With interest we read the article by [1] about a retrospective study of 220 patients with sudden unexpected death in epilepsy (SUDEP) from the North American SUDEP Registry (NASR) undergoing autopsy [1].It was concluded that intensive collaboration between death investigators and epilepsy communities is warranted and will help to advance the understanding of SUDEP [1]. We have the following comments and concerns.

The main shortcoming of the study is that no information about findings of brain autopsy were provided. In most of the autopsies the brain is not systematically investigated [2] Thus, ischemic stroke, intracerebral bleeding, subarachnoid bleeding, subdural hematoma, or sinus venous thrombosis may be missed as causes of SUDEP resulting in false classification. We should know in how many of the included patients the skull was opened and the brain was systematically investigated. 

Epilepsy patients dying unexpectedly may not only have a single disorder, such as epilepsy, but multiple diseases. Among these diseases, some may be hereditary. A prerequisite to diagnose genetic disorders, however, is to take a thorough family history. However, nothing is reported about the family history of the included patients, neither with regard to genetic epilepsy nor with regard to other hereditary diseases. Thus, it is crucial for such a retrospective approach to gain as much information as possible about first-degree family members of the included patients. 

A further shortcoming of the study is that several brain-heart connections [3] resulting in secondary affection of inner organs, such as the heart or the lungs, during seizures, were not considered. One of these secondary compromises during a seizure is Takotsubo-syndrome (TTS) [4].TTS is usually a transient, acute systolic dysfunction of the left ventricle, characterised by hypokinesia, dyskinesia, or akinesia of certain portions of the left ventricular myocardium [4]. Four types of TTS are delineated, the classical (apical) type, the mid-ventricular type, the basal type, and the global type [5]. Though TTS resolves spontaneously in the majority of the cases, complications and fatalities occur, particularly among those developing global TTS. Autopsy of the heart in SUDEP patients dying from TTS may be non-informative and thus TTS may go unrecognised as an explanation of SUDEP. Since epilepsy is the second most frequent cerebral cause of TTS [6] it can be expected that it is responsible for death at least in some of the 220 cases.

Another secondary condition of the brain-inner organ connection not considered in the study is neurogenic pulmonary oedema (NPE) [7]. NPE is characterised by acute respiratory distress triggered by acute, severe cerebral compromise. NPE is diagnosed in the presence of pink, frothy sputum, pulmonary edema, bilateral opacities on X-ray, PaO2:PiO2 <200mm Hg, acute CNS compromise with increased intra-cranial pressure, rapid resolution within 48-72h, and the absence of alternative causes of respiratory distress [7]. One of the most frequent causes of NPE is epilepsy. 

Overall, to further unravel the enigmas of SUDEP, we suggest investigating also the brain on autopsy, to take a thorough family history, and to consider TTS and NPE as secondary complications of seizures and thus causes of SUDEP. 

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Universidad Federal de São Paulo/Escola Paulist de Medicina (UNIFESP/EPM). São Paulo, Brasil.

1. Verducci, C., Friedman, D., Donner, E. J., Laze, J., & Devinsky, O. (2020). SUDEP classification: Discordances between forensic investigators and epileptologists. Epilepsia.

2. Thom, M., Michalak, Z., Wright, G., Dawson, T., Hilton, D., Joshi, A., ... & Sisodiya, S. M. (2016). Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings. Neuropathology and applied neurobiology, 42(5), 463-476.

3. Finsterer, J., & Wahbi, K. (2016). Cardiac disease in brain-heart disorders. Acta cardiologica, 71(4), 389-394.

4. Pal, S., Broker, M., Wagner, H., Aronow, W. S., & Frishman, W. H. (2020). Stress (Takotsubo) Cardiomyopathy; A Review of its Pathophysiology, Manifestations, and Factors that Affect Prognosis. Cardiology in Review.

5. Aizawa, K., & Suzuki, T. (2013). Takotsubo cardiomyopathy: Japanese perspective. Heart Failure Clinics, 9(2), 243-247.

6. Finsterer, J., & Wahbi, K. (2014). CNS disease triggering Takotsubo stress cardiomyopathy. International journal of cardiology, 177(2), 322-329.

7. Finsterer, J. (2019). Neurological perspectives of neurogenic pulmonary edema. European neurology, 81(1-2), 94-102.