We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.
We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.
As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, al...
We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.
We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.
As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, although patient 3 had atrial fibrillation, the D- dimer 16,100 is well in excess of what has previously been described in AF-related ischaemic stroke and seemed likely to be relevant.
We agree that a detailed investigation for other potential causes and mechanisms is important, even in the presence of evidence of a prothrombotic state associated with COVID-19. All six patients had prolonged ward cardiac monitoring and - apart from the known atrial fibrillation in patients 2 and 3 - none of them had relevant rhythm abnormalities. Moreover, all patients had complete vascular imaging from aortic arch to the intracranially vessels, and no contributory vascular stenosis was identified in any of the patients. These findings strongly support a prothrombotic state as being relevant to the large-vessel occlusions we observed. Furthermore, our observations are consistent with several other recent reports (2-5).
We acknowledge the research and clinical value of the TOAST (trial of ORG 10172 in acute stroke treatment) classification, which would probably categorise patients 2 and 3 as undetermined. However, we suggest that the prothrombotic and inflammatory syndrome seen after or during COVID-19 might interact with conventional vascular risk factors, disease processes and mechanism to result in large-vessel occlusion. Thus, acute treatment should be tailored to all relevant factors identified wherever possible. Therapeutic anticoagulation might be indicated but the intracranial bleeding risk needs to be considered in the presence of recent cerebral infarction.
Further data are urgently needed to confirm whether the pattern of stroke that we reported in association with COVID-19 is consistently seen in other populations. Case-control studies of COVID-19 associated stroke and non-COVID-19 associated ischaemic stroke could be informative in determining whether, and if so, how, COVID-19 modifies the clinical manifestations of acute cerebrovascular disease.
1. Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry 2020 doi: 10.1136/jnnp-2020-323586 [published Online First: 2020/05/02]
2. Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med 2020 doi: 10.1056/NEJMc2009787 [published Online First: 2020/04/29]
3. Avula A, Nalleballe K, Narula N, et al. COVID-19 presenting as stroke. Brain Behav Immun 2020 doi: 10.1016/j.bbi.2020.04.077 [published Online First: 2020/05/04]
4. Viguier A, Delamarre L, Duplantier J, et al. Acute ischemic stroke complicating common carotid artery thrombosis during a severe COVID-19 infection. J Neuroradiol 2020 doi: 10.1016/j.neurad.2020.04.003 [published Online First: 2020/05/04]
5. Moshayedi P, Ryan TE, Mejia LLP, et al. Triage of Acute Ischemic Stroke in Confirmed COVID-19: Large Vessel Occlusion Associated With Coronavirus Infection. Front Neurol 2020;11:353. doi: 10.3389/fneur.2020.00353 [published Online First: 2020/04/21]
Alain Buguet1, Manny W. Radomski2, Jacques Reis3, Raymond Cespuglio4, Peter S. Spencer5, Gustavo C. Román6
Authors’s affiliations
• UMR 5246 CNRS, Claude-Bernard Lyon-1 University, Villeurbanne, France
• Physiology, Faculty of Medicine, University of Toronto, Canada
• Faculté de Médecine, Université de Strasbourg, Strasbourg, France
• Neurocampus Michel Jouvet, Claude-Bernard Lyon-1 University, Lyon, France
• Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
• Department of Neurology, Neurological Institute, Houston Methodist Hospital, USA, and Weill Cornell Medical College, Cornell University, New York, NY, USA
• Correspondence to Prof. Alain Buguet, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France; a.buguet@free.fr
Introduction
We read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and fol...
Alain Buguet1, Manny W. Radomski2, Jacques Reis3, Raymond Cespuglio4, Peter S. Spencer5, Gustavo C. Román6
Authors’s affiliations
• UMR 5246 CNRS, Claude-Bernard Lyon-1 University, Villeurbanne, France
• Physiology, Faculty of Medicine, University of Toronto, Canada
• Faculté de Médecine, Université de Strasbourg, Strasbourg, France
• Neurocampus Michel Jouvet, Claude-Bernard Lyon-1 University, Lyon, France
• Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
• Department of Neurology, Neurological Institute, Houston Methodist Hospital, USA, and Weill Cornell Medical College, Cornell University, New York, NY, USA
• Correspondence to Prof. Alain Buguet, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France; a.buguet@free.fr
Introduction
We read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and following SARS-CoV-2 infection.
Sleep disorders and influenza pandemics
The Spanish flu pandemic caused by the H1N1 influenza virus of avian origin spread worldwide during the years 1918-1919. Throughout World War I, between 1915 and 1917, Jean-René Cruchet and Constantin von Economo described the occurrence of sleep-wake disorders following the initial pharyngitis. von Economo coined the name encephalitis lethargica for this condition characterized by an initial phase of hypersomnia (“somnolent ophthalmoplegia” or “sopor”).2 He also observed insomnia associated with basal ganglia “choreatic” dysfunction, circadian sleep disruption (“inversion of sleep”), sleep paralysis (“dissociation of cerebral and body sleep” and “akinetic cases”), and “somnambulism.” Identification of the clinical and neuropathological features of these disorders by von Economo launched the search for sleep-wake regulatory networks. He described the “centre for regulation of sleep” in the anterior hypothalamus and the “wake centre” in the posterior hypothalamus.2
During more recent pandemics such as the H2N2 influenza type A 1957-1958 Asian flu, or the influenza B in Japan,3 sporadic cases of Kleine-Levin syndrome were reported. This is a rare disorder characterized by recurrent episodes of excessive daytime sleepiness (hypersomnia) along with cognitive and behavioural changes. However, sleep reports were lacking after the subsequent re-emergence in 1968-1969 of the Hong-Kong flu pandemic attributed to H3N2 influenza type A virus. Four to six months after the 2009-2010 H1N1 influenza epidemic, narcoleptic syndromes were reported in Chinese children, 4 and seasonal distribution of narcoleptic syndromes was suspected after winter upper respiratory infections.
Pathways used by neurotropic influenza viruses and coronaviruses
The probable transmission pathway of H1N1 was elucidated in intranasally-infected mice that developed narcolepsy-like syndromes. 5 The virus infected the olfactory nerves (CN I) crossed the olfactory epithelium and cribriform plate (day 0 post-infection), olfactory bulb glomerular layer (day 14), and mitral and granular cells (day 28). From the olfactory bulb, the virus progressed retrogradely to orexin- and melanin-concentrating-hormone nuclei located in the lateral hypothalamus (day 28). The virus then spread to the pontine dorsal raphe and locus coeruleus nuclei.
Neurotropic coronaviruses may reach their central nervous system targets by transynaptic transmission, as shown in porcine HEV 67N coronavirus and avian bronchitis virus infections. 5 Another route is the trigeminal pathway, either from collateral nerve endings in the nasal mucosa or directly from the buccal mucosa to the cranial nerve V (CN V) nucleus. 5
Do coronaviruses behave in a similar manner? In humans, a shortcut for influenza and other viruses is considered to be through the olfactory pathway to the brain. Following SARS-CoV-1 infection patients suffered from nonrestorative sleep related to sleep instability. Sleep alterations may relate to the reported presence of cytoplasmic viral particles and viral genome sequences in hypothalamic neurons.1 Transit of viruses can occur from blood by crossing the blood-brain barrier (BBB) or via the weaker BBB of the median eminence, but neural pathways appear to be more direct.
Anosmia and ageusia represent two clinical symptoms that support the diagnosis of COVID-19. These two manifestations may occur in 86% to 88% of the cases before the appearance of the general symptoms associated with COVID-19 infection.1 The neurotropic potential of SARS-CoV-2 infection is enhanced by the presence of angiotensin-converting enzyme 2 (ACE2) receptors in neurons and glial cells. ACE2 receptors are the main attachment point for the spike S glycoprotein that mediates coronavirus entry into the host. Therefore, the above clinical symptoms in the absence of nasal congestion and rhinorrhoea implicate involvement of the olfactory nerve (CN I) and gustatory nerves. The latter nerve tracts come from the tongue and the oral cavity (CN VII and IX) and from the pharynx (CN X). Most probably, the virus may use cranial nerve tracts to enter the CNS, reaching preferentially some specific neuronal networks, notably basal ganglia, hypothalamic regulatory networks of hunger, thirst or body temperature, and sleep-wake networks (anterior and posterior hypothalamus, and mesencephalon-pontine nuclei).6 Neural invasion from infected lungs via CNs IX-X has also been postulated. Involvement of brainstem respiratory centres may be responsible for the extremely high case-fatality rate (49%) of COVID-19 patients in critical condition requiring respiratory support.1
Conclusion
Based on the foregoing observations, we propose that sleep specialists around the world remain aware of the possibility of COVID-19-related sleep disorders now and into the future. We also propose that patients exhibiting symptoms suggestive of cerebral invasion undergo sleep investigation. Such information should provide a better understanding of the impact of COVID-19 on the brain and assist in the clinical evaluation and the development of treatment strategies.
References
1. Román CG, Spencer PS, Reis J, et al. The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries. J Neurol Sci [published online 2020 May 6]. doi: 10.1016/j.jns.2020.116884
2. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249-259. doi: 10.1097/00005053-193003000-00001
3. Kodaira M, Yamamoto K. First attack of Kleine-Levin syndrome triggered by influenza B mimicking influenza-associated encephalopathy. Intern Med 2012;51:1605-8. doi: 10.2169/internalmedicine.51.7051
4. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 pandemic in China. Ann Neurol 2011;70:410-417. doi: 10.1002/ana.22587
5. Tesoriero C, Codita A, Zhang M-D, et al. H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice. Proc Natl Acad Sci U S A 2016;113:E368-E377. doi: 10.1073/pnas.1521463112
6. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol.2020;92(6) [published online 2020 Feb 27]. doi: 10.1002/jmv.25728
Footnotes
Contributors: All authors are lead authors. AB proposed and drafted the manuscript for intellectual concept; AB, MWR, JR, RC, PSS, GCR: conceptualisation, literature search and analysis; AB, MWR, JR, RC, PSS, GCR: writing and revision of the manuscript for intellectual content. GCR is Chair, Environmental Neurology Specialty Group of the World Federation of Neurology of which AB, JR and PSS are members.
Funding: GCR’s research is funded by the Wareing Family Fund, Houston Texas, USA.
Competing Interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-third of severe SARS patients developed venous thromboembolism including pulmonary embolism6,7. Three of the 5 stroke patients had also received LMWH. Three patients had unremarkable procoagulant work-up. While we did not measure D-dimer systematically 2 had evidence of disseminated intravascular coagulation, both whom died. Mao et al. and Oxley et al. highlight the possible significance of raised D-dimer in COVID-19 patients who developed stroke2,5. Furthermore, intravenous immunoglobulin (IVIg) was given empirically to 3 of our patients, at 2, 5 and 16 days before stroke onset, that could have compounded the thromboembolic risk.
Experimental, albeit conflicting, evidence suggests that the SARS-CoV1 virus, which causes SARS, could activate transcription of a prothrombinase gene, coding Fibrinogen-like 2 (FGL2)9. FGL2 is a multi-functional protein that activates prothrombin to generate thrombin that in turn converts fibrinogen into fibrin, possibly explaining the extensive fibrin deposition in the lungs of SARS patients as well as inducing a prothrombotic state. Interestingly, the proteolytic activity of FGL2 is independent of factor X and cannot be inhibited by antithrombin III9, perhaps explaining LMWH’s apparent lack of efficacy in our patients.
Ischemic stroke appears to be an infrequent complication of corona virus infections, occurring mainly in the very ill patients with multiple contributory co-morbidities. However, in contrast to SARS, which affected fewer than 9000 people globally COVID-19 has already infected more than 2 million, a sizeable proportion of whom are critically ill. Our experience with SARS prompts us to recommend vigilance against thromboembolism in general and specifically as a mechanism for ischemic stroke, particularly if empirical treatment with IVIg or convalescent plasma is attempted.
References:
1) Manji H, Carr AS, Brownlee WJ. Neurology in the time of covid-19. J Neurol Neurosurg Psychiatry. 2020 Apr 20. pii: jnnp-2020-323414.
2) Ling Mao1; Huijuan Jin; Mengdie Wang1; et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Published online.
3) Helms J, Kremer S, Merdji H. Neurologic Features in Severe SARS-CoV-2 Infection.N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597.
4) Zhang Y, Xiao M, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.N Engl J Med. 2020 Apr 8.
5) Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020 Apr 28.
6) Umapathi T, Kor AC, Venketasubramanian N,et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-31.
7) Lew TW, Kwek TK, Tai D, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003; 290(3):374-80.
8) Chong PY, Chui P, Ling AE, Franks TJ,et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 128:195–204
9) Yang G, Hooper WC. Physiological functions and clinical implications of fibrinogen-like 2: A review World J Clin Infect Dis. 2013 Aug 25;3(3):37-46.
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to...
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to DBS (0.189±0.03 vs. 0.167±0.04, respectively; P<0.001). Due to perceived advantages of DBS over ABL, this result was surprising and inquiries were raised about the reliability of the analysis. A primary concern was whether study rigor could have impacted our finding. In this follow-up study, we performed an in-depth assessment of rigor of the ABL vs. DBS studies that previously met criteria for inclusion.
Methods:
Assessment of rigor requires the selection of a grading scale. However, as rigor scales are designed for a specific type of study, a single type of scale is incapable of properly assessing the variety of analyzed study types (e.g., RCT, cohort, and case series). To circumvent this issue, we decided to score only case series because they were the most common study type in both treatment groups. These studies were assessed with the Institute of Health Economics (IHE) quality appraisal checklist, which is a validated scale designed exclusively for case series.[2,3] These rigor scores were then used as covariates to a mixed-effects model of treatment against outcome (i.e. Y-BOCS score, adverse event (AE) incidence, and overall utility).
Results:
There were a total of 20 DBS and 17 ABL case series used in the meta-analysis; they represent 71.4% and 94.4%, respectively, of all studies in each treatment group. For overall number of patients, case series contribute 68.7% (125/182) and 97.7% (347/355) to DBS and ABL groups, respectively. In addition, they represent 40% (4/10) and 83.3% (10/12) of DBS and ABL studies that report AE incidence. DBS studies had significantly higher rigor scores than ABL studies (13.5/20 versus 11.0/20, respectively; p<0.001).
Similar to the results of Kumar et al., ABL still imparts a significantly higher utility than DBS with rigor as covariate in the mixed-effects model of treatment (p<0.0001). AE incidence was also significantly lower in ABL case studies (p=0.0024). For Y-BOCS score, ABL case series report greater percent reduction compared to DBS studies, though it was only marginally significant (p=0.0609). When rigor added to the mixed-effects model of treatment against outcome, neither the treatment group nor the rigor scores were significant predictors of % Y-BOCS score reduction (p=0.2261 and 0.4179, respectively). Similarly, neither treatment group nor rigor was a significant predictor of AE incidence (p=0.2223 and 0.4602, respectively). When considered as the sole predictor, rigor was not found to be significant predictor of % Y-BOCS score reduction (p = 0.1115). However, higher rigor scores were predictive of higher AE incidence (p = 0.0064).
Discussion:
Rigor is an important consideration as it may lend insight to a study’s validity and robustness. One hypothesis of ABL’s superiority over DBS was that ABL studies were less rigorous, producing outcomes that may be less reflective of reality. As rigor was not a significant covariate for utility, it suggests that Kumar et al.’s original conclusion of ABL superiority is accurate. However, even though rigor is not a significant covariate of % Y-BOCS score reduction, it is a significant predictor for AE incidence. Higher rigor studies generally had a higher reported AE incidence.
A notable limitation to this analysis is the exclusive use of case series. The mixed collection of study types precluded the perfect fit of a single scale to all studies. Since case series only represent a portion of all studies, our calculations slightly vary from those reported previously in Kumar et al. Nevertheless, case series represent the vast majority of studies and patients in both DBS and ABL groups. Though not a perfect facsimile, they are still highly representative. Regarding AE incidence, DBS case series constitute only 40% of overall DBS studies with AE reports. Yet, they were sufficient in establishing the significant association of high rigor and AE incidence. Given that the remaining DBS studies likely have even higher rigor (i.e. RCTs and cohort studies), an even stronger association with their inclusion is not an unreasonable inference. Furthermore, although treatment types were no longer significant predictors, this may be a consequence of working with fewer studies and overfitting data.
While study rigor was not a significant covariate for the current utility calculation, it is nevertheless an important consideration for similar meta-analyses, especially when assessing older and newer technologies. As the field of functional neurosurgery advances, there will be a greater need for similar comparisons to evaluate and guide clinical decision-making and adoption of novel techniques. Developments in DBS technologies can all plausibly improve DBS utility for OCD, necessitating further studies. Despite its limitations as an imperfect measure, study rigor may provide valuable insight into the reliability of reported data.
Bibliography:
1. Kumar KK, Appelboom G, Lamsam L, et al. Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: A meta-analytic study. J Neurol Neurosurg Psychiatry 2019;90:469–73. doi:10.1136/jnnp-2018-319318
2. Institute of Health Economics. Quality Appraisal Checklist for Case Series Studies. 2014;:1–2.
3. Guo B, Moga C, Harstall C, et al. A principal component analysis is conducted for a case series quality appraisal checklist. J Clin Epidemiol 2016;69:199–207.e2. doi:10.1016/j.jclinepi.2015.07.010
De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...
De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information regarding the monitoring ability for ALS progression. In combination with clinical findings, biological monitoring method might be important for medication efficacy.
References
1. De Schaepdryver M, Lunetta C, Tarlarini C, et al. Neurofilament light chain and C reactive protein explored as predictors of survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2020;91(4):436-437. doi: 10.1136/jnnp-2019-322309
2. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):157-164. doi: 10.1136/jnnp-2018-318704
3. Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019;45(3):291-304. doi: 10.1111/nan.12511
4. Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020;27(2):251-257. doi: 10.1111/ene.14063
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in se...
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):157-164. doi: 10.1136/jnnp-2018-318704
2. Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019;45(3):291-304. doi: 10.1111/nan.12511
3. Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020;27(2):251-257. doi: 10.1111/ene.14063
4. Kawada T. Serum neurofilament light chain in patients with amyotrophic lateral sclerosis. Eur J Neurol. 2020 Mar 18. doi: 10.1111/ene.14223
Oliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and ev...
Oliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and events cannot justify for compiling data of PSP and MSA for the analysis.
Second, dell'Aquila et al. also performed a retrospective cohort study to identify clinical predictors of survival in patients with PSP (3). Adjusted HR (95% CI) of older age at onset, early dysphagia and early cognitive deficit for mortality were 2.8 (1.3-5.7), 2.3 (1-5.3) and 3.6(1.6-8.2), respectively. As only 25 patients were used for multivariate analysis, unstable estimates with wide ranges of 95% CI were presented. But they mentioned that some clinical milestones before death should be considered as possible endpoints in further study, and Oliveira et al. presented such events for the risk assessment of PSP. Quality of life in patients with PSP might degrade according to the progression of disease, and I appreciate Oliveira et al. for selecting first disease milestone of PSP as events.
REFERENCES
1 Oliveira MCB, Ling H, Lees AJ, et al. Association of autonomic symptoms with disease progression and survival in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2019;90:555-61.
2 Glasmacher SA, Leigh PN, Saha RA. Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017;88:402-11.
3 dell'Aquila C, Zoccolella S, Cardinali V, et al. Predictors of survival in a series of clinically diagnosed progressive supranuclear palsy patients. Parkinsonism Relat Disord 2013;19:980-5.
Kaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with m...
Kaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with mortality by survival analysis. RBC4 can be considered as a biomarker for insulin resistance and vitamin A metabolism, and the lack of vitamin A and insulin resistance might also be related to the pathogenesis of ALS.
Finally, other medications for ALS treatment can be considered for the analysis. Freedman et al. examined the association between lipid-lowering medication and ALS risk (4). Adjusted odds ratios (ORs) (95% confidence interval [CI]) of statins and fibrates for ALS were 0.87 (0.83-0.91) and 0.88 (0.80-0.97), respectively. In contrast, other three cholesterol-lowering medications such as nitrates, bile acid sequestrants and ezetimibe did not significantly associate with ALS. Although confounders and mediators cannot be clearly identified for the prognosis of ALS, basic parameters such as smoking and body mass index might be important variables for the adjustment.
REFERENCES
1 Kaji R, Imai T, Iwasaki Y, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry 2019;90:451-7.
2 Ito S, Izumi Y, Niidome T, et al. Methylcobalamin prevents mutant superoxide dismutase-1-induced motor neuron death in vitro. Neuroreport 2017;28:101-7.
3 Rosenbohm A, Nagel G, Peter RS, et al. Association of serum retinol-binding protein 4 concentration with risk for and prognosis of amyotrophic lateral sclerosis. JAMA Neurol 2018;75:600-7.
4 Freedman DM, Kuncl RW, Cahoon EK, et al. Relationship of statins and other cholesterol-lowering medications and risk of amyotrophic lateral sclerosis in the US elderly. Amyotroph Lateral Scler Frontotemporal Degener 2018;19(7-8):538-46.
Elucidating the nature of the foreign accent syndrome (FAS) can contribute to improve its diagnosis and treatment approaches. To understand this apparently rare syndrome, McWhirter et al. 1 studied a large case series of 49 subjects self-reporting having FAS. The participants were recruited via unmoderated online FAS support groups and surveys shared with neurologists and speech-language therapists from several countries. Participants completed an online protocol including validated scales tapping somatic symptoms, anxiety and depression, social-occupational function, and illness perception. They were also requested to provide speech samples recorded via computers or smartphones during oral reading and picture description. The overall clinical presentation of FAS in each participant was classified by consensus reached by three authors (2 neuropsychiatrists and 1 neurologist) in (1) “probably functional”, (2) “possibly structural” or (3) “probably structural”, wherein (1) meant no evidence of a neurological event or injury suggestive of a functional disorder but with no spontaneous remission; (2) alluded to the presence of some features suggestive of a functional disorder but with some uncertainty about a possible structural basis; and (3) denoted the evidence of a neurological event or injury coincident with the onset of FAS. The recorded speech samples were examined by experts to diagnose FAS and their frequent associated speech-language deficits (apraxia of speech, dysar...
Elucidating the nature of the foreign accent syndrome (FAS) can contribute to improve its diagnosis and treatment approaches. To understand this apparently rare syndrome, McWhirter et al. 1 studied a large case series of 49 subjects self-reporting having FAS. The participants were recruited via unmoderated online FAS support groups and surveys shared with neurologists and speech-language therapists from several countries. Participants completed an online protocol including validated scales tapping somatic symptoms, anxiety and depression, social-occupational function, and illness perception. They were also requested to provide speech samples recorded via computers or smartphones during oral reading and picture description. The overall clinical presentation of FAS in each participant was classified by consensus reached by three authors (2 neuropsychiatrists and 1 neurologist) in (1) “probably functional”, (2) “possibly structural” or (3) “probably structural”, wherein (1) meant no evidence of a neurological event or injury suggestive of a functional disorder but with no spontaneous remission; (2) alluded to the presence of some features suggestive of a functional disorder but with some uncertainty about a possible structural basis; and (3) denoted the evidence of a neurological event or injury coincident with the onset of FAS. The recorded speech samples were examined by experts to diagnose FAS and their frequent associated speech-language deficits (apraxia of speech, dysarthria, dysprosody and aphasia) and the abnormal segmental and suprasegmental features that characterize FAS. The main finding of this study was that the authors’ consensus classified 71 % (35 subjects) of the participants as “probably functional”, 8% (4 subjects) as “possibly structural”, and 20% (10 subjects) as “probably structural”. The high prevalence of participants meeting the “probably functional” and “possibly functional” criteria for FAS (79%) appears difficult to reconcile with previous data. 2,4 This overestimation may spuriously inflate the number of functional cases, thus biasing the currently accepted relative frequency of the FAS variants.2 It is also conceivable that subjects with “functional” FAS completed the evaluation because they feel more urge to be evaluated than those with other variants. Below, we briefly examine the caveats of this study concerning the validity of the assessment results.
First, only 13 out of 49 (26%) participants provided samples of speech production and 10 of them were classified as having “probably functional” FAS, whereas the remaining 3 cases were considered to have “probably structural” FAS. This makes the diagnosis of FAS elusive in most participants (74%) who did not submit speech samples for expert evaluation, a requirement needed for establishing the precise diagnosis of FAS.3
Second, McWhirter et al. 1 identified some features of the speech (i.e., periods of remission, ability to copy other accents, lack of typical speech-language deficits accompanying neurogenic FAS) in “functional” FAS that considered helpful for identifying such cases. Nevertheless, these characteristics have also been observed in neurogenic cases. Alternation between foreign accent, loss of regional accent, and using a previously heard accent in the same individual have been reported in a variant of neurogenic FAS (see Berthier et al., 2015 in 2). Cases with no or rapidly resolving dysarthria, apraxia of speech or aphasia but persistent foreign accent have been described as “pure” neurogenic FAS (see references in 4). The fluctuating course of FAS related to psychiatric disorders (schizophrenia and bipolar disorder) could not viewed as functional; rather, it has a neurochemical correlate (e.g., withdrawal of neuroleptics) involving abnormal dopaminergic neurotransmission (see Reeves & Norton, 2001; and Poulin et al., 2007 in 4). In this regard, anxiety and depression in the McWhirter et al’s sample occurred more frequently in the “structural” group than in the “functional” FAS cases. 1 Thus, these neuropsychiatric disorders do not have a discriminative value between subtypes.
Third, 11 (22%) participants in the present study had suffered from stroke, but the authors reported structural lesions on neuroimaging in only 5 of them (10%), all belonging to the "probably structural" group (data from Table 1). No information on lesion characteristics (i.e., location, size) was provided. Recent developments on the neuroscience of accent (see 2) may explain why the scarcity of brain damage in McWhirter et al.’s study1 does not undermine the role of structural or functional lesions in those participants with normal neuroimaging. In the present study this was particularly pertinent for those cases associated with stroke, mild traumatic brain injury, Parkinson’s disease, headaches, or seizures. Overall, focal lesions responsible from FAS are very small (involving a single gyrus or portions of a nucleus) compromising of one or more components of the speech production network.3,4 and these lesions may be easily overlooked if sophisticated neuroimaging methods are not used. Note that functional and structural brain changes have been reported even in cases of psychogenic and developmental FAS when high resolution magnetic resonance imaging (MRI), diffusion tensor imaging, positron emission tomography or functional MRI were used.3-5
Fourth, the differentiation between “functional” and “structural” FAS may be deemed artificial considering the current limitations of conventional neuroimaging methods (computed tomography, low resolution MRI). 4 Such limitations prevent unveiling the neural basis of cases which until now fall under the umbrella of “functional” disorders.3 For example, the demarcation of a “possible functional FAS” (functional disorder with an uncertain structural basis)1 is uncertain. How can we interpret the hybrid identity in such FAS cases? How the attending professionals can dissect the psychogenic from the neurogenic nature of FAS to provide an integrated explanation to the affected person? We have reported that the interpretation of FAS as psychogenic in cases associated with previously undetected small stroke lesions 4 or developmental brain anomalies 3 created a social stigma in the affected persons which, in turn, heightened the negative connotation of living with a FAS.
The differentiation between FAS variants does not depends solely on the segmental and suprasegmental alterations 5 nor in the frequency of comorbid psychiatric disorders. Therefore, the implementation of other methodologies to refine the differential diagnosis between FAS variants is needed. We trust that multimodal neuroimaging and other ancillary methods will contribute to illuminate the still hidden origins of FAS subtypes.
References
1. McWhirter L, Miller N, Campbell C, et al. Understanding foreign accent syndrome. J Neurol Neurosurg Psychiatry. 2019 Mar 2. pii: jnnp-2018-319842. doi: 10.1136/jnnp-2018-319842.
2. Moreno-Torres I, Mariën P, Dávila G, et al. Editorial: Language beyond Words: The Neuroscience of Accent. Front Hum Neurosci. 2016 Dec 20;10:639. doi: 10.3389/fnhum.2016.00639.
3. Berthier ML, Roé-Vellvé N, Moreno-Torres I et al. Mild Developmental Foreign Accent Syndrome and Psychiatric Comorbidity: Altered White Matter Integrity in Speech and Emotion Regulation Networks. Front Hum Neurosci. 2016 Aug 9;10:399. doi: 10.3389/fnhum.2016.00399.
4. Moreno-Torres I, Berthier ML, Del Mar Cid M. et al. Foreign accent syndrome: a multimodal evaluation in the search of neuroscience-driven treatments. Neuropsychologia 2013; 51:520-37. doi: 10.1016/j.neuropsychologia.2012.11.010.
5. Keulen S. Foreign Accent Syndrome: A Neurolinguistic Analysis. PhD Thesis. University of Groningen (The Netherlands) and Vrije Universiteit Brussel (Belgium). May 18th, 2017.
We, the authors, thank Berthier for his comments on our study of 49 individuals with self-reported Foreign Accent Syndrome.
In response, we would first like to clarify that we do not use Berthier’s term ‘psychogenic’, but ‘functional’ in our paper, referring to foreign accent symptoms due to changes in neural function rather than (or in addition to) the direct effects of a structural lesion. The body-mind dualism implied by the terms ‘psychological/psychogenic’ vs ‘neurogenic’ no longer holds water. Berthier himself notes that the differentiation between “functional” and “structural” may be artificial and that there has been great progress in “unveiling of the neural basis” of functional disorders. As we frequently emphasise in explaining the diagnosis to individuals with functional neurological disorders, their symptoms are definitely ‘real’; not ‘imagined’; and have a basis in changes in neural function which we are beginning to understand more clearly [1,2].
We accept the limitations provided by our method of data collection, including limited data about investigations and a likelihood of selection bias where those with predominantly functional FAS may be somewhat over-represented in our sample. We wish to clarify, however, that cases were classified as ‘probably functional’ on the basis of reported positive clinical features of a functional disorder (e.g. periods of return to normal accent, adoption of stereotypical behaviours) and not by the presence...
We, the authors, thank Berthier for his comments on our study of 49 individuals with self-reported Foreign Accent Syndrome.
In response, we would first like to clarify that we do not use Berthier’s term ‘psychogenic’, but ‘functional’ in our paper, referring to foreign accent symptoms due to changes in neural function rather than (or in addition to) the direct effects of a structural lesion. The body-mind dualism implied by the terms ‘psychological/psychogenic’ vs ‘neurogenic’ no longer holds water. Berthier himself notes that the differentiation between “functional” and “structural” may be artificial and that there has been great progress in “unveiling of the neural basis” of functional disorders. As we frequently emphasise in explaining the diagnosis to individuals with functional neurological disorders, their symptoms are definitely ‘real’; not ‘imagined’; and have a basis in changes in neural function which we are beginning to understand more clearly [1,2].
We accept the limitations provided by our method of data collection, including limited data about investigations and a likelihood of selection bias where those with predominantly functional FAS may be somewhat over-represented in our sample. We wish to clarify, however, that cases were classified as ‘probably functional’ on the basis of reported positive clinical features of a functional disorder (e.g. periods of return to normal accent, adoption of stereotypical behaviours) and not by the presence of psychiatric comorbidity [3].
We agree with Berthier that positive features do not exclude the presence of any structural lesion; but we reach a very different conclusion. So, where Berthier indicates that this discounts the discriminative utility of these features, we conclude that the presence of these features suggests that FAS may have a partially or entirely functional basis even in those with a structural lesion. We hope that future prospective research will test this hypothesis.
In our collective clinical experience, positive identification of functional neurological symptoms is universally helpful, including in those with comorbid structural lesions. Functional symptoms are potentially reversible, and respond to different therapeutic methods: for example, physiotherapy for functional movement disorders concentrates on distracting somatosensory attention away from the affected limb and encouraging natural ‘automatic’ movements rather than concentrated repeated strength exercises using the affected limb [4]. It seems likely that similar treatment approaches might be helpful in those with partially or predominantly functional FAS.
Berthier questions how we can “dissect the psychogenic from the neurogenic to provide an integrated explanation to the affected person?” In our experience, individuals who have both ‘structural’ and ‘functional’ symptoms (such as those with epilepsy and dissociative seizures) are generally both receptive to and interested in an integrated explanation of the ways in which some of their symptoms may have a functional basis and therefore potential for improvement.
The ‘social stigma’ which Berthier notes may be associated with a functional diagnosis, and which unfortunately can also come from health professionals, is perhaps the most important problem which Berthier identifies in his letter. We agree that multimodal neuroimaging may continue to better our understanding of the mechanisms of various FAS subtypes, and hope that this work will move forward collaboratively, embracing the possibility that a new foreign accent may sometimes arise as a result of disruptions not directly related to a structural lesion.
1 Hallett M, Stone J, Carson A. Functional Neurologic Disorders, Volume 139 of the Handbook of Clinical Neurology series. Amsterdam: Elsevier 2016.
2 Espay AJ, Aybek S, Carson A, et al. Current Concepts in Diagnosis and Treatment of Functional Neurological Disorders. JAMA Neurol
3 Lee O, Ludwig L, Davenport R, et al. Functional foreign accent syndrome. Pract Neurol 2016.
4 Nielsen G, Stone J, Edwards MJ. Physiotherapy for functional (psychogenic) motor symptoms: A systematic review. J Psychosom Res 2013
Dear Editor,
We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.
We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.
As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, al...
Show MoreAlain Buguet1, Manny W. Radomski2, Jacques Reis3, Raymond Cespuglio4, Peter S. Spencer5, Gustavo C. Román6
Authors’s affiliations
• UMR 5246 CNRS, Claude-Bernard Lyon-1 University, Villeurbanne, France
• Physiology, Faculty of Medicine, University of Toronto, Canada
• Faculté de Médecine, Université de Strasbourg, Strasbourg, France
• Neurocampus Michel Jouvet, Claude-Bernard Lyon-1 University, Lyon, France
• Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
• Department of Neurology, Neurological Institute, Houston Methodist Hospital, USA, and Weill Cornell Medical College, Cornell University, New York, NY, USA
• Correspondence to Prof. Alain Buguet, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France; a.buguet@free.fr
Introduction
Show MoreWe read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and fol...
Dear Editor,
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...
Show MoreIntroduction:
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to...
Show MoreDe Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...
Show MoreVerde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in se...
Show MoreOliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and ev...
Show MoreKaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with m...
Show MoreElucidating the nature of the foreign accent syndrome (FAS) can contribute to improve its diagnosis and treatment approaches. To understand this apparently rare syndrome, McWhirter et al. 1 studied a large case series of 49 subjects self-reporting having FAS. The participants were recruited via unmoderated online FAS support groups and surveys shared with neurologists and speech-language therapists from several countries. Participants completed an online protocol including validated scales tapping somatic symptoms, anxiety and depression, social-occupational function, and illness perception. They were also requested to provide speech samples recorded via computers or smartphones during oral reading and picture description. The overall clinical presentation of FAS in each participant was classified by consensus reached by three authors (2 neuropsychiatrists and 1 neurologist) in (1) “probably functional”, (2) “possibly structural” or (3) “probably structural”, wherein (1) meant no evidence of a neurological event or injury suggestive of a functional disorder but with no spontaneous remission; (2) alluded to the presence of some features suggestive of a functional disorder but with some uncertainty about a possible structural basis; and (3) denoted the evidence of a neurological event or injury coincident with the onset of FAS. The recorded speech samples were examined by experts to diagnose FAS and their frequent associated speech-language deficits (apraxia of speech, dysar...
Show MoreWe, the authors, thank Berthier for his comments on our study of 49 individuals with self-reported Foreign Accent Syndrome.
In response, we would first like to clarify that we do not use Berthier’s term ‘psychogenic’, but ‘functional’ in our paper, referring to foreign accent symptoms due to changes in neural function rather than (or in addition to) the direct effects of a structural lesion. The body-mind dualism implied by the terms ‘psychological/psychogenic’ vs ‘neurogenic’ no longer holds water. Berthier himself notes that the differentiation between “functional” and “structural” may be artificial and that there has been great progress in “unveiling of the neural basis” of functional disorders. As we frequently emphasise in explaining the diagnosis to individuals with functional neurological disorders, their symptoms are definitely ‘real’; not ‘imagined’; and have a basis in changes in neural function which we are beginning to understand more clearly [1,2].
We accept the limitations provided by our method of data collection, including limited data about investigations and a likelihood of selection bias where those with predominantly functional FAS may be somewhat over-represented in our sample. We wish to clarify, however, that cases were classified as ‘probably functional’ on the basis of reported positive clinical features of a functional disorder (e.g. periods of return to normal accent, adoption of stereotypical behaviours) and not by the presence...
Show MorePages