Bocci T.

Bulfamante G.

Campiglio L.

Chiumello D.

Coppola S.

Falleni M.

Priori A.

English

AIR Universita degli studi di Milano

Vol:.(1234567890)Journal of Neurology (2021) 268:3598–3600https://doi.org/10.1007/s00415-021-10474-01 3LETTER TO THE EDITORSBrainstem clinical and neurophysiological involvement in COVID‑19Tommaso Bocci1,4,5 · Gaetano Bulfamante2,4 · Laura Campiglio1,4,5 · Silvia Coppola3,4 · Monica Falleni2,4 · Davide Chiumello3,4 · Alberto Priori1,4,5,6Received: 17 December 2020 / Revised: 12 February 2021 / Accepted: 13 February 2021 / Published online: 18 March 2021 © The Author(s) 2021Dear Sirs,Whilst respiratory failure in COVID-19 arises from severe interstitial lung involvement [17], SARS-CoV-2 likely spreads also through the nervous system [3, 6]. Before that SARS-CoV-2 emerged at a global scale [14], other corona-viruses have been proven to invade the brainstem in mice [5] and humans [1, 2, 7]. SARS-Cov-2 might spread cell-to-cell in a prion-like way [3, 8, 11], along the vagus nerve, reach-ing respiratory centers in the brainstem, possibly adding a neurogenic component to the respiratory failure [11, 15]. To test this hypothesis, we assessed neurophysiologically and clinically the brainstem in patients admitted to the Intensive Care Unit (ICU; time of hospitalization: 10.5 ± 4.8 days, mean ± standard deviation).The blink reflex (BR) was assessed in 11 severe COVID-19 patients (9 males, mean age 55.2 ± 7.1 years, range 48–70; Fig. 1) [4, 9]. Diagnosis of COVID-19 was confirmed by positive results on a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay performed on nasopharyngeal and throat swab, or on lower respiratory tract specimens; each patient suffered from interstitial pneumonia typical of SARS-CoV-2 disease and was intubated at the time of the neurological evaluation. The BR includes two responses: the first is mediated by a disynaptic pathway between the sensory nucleus of the trigeminal nerve (V) in the mid pons and the ipsilateral facial nucleus in the lower pontine teg-mentum. The second response (RII) originates through a multi-synaptic circuit in the medulla oblongata [9]. The supraorbital nerve was stimulated through a pair of silver chloride cup electrodes with the cathode over the supraor-bital foramen and the anode 2 cm above (constant current stimulation, pulse width 200 µs, inter-trial interval ranging between 25 and 35 s to avoid habituation) [4, 9]. A total of 8 blink reflexes were recorded on each side and data were col-lected from superimposed traces. Electromyographic signal was captured by surface electrodes and analyzed (band-pass 10 Hz–10 kHz, sampling rate 5 kHz, sensitivity set 200 µV/Div; sweep speed 10 ms/Div). Neurophysiological responses in COVID-19 patients were compared with those from 15 age-matched healthy volunteers and 5 non-COVID ICU intu-bated patients (Fig. 1). The glabellar and corneal reflexes were also clinically tested; the response to both reflexes was labeled as normal (score = 2), reduced (1) or absent (0).At the time of evaluation, patients were awake and in the 60 min before none of them assumed drugs interfering with neuromuscular transmission or depressing the central nervous system.Whereas all the COVID-19 patients had normal pontine RI latencies (p = 0.1), in two of them the RII was absent and in the remaining cases markedly abnormal, both the ipsi-lateral (latency: p < 0.0001; amplitude: p < 0.0001; dura-tion: p < 0.0001) and the contralateral response (latency: p = 0.0014; amplitude: p < 0.0001; duration: p < 0.0001; see Table 1).Among COVID-19 patients, four had an absent glabellar reflex (score = 0), while the others had a markedly impaired reflex (score = 1). The corneal reflex was present in eight COVID-19 patients out of 11, and reduced in the remaining three. Non-COVID patients showed normal glabellar and corneal reflexes.Our findings provide  the neurophysiological and clinical evidence of SARS-Cov-2-related brainstem involvement in  * Alberto Priori  alberto.priori@unimi.it1 Clinical Neurology Unit, University of Milan, Milan, Italy2 Pathology and Medical Genetics Unit, University of Milan, Milan, Italy3 Intensive Care, Anesthesia and Resuscitation Unit, University of Milan, Milan, Italy4 ASST Santi Paolo and Carlo and Department of Health Sciences, University of Milan, Milan, Italy5 “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy6 Divisione di Neurologia I, Ospedale Universitario San Paolo, Via Antonio di Rudinì 8, 20142 Milan, Italy3599Journal of Neurology (2021) 268:3598–3600 1 3severe Covid-19 patients, especially at the medullary level. Our results agree with recent histopathological data show-ing a preferential involvement of the lower medulla, with-out any evidence of intracerebral bleeding or small-vessels thromboses, and confirming the intraneuronal localization of SARS-Cov-2 nucleoprotein [13].Although SARS-Cov-2-related Guillain-Barré syn-drome has been recently reported, mainly of axonal type and with an early involvement of the cranial nerves [16], normal RI latencies and amplitudes rule out this diagnosis in our patients.Fig. 1  Neurophysiology a The blink reflex (BR) in two representa-tive cases: eight superimposed raw traces, recorded in a COVID-19 patient (top) and in in a non-COVID-19 patient (bottom); note that, in the COVID-19 case, ipsilateral RII responses had markedly pro-longed latencies and contralateral RII were absent. b Histograms showing RI and RII (ipsilateral and contralateral responses) onset latency (top), amplitudes (middle) and duration (bottom), comparing age- and sex-matched healthy controls (HC, black), non-COVID ICU patients (NC-19, gray) and COVID-19 patients (C-19, dark gray). Note that, whereas RI latencies did not differ among groups, both RII latencies and duration (ipsilateral and contralateral) were significantly prolonged in COVID-19 patients. The bulbar RII amplitude was significantly decreased in COVID-19 group. Histograms are mean values, error bars are standard deviation. In the neurophysiological assessment, parametric analyses were used, as all datasets passed the Shapiro–Wilk test for normality (p > 0.05). A one-way repeated meas-ures ANOVA was used to compare neurophysiological data among groups (healthy volunteers, COVID-19 and other ICU patients) and the Bonferroni method served as post-hoc comparison (statistical sig-nificance set at p < 0.017; ***p < 0.0001; **p < 0.01)Table 1  Data concerning the medullary RII component of the blink reflex (BR)Ipsilateral R2 Contralateral R2Latency (ms) Amplitude (µV) Duration (ms) Latency (ms) Amplitude (µV) Duration (ms)Covid-19 40.1 ± 7.0 261.6 ± 235 45.9 ± 8.7 41.2 ± 7.5 172.6 ± 171.2 48.3 ± 9.1Healthy Controls 33.3 ± 2.7 638.7 ± 316 32.2 ± 4.2 35.9 ± 4.1 443.0 ± 239 37.0 ± 6.3Non Covid-19 ICU patients 32.2 ± 1.0 597.2 ± 192 35.7 ± 6.7 34.7 ± 1.3 421.5 ± 131 39.4 ± 5.53600 Journal of Neurology (2021) 268:3598–36001 3From a clinical perspective, the glabellar reflex was impaired more than the corneal. The two reflexes rely on slightly different circuits, targeting the pontine sensory nucleus and the nucleus of the spinal tract of the trigemi-nal nerve, then projecting to the facial nucleus and reticular formation (RF). However, the amount of fibers reaching the interneuronal network of the medullary reticular formation is lower for the corneal than for the glabellar reflex, probably accounting for the differences we observed [9].Overall, our results suggest that the brainstem involve-ment likely contributes to respiratory failure in COVID-19 patients as postulated by Manganelli [12] and Baig [3].Yet,  BR assesses a ponto-medullary circuitry partly involving the reticular formation [9] close to the respiratory nuclei. The reticular formation itself modulates the activity of the respiratory centers [10].Author contributions Concept and design: TB, and AP. Acquisition and statistical analysis: TB, LC, SC, MF. Interpretation of the data: TB, GB, LC, SC, MF, DC and AP. Drafting of the manuscript: TB and AP. Critical revision of the manuscript for important intellectual content: GB, DC and AP.Funding The Authors declare no funding source.Data availability The corresponding author has full access to data and has the right to publish such data. Data will be available upon reason-able request to the corresponding author.Compliance with ethical standards Conflicts of interest None of the authors have no conflict of interest to report.Ethical approval The study was approved by the institutional review board and the ethics committee at “Azienda Socio-Sanitaria Territoriale Santi Paolo e Carlo”. The study has been performed in accordance with the ethical standards laid down in the Declaration of Helsinki.Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.References 1. 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Brainstem clinical and neurophysiological involvement in COVID-19

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Brainstem clinical and neurophysiological involvement in COVID-19

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