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Table 1Central and Peripheral neurological/neuromuscular disorders associated with SARS-CoV-2
*Miller Fisher syndrome
**examples include acute demyelinating encephalomyelitis, acute necrotizing encephalopathy, Bickerstaff’s encephalitis, limbic encephalitis
Serum biomarkers for signs of brain injury, axonal degradation or blood brain barrier integrity such as Glial Fibrillary Acidic Protein (GFAP) and neurofilament light (Nfl) have been shown to be elevated in severe cases (9Kanberg N. Ashton N.J. Andersson L.M. et al.Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19.), but can increase with age as well. In addition to GFAP and Nfl, other markers such as total Tau ubiquitin carboxyl-terminal esterase L1 (UCH-L1) have also shown to correlate with severity and higher mortality (10De Lorenzo R. Lore N.I. Finardi A. et al.Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients.). Other COVID-19 specific biomarkers such as cytokines and chemokines is beyond the scope of this chapter, and there are not enough large population studies to show consistent correlation of these markers with neurological manifestations. Clinical and routine use of specific serum biomarkers therefore is unclear, and largely for research purposes at best.Advanced neuroimaging studies such as CT, MRI, and PET scans may be helpful in the early stages with common findings such as bilateral anterior and posterior white matter hyperintensities on MRI or hypodensities on CT (11Egbert A.R. Cankurtaran S. Karpiak S. Brain abnormalities in COVID-19 acute/subacute phase: a rapid systematic review.), but it’s use in chronic PASC stages is not as clearly defined and can also be limited in interpretation if there is lack of premorbid imaging data. Furthermore, correlating neuroimaging findings with PASC related neurologic sequelae can be difficult when trying to distinguish between findings directly caused by SARS-CoV-2 versus neuropathology findings exacerbated by SARS-CoV-2 (6Central nervous system outcomes of COVID-19.). Dynamic brain changes such as hypoperfusion, white matter and gray matter changes, subcortical nuclei volume differences and cortical thickness changes have been shown even in patients without neurological manifestations, and though some patients with mild acute infection may have shown some recovery to baseline 10 months later, many patients with severe infection and oftentimes the elderly older than 60 years did not recover to baseline (12Tian T, Wu J, Chen T, et al. Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations. JCI Insight. 2022;7(4):e155827. Published 2022 Feb 22.
). In the next sections, we will review some specific examples as it pertains to the CNS, PNS, and neuromuscular systems.CNS complicationsOne study showed the most common new onset central neurological sequelae were encephalopathies (51%), seizure (12%), stroke (14%), and hypoxic/ischemic injury (11%) (13Frontera JA, Sabadia S, Lalchan R, et al. A prospective study of neurologic disorders in hospitalized patients with COVID-19 in New York City. Neurology. 2021;96:e575. e86.
). These complications can often be associated with poorer prognosis. For example, patients with stroke and COVID-19 have a higher mortality of 39% when compared to patients with stroke without COVID-19 (14Trejo-Gabriel-Galán J.M. Stroke as a complication and prognostic factor of COVID-19.), particularly in the acute phase of illness.Encephalopathies with alteration of consciousness and delirium can result from systemic inflammation, sepsis and cytokine storm. Viral encephalitis can result from direct neuronal damage and immune mediated elevated interleukin activity due to the high binding affinity of SARS-CoV-2 to ACE 2 receptors. If not acutely reversed or sub-acutely identified, progression into more severe irreversible damage can occur and lead to worse prognosis and lower survival rate.
For cerebrovascular disease associated with COVID-19, though microbleeds can occur from disruption of blood brain barrier, ischemic infarcts are the most common (15Hernández-Fernández F, Sandoval Valencia H, Barbella-Aponte RA, Collado-Jiménez R, Ayo-Martín Ó, Barrena C, Molina-Nuevo JD, García-García J, Lozano-Setién E, Alcahut-Rodriguez C, Martínez-Martín Á, Sánchez-López A, Segura T. Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description. Brain. 2020 Oct 1;143(10):3089-3103.
, 16Fraiman P. Godeiro Junior C. Moro E. Cavallieri F. Zedde M. COVID-19 and cerebrovascular diseases: a systematic review and perspectives for stroke management.). Pathophysiology is still largely unknown, but it has been suggested to be related to hypercoagulability due to: 1) viral neuroinvasion can secondarily induce coagulopathy through endothelial inflammation, 2) destabilization of pre-existing atheroma plaques, or 3) formation of clots from myocardial damage (16Fraiman P. Godeiro Junior C. Moro E. Cavallieri F. Zedde M. COVID-19 and cerebrovascular diseases: a systematic review and perspectives for stroke management.). Elderly patients with vascular co-morbidities are at highest risk, and typically results in multi-vessel or large territory infarcts with associated severe functional impairments often requiring intensive comprehensive neurorehabilitation.Seizure disorders associated with COVID-19 are increasing in incidence, either as a result of lowered seizure threshold or as a complication of severe hypoxic brain injury from septic encephalopathy and respiratory failure (2Camargo-Martínez W. Lozada-Martínez I. Escobar-Collazos A. Navarro-Coronado A. Moscote-Salazar L. Pacheco-Hernández A. Janjua T. Bosque-Varela P. Post-COVID 19 neurological syndrome: Implications for sequelae's treatment.). One proposal of new onset seizures, or de novo status epilepticus, is due to the activation of neuroinflammatory cascade causing more neuronal depolarization and metabolic derangements that can induce status (17Seizures associated with coronavirus infections.). Seizures can be associated with worse functional outcomes and impact rehabilitation potential, so it is paramount to take measures in preventing hypoxia and controlling electrolyte imbalance acutely, optimizing pulmonary hygiene, starting respiratory exercises and progressing to aerobic exercises to improve pulmonary function to help reduce seizure risk.There have also been reports of multiple sclerosis and anti-myelin oligodendrocyte glycoprotein antibody-associated disease associated with COVID-19, but these are rare (18Palao M. Fernández‐Díaz E. Gracia‐Gil J. Romero‐Sánchez C.M. Díaz‐Maroto I. Segura T. Multiple sclerosis following SARS‐CoV‐2 infection.,19Pinto AA, Carroll LS, Nar V, Varatharaj A, Galea I. CNS inflammatory vasculopathy with antimyelin oligodendrocyte glycoprotein antibodies in COVID‐19.
). Cerebellar ataxia and myoclonus have been described after resolution of respiratory symptoms post COVID-19 (20ábano‐Suárez P. Bermejo‐Guerrero L. Méndez‐Guerrero A. Parra‐Serrano J. Toledo‐Alfocea D. Sánchez‐Tejerina D. et al.Generalized myoclonus in COVID‐19.). Patients with pre-morbid Parkinson’s Disease (PD) may also experience exacerbations due to COVID-19 infection, but there have also been several case and observational studies suggesting an association with SARS-CoV-2 induced PD in younger patients without family or personal history of PD (21Méndez‐Guerrero A. Laespada‐García M.I. Gómez‐Grande A. Ruiz‐Ortiz M. Blanco‐Palmero V.A. Azcarate‐Diaz F.J. et al.Acute hypokinetic‐rigid syndrome following SARS‐CoV‐2 infection.,22Bouali-Benazzouz R. Benazzouz A. Covid-19 Infection and Parkinsonism: Is There a Link?.). Viral induced parkinsonism is not new, as it has been demonstrated with other viruses (HIV, West Nile, herpes virus) and thought mainly from indirectly causing neurodegeneration of substantia nigra through inflammatory mediators. However, a definitive correlation between SARS-CoV-2 and PD has yet to be established and larger controlled studies are still needed.Headache is the second most common neurologic symptom post COVID-19. Prevalence of post-COVID headaches does not seem to vary between hospitalized and non-hospitalized patients but does decrease over time (23Fernández-de-Las-Peñas C. Navarro-Santana M. Gómez-Mayordomo V. Cuadrado M.L. García-Azorín D. Arendt-Nielsen L. Plaza-Manzano G. Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature.). Cytokine storm and pro-inflammatory state is thought to contribute to post COVID-19 headaches, with migraine and tension type phenotypes being more common. Typical headache features include localizing to bifrontal and temporal regions, throbbing nature, and associations with photophobia and phonophobia. Further discussion of post-COVID headaches can be found later in this chapter.Other common symptoms such as smell and taste disturbances may also persist beyond acute COVID-19 infection, though recent variants (i.e. delta and omicron) have been associated with decreased frequency of these symptoms as compared to the alpha strain. Pathophysiology is presumed to be related to damage to olfactory centers of the brain, olfactory receptor neurons, cytokine storm, nasal obstruction and rhinorrhea (24Khani E. Khiali S. Beheshtirouy S. Entezari-Maleki T. Potential pharmacologic treatments for COVID-19 smell and taste loss: A comprehensive review.). Obtaining an MRI with focus on olfactory bulbs may show thinning and less hyperintensity, however it can also be normal in patients with anosmia. For gustatory disturbances, there are also a very high number of ACE 2 receptors in salivary glands and taste buds (25Doyle M.E. Appleton A. Liu Q.R. Yao Q. Mazucanti C.H. Egan J.M. Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).), making them easy viral targets.Cognitive impairment post COVID-19 consistent with dysexecutive function and more commonly known as “brain fog.” In a large retrospective cohort study on neurologic and psychiatric risk trajectories after SARS-CoV-2 infection, it was found that risk of cognitive deficits were increased at a 2-year follow-up period up to 36% (26Taquet M. Sillett R. Zhu L. et al.Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients.). Symptoms are primarily impaired short term memory, decreased attention and concentration, word finding difficulties and poor executive function. Can also be associated with neuropsychiatric disorders such as depression, anxiety, post-traumatic stress disorder and insomnia. More information on this topic can be found in Chapter 5.PNS complicationsPNS involvement can manifest in various ways such as peripheral neuropathy, non-specific paresthesias, brachial plexopathies, isolated peripheral facial paralysis, sensorineuronal hearing loss, and compression neuropathies ().GBS is a known, though rare, acute complication of COVID-19. In a systematic review, median onset of GBS post COVID-19 was 10 days, and typically the demyelinating form (27De Sanctis P. Doneddu P.E. Viganò L. Selmi C. Nobile‐Orazio E. Guillain‐Barré syndrome associated with SARS‐CoV‐2 infection.). Independent from COVID-19, the ascending paralysis and neuropathy that can occur in more severe cases of GBS can frequently involve the respiratory system. With SARS-CoV-2 being a primarily respiratory illness, concurrent development of GBS because of the pro-inflammatory cascade activation may further compound an already weakened pulmonary function and lead to more fatality. A subvariant, Miller Fisher syndrome, has been identified in a case study (28Gutiérrez-Ortiz C. Méndez-Guerrero A. Rodrigo-Rey S. San Pedro-Murillo E. Bermejo-Guerrero L. Gordo-Mañas R. de Aragón-Gómez F. Benito-León J. Miller Fisher syndrome and polyneuritis cranialis in COVID-19.). After acute infection resolution, long term neurological sequelae may persist and neurorehabilitation including admission to an inpatient rehabilitation unit may be indicated once pulmonary status is stabilized.Cranial neuropathies such as trigeminal neuropathy, abducens nerve palsy have been reported (8Sharifian-Dorche M. Huot P. Osherov M. Wen D. Saveriano A. Giacomini P.S. Antel J.P. Mowla A. Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic.) Compression neuropathies can also occur, particularly due to supine positioning from prolonged bedrest. Order from most to least common peripheral nerve compression are ulnar, radial, sciatic, brachial plexus, and median nerves (). Frequent repositioning and range of motion to avoid prolonged pressure points along elbow and shoulder is important during acute phase of illness.Implications of autonomic nervous system involvement can manifest as dysautonomia or even postural orthostatic tachycardia syndrome, which will be discussed further in Chapter 7.
Neuromuscular complicationsMuscle injury and myalgia is a common neurological sequelae after COVID-19, and in one systematic review, found to be the most common symptom (29Pinzon R.T. Wijaya V.O. Buana R.B. Al Jody A. Nunsio P.N. Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis.). Generalized non-specific muscle weakness from prolonged hospital course from severe cases have been described, but there have also been cases where weakness has preceded acute infection as a prodromal symptom (29Pinzon R.T. Wijaya V.O. Buana R.B. Al Jody A. Nunsio P.N. Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis.). Muscle soreness or myalgias may result from direct injury to muscle secondary to viral inflammation, which may correlate with elevated levels of creatinine kinase. ICU acquired weakness can result from myopathic causes such as critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of both. A high clinical suspicion and knowledge of risk factors for CIM/CIP (meta-analysis data from Yang et al (30Yang T. Li Z. Jiang L. Wang Y. Xi X. Risk factors for intensive care unit-acquired weakness: A systematic review and meta-analysis.) is summarized in table 2) should prompt an electrodiagnostic workup to better guide rehabilitation interventions.Table 2Risk factors for ICU acquired weakness
SARS-CoV-2 can also be associated with neuromuscular junction disorders and autoimmune induced myositis. There have been several case studies describing systemic myasthenia gravis occurring 5-7 days after acute COVID-19 (31Restivo D.A. Centonze D. Alesina A. Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 Infection., 32Assini A. Gandoglia I. Damato V. Rikani K. Evoli A. Del Sette M. Myasthenia gravis associated with anti-MuSK antibodies developed after SARS-CoV-2 infection.). Like other infections inducing autoimmune neurologic conditions, COVID-19 can potentially trigger this by similar mechanisms. In the case of myasthenia gravis, antibodies against SARS-CoV-2 can potentially interact with acetylcholine receptor subunits or have similarities to components of the neuromuscular junction (31Restivo D.A. Centonze D. Alesina A. Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 Infection.). Other autoimmune conditions reported include dermatomyositis, which may also induce myositis through activation of the antiviral cytokine type I interferon ().HeadacheA complete history including identifying headache phenotype, triggers, associated symptoms, and premorbid headache history will be important. A comprehensive neurological and musculoskeletal exam that encompasses cranial nerves, sensorimotor evaluation, reflexes, proprioception, and gait assessment can be helpful in identifying any findings that may indicate a more focal pathology requiring imaging workup. It is important to note that premorbid headaches can potentially be exacerbated by COVID-19 infection; however, new onset migraine headaches with auras, positional headaches should prompt more workup and advanced neuroimaging (CT, MRI) should be considered. Because post-COVID headaches can correlate with neuropsychiatric conditions, optimization of other factors that can worsen headaches such as sleep disturbances, depression, anxiety, and post-traumatic stress disorder will also be important.
A consensus for pharmacologic management does not exist specifically for post-COVID headaches but given that the migraine phenotype tends to be more common (35Al-Hashel J.Y. Abokalawa F. Alenzi M. Alroughani R. Ahmed S.F. Coronavirus disease-19 and headache; impact on pre-existing and characteristics of de novo: a cross-sectional study.), American Academy of Neurology guidelines for episodic migraine prevention can be followed for management. For example, there is strong Level A evidence for use of antiepileptics (sodium valproate, topiramate, divalproex sodium) and beta-blockers (metoprolol, propranolol, timolol) for preventative treatment. Triptans can be effective abortive agents in general, however frovatriptan has strong Level A evidence for menstrual associated migraines prophylaxis. Magnesium oxide and riboflavin are also effective for migraine prevention.Smell and taste disturbancesSmell disturbances (parosmia) or smell loss (anosmia) can persist beyond the acute infectious period and be a common PASC symptom. There are no current standardized treatment recommendations for smell dysfunction, however, research trials are ongoing. Interventions such as oral corticosteroids combined with nasal irrigation, palmitoylethanolamide, and luteolin have been studied but uncertain conclusive outcomes given small study size (36O'Byrne L, Webster KE, MacKeith S, Philpott C, Hopkins C, Burton MJ. Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction. Cochrane Database Syst Rev. 2022;9(9):CD013876. Published 2022 Sep 5.
). Many other agents such as intranasal insulin, phosphodiesterase inhibitors, intranasal vitamin A and zinc have been studied, but all yielded mostly weak, moderate evidence of efficacy or no benefit or harm identified (37Khani E. Khiali S. Beheshtirouy S. Entezari-Maleki T. Potential pharmacologic treatments for COVID-19 smell and taste loss: A comprehensive review.). Olfactory training with four categories of scents (citrus, flower, spice, herbaceous) done at least twice daily, 10 seconds each nostril, for at least 12 weeks has been the most well studied and effective therapeutic intervention for post-viral anosmia (38Hummel T. Rissom K. Reden J. Hähner A. Weidenbecher M. Hüttenbrink K.B. Effects of olfactory training in patients with olfactory loss.). Alpha lipoic acid, often a over the counter antioxidant and insulin-memetic supplement, can be prescribed at 600mg daily for smell dysfunction associated with viral infections (39Hummel T. Heilmann S. Hüttenbriuk K.B. Lipoic acid in the treatment of smell dysfunction following viral infection of the upper respiratory tract.), and it is in this author’s experience that it has been effective when paired with smell therapy in treating post-COVID anosmia, but it can take at least 3 months of medication administration before effect and further research is still needed to establish more definitive efficacy. However, recently some providers have noticed an increasing number of case reports evidence of neural epidermal growth factor-like 1 (NELL1) associated glomerulonephritis linked to alpha lipoic acid administration (40Spain R.I. Andeen N.K. Gibson P.C. et al.Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.), with acute presentation of proteinuria and acute nephrotic syndrome that resolved with medication cessation. Though still relatively rare and more studies are needed for formal guidelines to be established, consideration of checking for proteinuria and hypoalbuminemia may be indicated should a patient develop acute onset edema.Taste disturbances or dysgeusia can also occur and be challenging to treat. In a case series, stellate ganglion block has been shown to reduce PASC symptoms including dysgeusia, suggesting dysautonomia may play a role (41Stellate ganglion block reduces symptoms of Long COVID: A case series.). Similar to olfactory dysfunction, data about specific treatment options remain limited.Summary and future directionsA wide variety of neurological and neuromuscular manifestations can occur after COVID-19, and certain complications can be associated worse prognosis, lower functional outcome and higher mortality. Early recognition as well as continued surveillance for emergence of new neurological symptoms or persistence of symptoms beyond acute infection as in the case of PASC can be challenging given general lack of consensus in diagnostic and therapeutic interventions. Other medical co-morbidities and concurrent neuropsychiatric conditions can further confound the clinical picture, so a multidisciplinary approach would be beneficial in providing a comprehensive and individualized care plan.
More research is needed for better understanding of neuropathophysiology to possibly elucidate potential drug targets. Larger scale research studies are still needed to demonstrate efficacy for certain interventions (i.e. smell and taste dysfunction). Though there may be evidence of atrophy to certain parts of the brain, changes in cerebral blood flow and cortical thickness associated with post-COVID 19 neurological changes (42Tian T, Wu J, Chen T, et al. Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations. JCI Insight. 2022;7(4):e155827. Published 2022 Feb 22.
), correlation of neurological sequelae and risk of neurogenerative disorders is speculation at best; however, elderly patients with premorbid vascular risk factors may be at an increased risk of more long-term cognitive impairment.
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