Neurological manifestations of long-COVID syndrome: a narrative review

Abstract

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for 'long-COVID' diagnosis. Nevertheless, 'long-COVID' is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of 'long-COVID' encompass fatigue; 'brain fog'; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of 'long-COVID', neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological 'long-COVID' sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological 'long-COVID' sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for 'long-COVID' are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological 'long-COVID' symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological 'long-COVID' sequelae.

Keywords: COVID-19; SARS-CoV-2; long-COVID; long-haul; neurological manifestations; post-acute sequelae of SARS-CoV-2.

Figure 1.

Potential pathophysiological mechanisms implicated in the manifestation of acute and ‘long-COVID’ manifestations in the central nervous system (CNS). (a) In acute COVID-19, SARS-CoV-2 cell entry within the CNS is facilitated by hematogenous or direct transsynaptic pathways via engagement of the angiotensin-converting enzyme 2 (ACE2) receptor, which is located on the surface of diverse cell types, including neurons, endothelial cells, and smooth muscle cells of cerebral blood vessels. SARS-CoV-2-induced cytokine storm may cause disruption of the tight junctions at the endothelial lining of the blood–brain barrier, which leads to increased blood–brain barrier permeability and allows the transmigration of virus-infected leukocytes into the CNS. In addition, the cytokine release precipitates platelet activation and adhesion, which causes further endothelial impairment and has been linked to the increased thrombotic risk noted in acute COVID-19. Once cytokines and leukocytes have crossed the blood–brain barrier, they activate microglial cells, which in turn trigger apoptotic cascades and demyelination. (b) In ‘long-COVID’, chronic inflammatory and secondary degenerative processes are thought to prevail in propagating neurological ‘long-term’ sequelae. In ‘ACE2-rich’ brain areas, including areas of the somatosensory cortex, rectal/orbital gyrus, temporal lobe, hypothalamus/thalamus, brainstem, and cerebellum, F-FDG brain PET studies in ‘long-COVID’ patients have revealed prominent hypometabolism. The reduced glucose metabolism observed in these areas may be further explained by oxidative stress processes, mitochondrial dysfunction, or impaired cerebral autoregulation, which are secondary to SARS-CoV-2 infection.

Figure 2.

Proposed diagnostic and therapeutic algorithm for patients presenting with neurological symptoms compatible with ‘long-COVID’. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome.