COVID-19 Infection: Impaired Olfaction, Movement Disorders, Encephalopathy, and Neuropsychiatric Manifestations

Introduction

Beyond the possibility of life-threatening consequences of pulmonary invasion and respiratory failure, COVID-19 infection imparts a wide range of neurological and neuropsychiatric consequences for many infected persons. This chapter reviews several of the problems that arise from central nervous system (CNS) involvement in patients with COVID-19. The emerging clinical experience and its medical literature have revealed several common and a few rare neurological outcomes caused by the virus, whose mode of entry into the CNS is still a matter of contention. Several possible pathways—hematogenous spread with direct invasion through blood-brain barrier, retrograde dissemination via trigeminal nerve, and passage through the cribriform plate into the olfactory bulb or cerebrospinal fluid—have been proposed. Possibly, each of them can be an explanation.

One of the most prominent neurological consequences of COVID-19, a decline in sense of smell, can be the sole manifestation of infection or can be the prelude to more serious systemic or CNS involvement. Other neurological features, like the few reported instances of movement disorders, seem to be relatively rare occurrences. An intensive neuropathological analysis of the effects of COVID-19 on the brain is still a work in progress throughout the medical community. In one of the few available autopsy reports from a well-characterized COVID-19 case, widespread CNS damage was found, with extensive white matter infarcts and hemorrhagic changes. No neuronal necrosis was found in cortical or subcortical gray matter (including the olfactory bulb). We are also limited in our understanding of what’s ahead in upcoming months and years for those who sustained COVID-19 infection (including those with relatively mild pulmonary symptoms). Fortunately, several programs including ours will be following long-term neurological and neuropsychiatric outcomes for persons who have encountered and survived COVID-19. There is considerable evidence that neurological symptomatology may be among the persisting health problems long after the course of the initial presentation of the viral illness. New neurological manifestations are also being recognized as COVID-19 cases undergo increased scrutiny, For example, one report among Northern Italian patients found 16% experienced vertigo (and at approximately 60 days afterwards, these symptoms persisted for 6.7% of the 143 patients evaluated).

Although up to date at the time of publication, this chapter should be viewed as a work in progress whose further perspectives will be enhanced by neuropathological study of human cases, discovery of relevant biomarkers, and possibly, the development of animal models. Topics to be considered including smell and taste impairments, movement disorders, encephalopathy, and neuropsychiatric manifestations.

Disorders of Olfaction and Taste From COVID-19 Infection

Anosmia, hyposmia, ageusia, and hypogeusia have been well documented in the recent medical literature describing the COVID-19. Though mentioned only rarely in the Chinese literature during the first weeks of the pandemic, subsequent studies published throughout Europe and the United States have emphasized its role as an early symptom of illness. In addition, these unique sensory deficits constitute a window into the pathophysiology of COVID-19 infection as it affects the CNS.

Between January and February 2020, Mao et al. retrospectively studied 214 hospitalized COVID-19-positive patients in Wuhan, China. Of these patients, 36.4% had neurologic manifestations of this disease; 5.1% reported olfactory dysfunction (OD) and 5.6% reported gustatory dysfunction (GD). Within a few weeks, further reporting from emerging cohorts of affected patients made it clear that this initial report likely underestimated the prevalence of OD and GD as neurological symptoms of COVID-19.

In a large multicenter cohort of 2013 COVID-19-positive patients in Europe, 87% reported impaired sense of smell and 56% reported impaired sense of taste. Similarly, a group in Italy noted that 74.2% of COVID-19-positive patients reported impaired sense of smell, taste, or both. This symptomatology in studies reporting relatively large populations of COVID-19-infected patients are outlined in Table 10.1 .

Interestingly, Lechien et al. noted that among those with subjective reports of either anosmia or hyposmia, many did not meet objective criteria for OD. In fact, 38% of those who reported complete anosmia were normosmic upon testing with a validated and highly reproducible bedside test, the Sniffin' Sticks. Further, Lechien et al. found no significant correlation between either subjective nasal obstruction or rhinorrhea with either objective hyposmia or anosmia. On the other hand, Vaira et al. found that 30% of patients whose history included no subjective report of OD nonetheless proved, upon Connecticut Chemosensory Clinical Research Center testing, to be hyposmic. These conflicting conclusions highlight the disparities that can occur with subjective olfaction reporting and emphasize the need for objective testing for OD.

Gustatory function can be evaluated objectively by patient- or operator-prepared solutions (salty, sweet, sour, and bitter). Patients are asked to rate quality of taste perception from 0 (complete ageusia) to 10 (normal taste perception) for each solution. Similar to olfactory testing, this validated tool can help clinicians distinguish between subjective and objective GD, and can differentiate OD-induced taste dysfunction from true GD.

Many of the common pathogens causing upper respiratory infections are known to impair the sense of smell in infected patients. OD in these cases is often secondary to an inflammatory process within the nasal mucosa that ultimately manifests as rhinitis and sometimes, nasal obstruction. Several groups have reported a lack of relationship between symptoms of nasal inflammation and objective OD, indicating that COVID-19-induced OD might require an alternate explanation.

CNS viral invasion has been described in the literature covering other viruses including parainfluenza virus, influenza A virus, and adenovirus, as well as other coronavirus strains, including Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). In fact, a mouse model of SARS demonstrated the virus’ transneuronal pathway through the olfactory bulb. The mechanism of OD in COVID-19 may be similar. There is evidence that the virus may travel trans-synaptically in a retrograde direction across the cribriform plate of the ethmoid bone into the neuroepithelium and olfactory bulb.

Viral invasion into the olfactory bulb may induce reactive astrogliosis, activation of microglia, and ultimately, direct damage to the primary organs of olfaction, olfactory receptors. In accordance with this theory, a similar path may be taken by the virus to injure gustatory receptors in GD. Neurological damage caused by the virus may explain one study’s findings that 20% of COVID-19 patients with anosmia did not recover within 2-months following the onset of OD.

The “neurotropic” hypothesis does not involve the angiotensin-converting enzyme-2 (ACE-2) receptor, the site known to interact with the virus and facilitate its fusion with the host cell. Therefore, an alternate hypothesis has been posed to explain the relationship between GD and COVID-19. ACE-2 receptors are prevalent in the oral cavity, with highest density on the tongue. Viral entry into cells via the ACE-2 receptor and subsequent inflammation may disrupt perception of taste signals as well as the renewal of taste buds.

A second hypothesis proposes that the virus enters the CNS via a hematogenous route. According to this mechanism, CNS manifestations arise from direct viral entry into the CNS because of an abnormally permeable blood-brain barrier. This hypothesis, however, does not readily explain anosmia or ageusia.

Anosmia and ageusia are intimately linked with respect to the processing of their respective sensory modalities in the CNS. A report by Speth et al. determined that the severity of OD was closely correlated with the presence of GD. The sense of smell and taste share regions in the brain that are dedicated to identifying, interpreting, and integrating these senses. Viral-induced inflammatory damage to the frontobasal region of the brain may partially explain OD and GD, as this region lies close to the olfactory bulb and expresses ACE-2 receptors.

Most patients with COVID-19-induced OD and GD recover within 3 weeks, with a median recovery time of 1 week. However, Li et al. found that in some cases, dysosmia may linger for 95 days or longer. In a single-center review of 143 COVID-19-infected patients in Northern Italy, 43% experienced anosmia and 13% persisted in this symptomatology at a mean of 60 days after the acute infection. Recovery from anosmia may reflect viral damage to basal cells, as invasion of these precursor cells can halt their progression to olfactory epithelium. Under normal circumstances, the recovery cycle for olfactory basal cells takes between 28 and 30 days. Therefore, reports of shorter “recovery” times may reflect partial return of the sense of smell rather than a complete objective recovery from anosmia. Regarding dysgeusia, a single-center study of 143 Northern Italian patients found that 48% were affected during the acute infection; the persistence of impaired taste at approximately 60 days later was 7%.

Conflicting data have been reported about GD. The rate of turnover for taste receptors cells is only 7–10 days. However, subjective GD may be unreliable as taste perception is intimately tied to accompanying aromas (requiring the input of olfactory function, whose recovery might be on a different time course).

Though cranial nerve 1 (olfactory) evaluation is often foregone in neurologic examinations performed by health-care providers, there are important lessons to be learned from acute anosmia and ageusia that often arise in the setting of COVID-19. First, these symptoms can represent the earliest or sole manifestations of disease in some cases. It is, therefore, critical to realize that COVID-19 can present with OD or GD in pauci-symptomatic, afebrile patients (especially women and younger adults). In a study by Speth et al., OD presented, on average, around day 3 after infection, but onset in the study population ranged from day 1 to 12 of symptomatic illness. Ageusia is not routinely tested in the neurological examinations of some practitioners, but the medical literature on this topic would suggest that positive screening with this examination might be indicative of COVID-19 infection.

Because they can be sensitive and early indicators of COVID-19 infection, impairment of both sense of smell and taste can serve as important clues for patients to perform self-isolation or seek COVID-19 testing. This is especially important since an estimated 40%–50% of COVID-19-positive patients are expected to be asymptomatic at initial positive polymerase chain reaction testing.

Early reports of prevalence may have underrepresented the true occurrence of OD and GD, as these manifestations may have been deemed too mild to be reported or documented in the electronic medical record of hospitalized patients. Further, patients may not have been inclined to report their OD or GD unless directly asked, and bedside examination of ill patients may skip detailed neurological testing that would otherwise detect such problems. Nonetheless, as subjective OD may not always indicate objective OD and vice versa, objective testing with odorants and taste solutions may be important to adopt. A proposed approach for the assessment and management of COVID-19-related OD, published in The Journal of the American Medical Association, recommends a full otolaryngologic examination which includes a three-pass nasendoscopy when appropriate PPE is available. It also recommends CT to assess the paranasal sinuses, and MRI brain to examine brain and olfactory tracts. A psychophysical assessment using validated tests of odorants/tastants should complement the subjective assessment. Treatment may be needed in persistent OD, i.e., lasting for 2 weeks or more. This includes olfactory training by sniffing specific odorants such as rose, lemon, cloves, and eucalyptus, at least twice daily for at least 3 months. Other promising therapies which work in postinfectious OD include intranasal vitamin A and systemic omega-3 but have not been tested in COVID-19 specifically. Corticosteroids, on the other hand, whether oral or intranasal, are not recommended due to lacking evidence of benefit and potential harm.

It is becoming increasingly evident that OD and GD can be helpful at recognizing possible COVID-19 infection and encouraging steps like self-isolation. Both anosmia and ageusia often present early in the course of the disease, especially in women and in younger adults. They can also be the only manifestation of COVID-19 infection. Asking patients if they have experienced these symptoms may be useful in triage settings, as affirmative answers should heighten suspicion for COVID-19 infection. The Centers for Disease Control and Prevention included “new loss of taste or smell” to its overview of common symptomatology.