Unusual Presentation of COVID-19 Headache and Its Possible Pathomechanism.

Headache was the most common neurological symptom during the H1N1 pandemic in 2009 and the most recrudescing symptom of human coronavirus (hCoV) in 2016. Even in this prevailing global coronavirus disease 2019 (COVID-19) pandemic, the main neurological symptom is found to be a headache. Headache phenotypes identified with COVID-19 are largely migraine, tension-type headache, or cough headache located in the frontotemporal or occipital region with wavering intensity and essentially of acute onset. We present two cases of unusual headache phenotypes with COVID-19 infection and attempt to shed light on their pathomechanism. Trigeminal autonomic cephalgia may be a possibility in our case, triggered by the virus itself, either directly or through an indirect path elaborated well in the pathomechanism segment. Severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) located in the peripheral nerve and intracranial vascular endothelium, sensitizing the trigeminovascular system by further interacting with higher cortical pain centers via the thalamic and hypothalamic nuclei, producing pain. CSF analysis along with opening pressure measurement in Case 2 may portray a comprehensive understanding of our patient's headache. Coupling with the dorsal pons and trigeminal nucleus caudalis (TNC), the hypothalamus could be the supreme generator for an attack. Hypothalamic perturbance could be a possible phenomenon for abnormal headache experiences and requires further validation. The possible COVID-19 pain pathway pathomechanism engaging interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) alpha aided with a cortical spreading depression disturbing the hypothalamus is also described in this study. Undoubtedly, this pandemic could prove to be a guiding tool for mankind, for a comprehensive understanding of the enigmatic concepts of headaches.