive neurologic antibody results (6-15).
Indeed, the misinterpretation of double negative VGKC-antibodies (dnVGKC; samples with VGKC-complex immunoprecipitation but no LGI1 or CASPR2 reactivity) remains a leading cause of AE misdiagnosis, a problem which now appears to overwhelm the rates of accurate AE diagnosis (16, 17). Patients given this misdiagnosis often experience adverse effects from immunotherapies, and suffer from a misdirected clinical journey (14) given most harbour an alternative, non-immunological underlying diagnosis.
An important explanation has been independently demonstrated in large-cohort studies: dnVGKC antibodies have a high false positive rate at approximately five percent in healthy and other neurological disorder control populations (1, 4). This rate is likely a conservative estimate, as many labs utilize a more liberal cut-off, further exacerbating the irrelevance of dnVGKC antibodies (18). If interpreted as a surrogate of disease incidence, one could conservatively diagnose AE in...
I enjoyed this article on this important area of non-traumatic non-aneurysmal convexity SAH. The authors seems to have not recognised the literature that points to convexity/Sulcal subarachnoid haemorrhage in the context of ipsilateral carotid artery stenosis, which in some case series make up a significant proprtion of the cases (10-50%, references below). Also I would be cautious about having dichotomoised age as a rule, but better as a guide. In the case of carotid artery stenosis this is seen in the under 60s sometimes.
Geraldes et al J Stroke Cereb Dis 23:e23-30, 2014.
Zhao et al J Int Med Res 2017 45:1870.
Renou et al 2012 Cerebrovasc Dis. 2012;34(2):147-52.
Forman et al; J Stroke Cerebrovasc Dis. 2019;28(12):104473.
Amantadine is not a N-metyhl-d-aspartate (NMDA) receptor agonist as stated in the paper, as it's a NMDA antagonist.
References:
- Vanle B, Olcott W, Jimenez J, Bashmi L, Danovitch I, IsHak WW. NMDA antagonists for treating the non-motor symptoms in Parkinson's disease. Transl Psychiatry. 2018 Jun 15;8(1):117. doi: 10.1038/s41398-018-0162-2. PMID: 29907742; PMCID: PMC6003962.,
- Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91-104. PMID: 7884411.
Note from the editors:
an erratum will be published
I read the article by Alvar Paris et al. with great interest. The consumption of nitrous oxide (N2O) has recently surfaced as an exponentially growing form of recreational abuse, particularly among students, due to its euphoric effects and accessibility. The European Monitoring Centre for Drugs and Drug Addiction has expressed concern in a recent report about the recreational use of N2O in Europe. 1
Show MoreThe most common neurological complications associated with N2O consumption are toxic polyneuropathy and subacute combined degeneration of the spinal cord (N2O-SACD), which may occur concurrently— a critical aspect that should not be overlooked. Initial clinical descriptions of N2O-SACD were reported in 2015 and complicated episodic use mediated through canisters. 2 Recently, the market for N2O distribution has expanded with diverse consumption accessories. The introduction of larger cylinders facilitates the consumption of significant amounts of N2O, posing younger individuals at an elevated risk of early and severe Vitamin B12 deficiency along with systemic complications. Consequently, new complications associated with N2O intoxication have been described, and their wide-ranging effects are regularly emphasized in the literature.
Beyond psychiatric symptoms like hallucinations, cognitive impairments including Gayet-Wernicke's encephalopathy have been recently reported. 3 These deficiencies are mediated by Vitamin B1 levels, suggesting a risk of broader deficie...
The authors of this article would like to apologise for omitting a reference to The Northwick Park Integrated Care Pathway (ICP) for Management of Hemiplegic Shoulder Pain. Further information about the pathway, its tools and ongoing development, may be found here (https://www.kcl.ac.uk/cicelysaunders/resources/management-of-hemiplegic-...) and in the following 2 citations:
D. Jackson, L. Turner-Stokes, A. Khatoon, H. Stern, L. Knight & A. O'Connell (2002). Development of an integrated care pathway for the management of hemiplegic shoulder pain, Disability and Rehabilitation, 24:7, 390-398,
Jackson D, Turner-Stokes L, Williams H, Das-Gupta R. Use of an integrated care pathway: a third-round audit of the management of shoulder pain in neurological conditions. J Rehabil Med. 2003 Nov;35(6):265-70.
I was interested to read the article by Andrew Larner in Practical Neurology suggesting that listening for orbital bruits is “useful for impressing students but is not very rewarding”.
I had not heard of Charles Warlow’s challenge before.
My mentor as a trainee, Bernard Gilligan, would routinely listen to carotids and orbits and often femoral arteries as well - we saw a lot of large vessel arterial disease in those days – and I got into the habit of auscultating at least carotids and orbits.
It paid off at least once: I enclose extracts from a letter I wrote in 2001.
Thank you for referring this most interesting 30 year old lady. She has had migraines from her early twenties. Initially they were quite occasional but severe when they occurred. They tended to be triggered by exams or stress.
She moved to Australia about 3 years ago and since then has had unusual episodes of bouts of migraine. In the first of these she had migraine every day for a week or so. Since then the attacks seem to be becoming more frequent and more prolonged so that the most recent one which finished about 2 weeks ago had lasted for 3 weeks or more.
Typically at the start of a bout she will have aura symptoms consisting of numbness of the left finger, arm and face and blurred vision in the left visual field. In the early days of a bout there may be no headache following this. However then a pattern establishes with headache occurring on a virtually...
Show MoreIn their review on vision loss in giant cell arteritis (GCA), the authors point out that anterior arteritic ischaemic optic neuropathy is the most common ophthalmic manifestation of the disease, followed by central retinal artery or cilioretinal artery occlusion and posterior ischaemic optic neuropathy. We do agree that these ocular findings must be quickly diagnosed to prevent devastating visual consequences. When diagnosed, however, not much can be done to restore the visual function. We rather believe that more emphasis should be given to other ophthalmic features that can occur as the initial manifestation of GCA and, when unrecognized, can result in an unfortunate late diagnosis. These include amaurosis fugax, uveitis, anterior or posterior scleritis and ocular pain. Awareness of these uncommon ocular conditions as the presenting signs of impending visual loss in GCA should prompt clinicians to consider this diagnosis in any elderly patient presenting with ophthalmic manifestations other than permanent visual loss, especially if other signs of GCA are detectable.
I read with great interest the excellent paper by Kumta and colleagues1 and the accompanying editorial2 concerning a patient with severe Guillain-Barré syndrome (GBS) requiring mechanical ventilation, who provided his experiences during the 31-day period of locked-in syndrome. I wish to open up some insights on the reported pain.
Show MorePhysical therapy, in particular the passive stretching of calf and masseter muscles, provoked him intense pain, the patient’s description being very impressive: “It felt like they were trying to tear the muscles off the bone … I’ve never known pain like it” 1. Pain due to peripheral nerve damage is basically divided into two major types: dysesthetic pain and nerve trunk pain, the distinction between them being based upon clinical observation and experience3. Reported aching characteristics in the current patient (excruciating, deep, and provoked by nerve stretch) points to nerve trunk pain.
Pain is an integral manifestation of GBS. In a series of 55 consecutive GBS patients, Moulin and colleagues analysed pain features4, which could be summarised as follows: i/ 49 (89%) patients described pain during the course of their illness; ii/ in around half of them, it was described as excruciating; and iii/ pain preceded weakness by a mean of 5.3 days in 14, and both symptoms appeared simultaneously in seven. Furthermore, in “pure” motor GBS syndromes, usually classified as acute motor axonal neuropathy (AMAN), nerve trunk pain may occur in a h...
Your artclce mentions phenytoin as a treatment that has been tried in open label studies. When I began as a neurologist I'd not heard of its use but was put on to it by a senior colleague. I do use carbamazepine as first line but have found phenytoin far superior to other second line agents. I draw the interested reader to the excellent article by Hellelink and Schatman (J Pain Res. 2017; 10: 1663-6 doi: 10.2147/JPR.S141896) which puts a case for phenytoin being considered first line.
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