Parkinsonism As A Third Wave Of The COVID-19 Pandemic?

Dec 18, 2018
Parkinsonism as a Third Wave of the COVID-19 Pandemic?
Article type: Review Article

Authors: Beauchamp, Leah C.a; b | Finkelstein, David I.a | Bush, Ashley I.a; c | Evans, Andrew H.d | Barnham, Kevin J.a; b; c; *

Affiliations: [a] Florey Institute of Neuroscience and Mental Health, Parkville, Australia | Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Australia | [c] Melbourne Dementia Research Centre, Parkville, Australia | [d] Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia

Correspondence: [*] Correspondence to: Kevin J. Barnham, PhD, Florey Institute of Neuroscience and Mental Health, Parkville, Australia. E-mail:

Keywords: Parkinson’s disease, parkinsonism, COVID-19, SARS-CoV-2

DOI: 10.3233/JPD-202211

Journal: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Accepted 27 August 2020
Published: 22 September 2020

Since the initial reports of COVID-19 in December 2019, the world has been gripped by the disastrous acute respiratory disease caused by the SARS-CoV-2 virus. There are an ever-increasing number of reports of neurological symptoms in patients, from severe (encephalitis), to mild (hyposmia), suggesting the potential for neurotropism of SARS-CoV-2. This Perspective investigates the hypothesis that the reliance on self-reporting of hyposmia has resulted in an underestimation of neurological symptoms in COVID-19 patients. While the acute effect of the virus on the nervous system function is vastly overshadowed by the respiratory effects, we propose that it will be important to monitor convalescent individuals for potential long-term implications that may include neurodegenerative sequelae such as viral-associated parkinsonism. As it is possible to identify premorbid harbingers of Parkinson’s disease, we propose long-term screening of SARS-CoV-2 cases post-recovery for these expressions of neurodegenerative disease. An accurate understanding of the incidence of neurological complications in COVID-19 requires long-term monitoring for sequelae after remission and a strategized health policy to ensure healthcare systems all over the world are prepared for a third wave of the virus in the form of parkinsonism.

For too long medical science has tended to relegate the 1918 influenza/encephalitis lethargica/parkinsonism puzzle to an intellectual ash heapapparently on the assumptions that these pandemics are past and of little and dwindling importance to current and future health. But failure to identify the 1918 influenza virus as the cause of encephalitis lethargica and parkinsonism has crippled progress towards the understanding of influenza pathology and epidemiology needed to fuel and guide prevention of these elusive yet exceedingly important diseases.

Reimert Ravenholt, 1982 [1].

In December 2019, pneumonia caused by a novel coronavirus, SARS-CoV-2, was reported for the first time in Wuhan, China [2]. On March 12, 2020, the World Health Organization (WHO) officially declared coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, a pandemic. At the time of preparing this manuscript, 23.7 million people had been infected, and >800,000 people had died from COVID-19 according to data from the WHO [3]. The presentation and nature of symptoms in COVID-19 appear to be ever-increasing, with new case-reports appearing daily. Extrapulmonary complications have been reported in many instances of infection, including neurological symptoms.

Several viruses are known to be neurotropic (capable of invading nerve cells), including herpes simplex virus, poliovirus, influenza Type A virus, and the coronaviruses [4–8]. In order to understand the pathogenesis of these viruses within the central nervous system, it is critical to understand the mechanisms of entry into the CNS. There are many ways in which viruses are hypothesized to enter the brain, including viremia, infection of the endothelial cells, and retrograde axonal transport [9]. The virus that has been studied the most, with a view to understanding CNS penetration and the subsequent neurotropism, is influenza. It has been reported that intranasal infection with H1N1 (swine flu) and H5N1 (avian flu) resulted in infection of the olfactory epithelium and transmission through the axons into the olfactory bulb of wildtype mice [10, 11]. Importantly there is a significant body of literature illustrating that the coronaviruses are neurotropic [12–19], and recent findings suggest dopaminergic neurons are permissive to SARS-CoV-2 infection [20].

Chronic neuroinflammation is thought to play a role in the pathogenesis of Parkinson’s disease (PD)/parkinsonism. In the brain, increases in complement protein pathways and activated microglia are seen in regions with degeneration [21]. The primary insult may be idiopathic, traumatic, or environmental, but inflammation is ubiquitous in areas of neurodegeneration. The question remains does inflammation result in neurodegeneration or does the underlying disease drive inflammation. For instance, epidemiological examinations involving non-steroidal anti-inflammatories shows that they are largely not effective in preventing PD [22, 23]. One recent proposal that PD may be initiated following continuous gut aggravation is gaining significant attention. The initiator of neuroinflammation may be the bacterial endotoxin, lipopolysaccharide (LPS) from the outer membrane of gram negative bacteria that are present in the mouth and gastrointestinal tract [24]. It is proposed that a level of endotoxin causes an ‘cytokine storm’ and parkinsonism [25]. Animal models show that a single injection of LPS can trigger neuroinflammation and subsequent loss of nigral cells [26, 27]. As such, early gastrointestinal dysfunction in people with PD may be more than a prodromal symptoms of PD but additionally represent an early environmental inflammatory trigger.

Infection by neurotropic viruses as well as the local induced immune response that result can irreversibly disrupt the complex structural and functional architecture of the central nervous system. Infectious pathogens (viral or bacterial) can trigger neuroinflammation via induction of pro-inflammatory cytokines in microglia, the principal immune cells of the CNS [11, 28]. This immune response of microglial activation and hypercytokinemia can induce further microglial activation. It has been reported that the dopaminergic neurons of the substantia nigra pars compacta are particularly susceptible to an environment of continual chronic inflammation and neuronal damage contributing to the neurodegeneration in PD and parkinsonism [29, 30] (reviewed in [31]). Neuroinflammation of this nature is one of the connecting phenomena that link infectious diseases and neurodegeneration. Besides immediate and direct effects, there are several neurological disorders often associated with autoimmune mechanisms that are assumed to be delayed virus-induced disorders: multiple sclerosis, Guillain-Barré syndrome, narcolepsy, and encephalitis lethargica. The clinical presentation of acute inflammation of the brain is also linked to delayed neuropathological manifestations later in life, such as parkinsonism [9, 32].

The etiology of PD and parkinsonism is yet to be fully understood and studying the underlying pathomechanisms may be important for the efficient development of preventative interventions. A single pathogen is unlikely to be responsible for the entire pathogenesis of PD, but there is some evidence that certain viral infections may increase the susceptibility of PD and parkinsonism. Acute parkinsonism is associated with neurotropic viruses, including coxsackievirus, St. Louis encephalopathy, and human immunodeficiency virus [33]. The first link between viruses and parkinsonism comes from the possible relationship between encephalitis lethargica and the 1918 Spanish Flu. In the acute form, encephalitis lethargica presented with annual, mostly winter peaks of varying size and severity that was most prevalent in the early 1920s [34]. In the acute stage the post-mortem histological appearances of the encephalitis lethargica brain were usually normal, but more advanced cases showed varying degrees of vascular congestion and perivascular lymphocytic cuffing. In chronic encephalitis lethargica there was less inflammation, but signs of degeneration in the midbrain, especially of the oculomotor nuclei and the substantia nigra. Subsequently, there was an was an increased 2-3 fold risk of parkinsonism reported in people born between 1888–1924 [1]. The aetiology of encephalitis lethargica is widely debated as advanced virological techniques were not available in the 1920s—but plausibly considered to be caused by another neurotropic virus epidemiologically comparable to polioencephalomyelitis. Other possibilities are also considered to be either environmental, parainfectious, auto-immune, or a combination of these insults (reviewed in: [35]). Temporally, an influenza causation provides a convenient explanation due to the disappearance of encephalitis lethargica after 1940 and the cessation of the 1918 influenza strain in humans after 1933 [36]. To date, evidence for influenza-induced encephalitis lethargica is inconclusive, however, as stated by McCall “an open mind about the influenza hypothesis avoids complacency about the potential for another encephalitis lethargica-like epidemic accompanying a new influenza pandemic” [36].

There is no evidence that these viruses are causally linked to parkinsonism or PD, however, there is a proposed hypothesis that “an unknown pathogen” results in a neuronal insult and is the first ‘hit’ in a dual ‘hit’ hypothesis of PD [37, 38]. This hypothesis proposes that there is an initial insult from a neurotropic pathogen that enters the brain through the nasal or gastric pathways and induces long-lived activation of the glial cells that predisposes the brain to oxidative insult in later life or alternatively may become primed to react abnormally to stimuli in the aging brain and to become neurotoxic and destructive during neurodegeneration. As such, the second ‘hit’ is pathogenic and deleterious due to an already primed neural system. It is for this reason that the current COVID-19 pandemic could provide valuable insights into the effect of viral infections/inflammation in neurodegenerative conditions to neurologists and neuroscientists, as there are many case reports of severe neurological complications in hospitalized patients, as well as sensory loss in many patients.

References for the following review of neurological symptoms in COVID-19 were identified by searches of PubMed between December 2019 and June 2020, and references from relevant articles. The search terms “SARS-CoV-19”, “COVID-19”, “neurological”, “encephalitis”, “hyposmia”, “anosmia”, and “olfaction” were used. There were no language restrictions. The final reference list was generated on the basis of relevance to the topics covered in this review.

To date, there have been a number of case reports and demonstrating the presence of neurological symptoms in COVID-19 (Table 1) and three major case series with neurological reports have been published. Mao et al. performed a retrospective case study on 214 hospitalized patients in China and demonstrated that 78 (36.4%) patients presented with varying neurological symptoms including headache, dizziness, hyposmia, and skeletal muscle symptoms [39]. Helms et al. evaluated 58 hospitalized patients in France, 8 (13.8%) had neurological symptoms upon admission into the intensive care unit (ICU), and a further 39 (67.2%) demonstrated neurological symptoms when sedation and neuromuscular blockers were withheld [40]. Romero-Sanchez analyzed the medical history of patients on the Spanish ALBACOVID registry [41]. Of the 841 patients in this study, 483 (57.4%) developed neurological symptoms and of the 197 people who died, neurological complications were determined to be the cause of death in 8 (4.1%). The neurological symptoms reported to date, range from severe, such as encephalitis (Table 1) in hospitalized patients to mild (e.g., hyposmia; Tables 2 and 3). It is important to note that there are no control groups associated with these reports, and it will be of great value to understand the prevalence of these neurological symptoms in non-COVID-19 pneumonia and acute respiratory distress syndrome induced by other infectious and non-infectious causes.

Table 1
Neurological manifestations in COVID-19

Symptom n (study/review) n symptom (%) Study type
Acute cerebrovascular disease 11069 332 (3.0) Systematic review [70]
Dizziness 2236 151 (6.8)
Headache 16446 3308 (20.1)
Hypogeusia 846 430 (50.8) Systematic review [71]
Impaired consciousness 2890 146 (5.1)
Guillain-Barre syndrome
23 Case reports [72]
1 Case report [73]
1 Case report [74]
2 Case report [75, 76]
26 Table 2
Hyposmia 16530 9728 (58.9%) Table 3 and 4
Table 2

Case reports of encephalitis in COVID-19

Author Country Patient age (y), sex Diagnosis
Benameur [60] USA 31, F Encephalitis

34, M

64, M
Bernard-Valnet [77] Switzerland 64, F 67 F Viral meningoencephalitis
Dogan [78] Turkey 53 ICU patients 6 (11.3%) meningoencephalitis
Efe [79] Turkey 35, F Encephalitis (confirmed in a lobotomized sample)
Huang [58] USA 40, F Encephalitis
Karimi [80] Iran 30, F Encephalitis
Lu [81] China 304 (hospitalized) 8 (2.6%) encephalopathy
Moriguchi [59] Japan 24, M Convulsive encephalopathy
Pilotto [82] UK 60, M Encephalitis
Poyiadji [83] USA 56, F Acute necrotizing hemorrhagic encephalitis
Wong [84] UK 40, M Rhombencephalitis
Table 3
Hyposmia in COVID-19 (self-reported questionnaire)

Author Country N (SARS-CoV-2 pos) N (olfactory disturbance) % Females (%) Age, y (mean±SD)
Abalo-Lojo [85] Spain 131 77 58.8 57.4 50.4
aBeltran-Corbellini [86] Spain 79 56 § 70.9 39.2 61.6±17.4
aGelardi [87] Italy 72 42 § 58.3 NR NR
aGiacomelli [44] Italy 59 31 § 52.5 32.2 60
Gudbjartsson [88] Iceland 1221 118 9.7 44.1 44.3
Haehner [89] Germany 34 22 64.7 54.6 41.3
aHornuss [90] Germany 45 22 48.9 44.4 56±16.9
aLechien [43] Multiple 417 357 85.6 63.1 36.9±11.4
Lee [91] Korea 3191 855 26.8 63.6 44.0
aLevinson [92] Israel 42 15 35.7 45.2 34.0
aMao [39] China 214 11 5.1 59.3 52.7±15.5
Menni [93] UK/USA 7178 4668 65.0 71.9/78.1 41.3±12.2/44.7±14.3
Paderno [94] Italy 508 283 55.7 44.0 55±15
Speth [95] Switzerland 103 63 § 31.2 51.5 NR
Spinato [45] Italy 202 130 § 64.4 52.0 56 (med)
aVaira [96] Italy 72 44 § 61.1 62.5 49.2±13.7
Wee [97] Singapore 154 35 22.7 NR NR
Yan [98] USA 59 40 67.8 49.2 Range 18–79
aYan [99] USA 128 75 58.6 52.2 53.5 (hospitalized),

43 (ambulatory)
adenotes studies performed on hospitalized patients; NR, not reported.

Table 4
Hyposmia in COVID-19 (clinical olfactory tests)

Author Country N (SARS-CoV-2 pos) N (olfactory disturbance) % Clinical olfactory test Females (%) Age, y (mean±SD)
aHornuss [90] Germany 45 38 84.4 Sniffin’ Sticks 44.4 56.0±16.9
Lechien [100] Multiple 2013 1754 87.1 Sniffin’ Sticks 67.5 38.9±11.6
Lechien [101] Belgium 86 53 61.6 Sniffin’ Sticks 65.1 41.7±11.8
aMoein [102] Iran 60 35 58.3 UPSIT 33.4 46.6±12.2
Vaira [103] Italy 345 244 70.7 OTT (ethyl-OH) 57.7 48.5±12.8
aVaira [96] Italy 72 60 83.3 CCCRC 62.5 49.2±13.7
aDenotes studies performed on hospitalized patients; CCCRC, Connecticut Chemosensory Clinical Research Centre test; OTT, olfactory threshold test; UPSIT, University of Pennsylvania Smell Identification Test.

Even though severe cases of neurological symptoms are relatively rare, there is evidence that the virus can affect the nervous system. This is reflected in the numbers of patients presenting with olfactory complications, with a variety of studies reporting that COVID-19 patients have concurrent hyposmia. However, given the imprecise nature of the methods used to evaluate olfactory performance the incidence of hyposmia associated with COVID-19 is likely to be under-reported. Published studies (Table 2), relying on self-reporting of olfactory alterations demonstrated a prevalence that ranged from 5.1–85.6% (mean±SD; 49.6±21.77%). These studies suggest that roughly half of the patients with clinically confirmed COVID-19 present with an olfactory deficit (or deficits in olfaction and taste). Self-assessment is notoriously unreliable, as people may not recognize a reduction in their sense of smell if it is not severe, or the patient has respiratory difficulties. To date, six studies have been performed that utilize clinical olfactory tests, including the Sniffin’ Sticks, University of Pennsylvania Smell Identification Test (UPSIT), and Connecticut Chemosensory Clinical Research Centre Test (CCCRC), that can quantify the degree of hyposmia and anosmia in patients (Table 2). These data demonstrate a range of olfactory disruption prevalence from 58.3–87.1%, (mean±SD; 74.2±12.47%), which is substantially higher than self-reported studies.

The problematic nature of self-evaluation of hyposmia has been reported in other disease cohorts [42] and is highlighted in two COVID-19 studies that compared self-reported with measured olfaction performance. In a study by Hornuss et al., 22 out of 45 COVID-19 patients (48.9%) self-reported a change in their sense of smell; however, using the “Sniffin’ Sticks” it was determined that 38 of the 45 COVID-19 patients had hyposmia or anosmia (84.4%). Vaira et al. found similar findings in that of 72 COVID-19 participants, 44 people reported olfactory deficits (14 olfactory deficits alone, 30 olfactory and taste deficits; 61.1%), however, using the CCCRC it was determined that 60 had either hyposmia or anosmia (83.3%). These data suggest that the number of studies relying on self-reporting of hyposmia results is unreliable and likely results in an under-estimation of olfactory deficits, and therefore neurological symptoms, in COVID-19 patients. Importantly, there are reports that hyposmia/anosmia precede other symptoms [43–45], and in some cases these are the only symptoms of COVID-19 [46, 47]. The reported recovery period is varied, with majority of people recovering between 1–28 days, and very few people showing no recovery in follow-up after one month [48]. Olfactory dysfunction may therefore go unrecognized by the individual affected by COVID-19—a phenomenon called olfactory anosognosia. In community studies, olfactory awareness is negatively related to age, cognitive decline, especially concerning memory and executive control such as attention, and male sex [49].

Viral and post-viral olfactory disorders usually occur after an upper respiratory tract infection (URTI) associated with a common cold or influenza. Estimates of its prevalence vary widely. Women are more often affected than men and post-UTRI disorders usually occur between the fourth and either decade of life [50]. The diagnosis is made according to the history, clinical examination, and olfactory testing. The exact location of the damage in post-UTRI is not yet known even though biopsies suggest direct damage of the olfactory receptor cells is likely. Further, central mechanisms may also be important. There is limited information on the viruses responsible that include influenza viruses, parainfluenza viruses, coronaviruses, respiratory syncytial virus, coxsackie virus, adenoviruses, poliovirus, enteroviruses, and herpesviruses. Spontaneous recovery may occur but there is no effective therapy except specific olfactory training. Olfactory anosognosia has not previously been described in cases of viral olfactory dysfunction. However, the high prevalence of olfactory anosognosia reported in COVID-19 here raises the possibility that this could reflect involvement of the central nervous system in COVID-19 infections.

One of the commonest causes of impaired olfactory function are the neurodegenerative disorders of Alzheimer’s and Parkinson’s disease. Hyposmia was first recognized as a possible symptom of PD well after James Parkinson’s descriptions of motor phenomenology and well after the encephalitis lethargica pandemic [51]. It has subsequently been found to be one of the earliest prodromal symptoms of PD and is present in up to 90% of patients with early-stage PD [52]. Intracellular aggregates of α-synuclein, the pathologic hallmark of PD, involve the olfactory bulb and anterior olfactory nucleus at Braak stage I [53]. While olfactory dysfunction is independent of cognitive impairment at baseline [54], patients with PD who exhibit decreased olfactory ability appear to have a significant increase in their risk of progression in the disease [55]. The percentage of olfactory anosognosia ranged from 63 to 80% in non-demented PD, significantly higher than that in healthy individuals [54, 56]. Furthermore, olfactory anosognosia accompanied by olfactory deficits in the de novo state can be a predictor of cognitive decline and conversion to dementia in PD [57].

The presence of neurological symptoms is evidence of the neurotropic potential of SARS-CoV-2. There are several reports of virus found in the CSF of patients [58–60], and there has also been one incidence of viral particles in the frontal lobe of a deceased COVID-19 patient [61]. Although parkinsonism linked to viruses is often considered post-encephalopathy, there is evidence that even in the absence of encephalitis, the brain is undergoing SARS-CoV-2-related changes [62]. The report by Politi et al. described a case of a 25-year-old female with a mild dry cough and persistent severe anosmia. This patient was positive for SARS-CoV-2 but had no fever and a negative chest and maxillofacial computerized tomography scan. MRI demonstrated the anosmic patient had cortical alterations in the right gyrus rectus, and subtle alterations in the olfactory bulbs, both of which resolved within 28 days. This case highlights the possibility of cerebral involvement in mild cases with only hyposmia as the sole neurological symptom. Although these changes were not found in two other anosmic COVID-19 patients, it suggests that SARS-CoV-2 has the potential to invade the brain through the olfactory pathways. Indeed, this has been demonstrated with SARS-CoV in vivo in which the virus was able to disseminate across the cribriform plate during infection and lead to a cerebral invasion [16]. Although there is a reasonable focus on the severe neurological symptoms in COVID-19 for the short-term management of these patients, the high prevalence of hyposmia, especially in mild cases, should be of concern due to the known correlation between neurotropic viruses and Parkinson’s disease/parkinsonism.

There may be a myriad of potential long-term neurological and neuropsychiatric complications secondary to SARS-CoV-2 infection including a potential link to worsening parkinsonism in patients with PD and possibly even delayed neurological effects including parkinsonism. It remains to be seen whether COVID-19 viral infections will be later linked to parkinsonism as is the case in other viruses. Also, unlike many neurological conditions, such as neuropathy, there are emerging tools available to identify parkinsonism early in the disease process. As such, this review serves as a ‘call to arms’ for the neurology community in preparation of a potential wave of parkinsonism to come.

There is insufficient data at this stage to quantify the increased risk of developing parkinsonism associated with COVID-19. The high prevalence of anosmia combined with a suspicion about a link between an encephalitis lethargica-type association with a historic influenza pandemic leads us to question whether history is repeating. Fortunately, this time we are more informed about the features of prodromal PD/parkinsonism and we are able to test the hypothesis that COVID-19-related neurological features may relate to neurodegenerative sequelae. At face value it is attractive to equate the hyposmia and anosmia in COVID-19 to the hyposmia and anosmia in parkinsonism, however this determination cannot be made without extensive studies. We are proposing there may be an increase in the risk profile of individuals with neurological complications associated with SARS-CoV-2 infection, as demonstrated by symptoms such as hyposmia or encephalitis that may reflect a neurological injury. Furthermore, individuals who have more severe symptoms may have a more dramatic change in their risk profile. History suggests that this may be problematic as PD/parkinsonism is the fastest growing neurological syndrome, predicted to affect more than 12 million people by 2040 [63]. This number alone is going to have significant social and economic consequences as it is a disease that progresses slowly, is very costly, and has no disease-modifying treatments. Spanish flu-induced encephalitis saw a latent interval between “recovery” and onset of parkinsonism of 5 years in half of the survivors of the encephalopathy [32]. Even if this number is an overestimation, with more than 23 million people infected with COVID-19 worldwide, the potential increase in the number of cases of parkinsonism in the coming years is going to have serious ramifications for the health care systems of many countries, and a well-considered proactive response should be implemented. Importantly, strategies involving herd immunity that require an infection rate of 60–70% need to be very carefully considered, although they may represent a short-term fix from the acute infection, there may well be disastrous long-term consequences.

Population-based studies of the neurological symptoms of COVID-19 that include appropriate COVID-19 controls with no neurological complications would be needed in order to study the susceptibility of population groups. Furthermore, it would be of great benefit to patients who present with neurological symptoms to undergo short-term studies that include quantitative analysis of olfaction, as well as studies for signs of neuroinflammation, microhemorrhages, cerebral alterations, and neuronal loss [64]. In terms of screening for parkinsonism, it is well understood that significant progression of the neurodegenerative process occurs prior to diagnosis. The current diagnosis of PD and parkinsonism relies on the clinical presentation of a movement disorder, that already reflects late-stage disease as 50–70% of dopaminergic neurons have already perished [65, 66]. By relying on the spontaneous observation of manifestation of neurological problems in recovered patients affected by COVID-19, the response to the potential long-term consequences of COVID-19 may therefore also prove ‘too little, too late, too flawed’ [67]. The best way to identify populations that are likely to develop parkinsonism will be to create a health registry of COVID-19 patients that undergo regular long-term neurological follow up for the signs of prodromal PD/parkinsonism, as well as blood tests for neurofilament light chain for signs of neurodegeneration [68]. The Movement Disorder Society research criteria for prodromal Parkinson’s disease identifies and assigns likelihood ratios to various prodromal symptoms associated with PD, including hyposmia, REM sleep behavior disorder, and constipation, and may help to guide the neurological follow up of COVID-19 patients [69]. This strategy will allow for the stratification of patients likely to develop parkinsonism and refer individuals for diagnostic dopamine neuroimaging studies. However, this risk assessment is designed for use in a research setting and requires further refinement before implementation into clinical practice. As such, now is the time for substantial investment in the early identification, diagnosis, and treatment of PD and parkinsonism to help arm clinicians with the best tools available to handle a potential influx of parkinsonism over the next half-century.

The world was caught off guard by the first wave of COVID-19, will we be ready for the third wave of neurological sequelae such as parkinsonism?

The authors have no conflicts of interest to declare that are relevant to the content of this article


Ravenholt RT , Foege WH (1982) 1918 influenza, encephalitis lethargica, parkinsonism. Lancet 2, 860–864.


Huang C , Wang Y , Li X , Ren L , Zhao J , Hu Y , Zhang L , Fan G , Xu J , Gu X , Cheng Z , Yu T , Xia J , Wei Y , Wu W , Xie X , Yin W , Li H , Liu M , Xiao Y , Gao H , Guo L , Xie J , Wang G , Jiang R , Gao Z , Jin Q , Wang J , Cao B (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506.


WHO, Situation Report - 209,


Steiner I , Kennedy PG , Pachner AR (2007) The neurotropic herpes viruses: Herpes simplex and varicella-zoster. Lancet Neurol 6, 1015–1028.


Luethy LN , Erickson AK , Jesudhasan PR , Ikizler M , Dermody TS , Pfeiffer JK (2016) Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system. Virology 487, 1–10.


Yamashita N (2016) Neurotropic influenza virus infections. In Neurotropic Viral Infections: Volume 1: Neurotropic RNA Viruses, Reiss CS, ed. Springer International Publishing, Cham, pp. 295-314.


Fazzini E , Fleming J , Fahn S (1992) Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson’s disease. Mov Disord 7, 153–158.


Fishman PS , Gass JS , Swoveland PT , Lavi E , Highkin MK , Weiss SR (1985) Infection of the basal ganglia by a murine coronavirus. Science 229, 877–879.


Ludlow M , Kortekaas J , Herden C , Hoffmann B , Tappe D , Trebst C , Griffin DE , Brindle HE , Solomon T , Brown AS , van Riel D , Wolthers KC , Pajkrt D , Wohlsein P , Martina BEE , Baumgartner W , Verjans GM , Osterhaus A (2016) Neurotropic virus infections as the cause of immediate and delayed neuropathology. Acta Neuropathol 131, 159–184.


Aronsson F , Robertson B , Ljunggren HG , Kristensson K (2003) Invasion and persistence of the neuroadapted influenza virus A/WSN/33 in the mouse olfactory system. Viral Immunol 16, 415–423.


Jang H , Boltz D , Sturm-Ramirez K , Shepherd KR , Jiao Y , Webster R , Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A 106, 14063–14068.


Perlman S , Evans G , Afifi A (1990) Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain. J Exp Med 172, 1127–1132.


Lavi E , Fishman PS , Highkin MK , Weiss SR (1988) Limbic encephalitis after inhalation of a murine coronavirus. Lab Invest 58, 31–36.


Perlman S , Jacobsen G , Afifi A (1989) Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves. Virology 170, 556–560.


Cabirac GF , Soike KF , Zhang JY , Hoel K , Butunoi C , Cai GY , Johnson S , Murray RS (1994) Entry of coronavirus into primate CNS following peripheral infection. Microb Pathog 16, 349–357.


Netland J , Meyerholz DK , Moore S , Cassell M , Perlman S (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 82, 7264–7275.


Murray RS , Cai GY , Hoel K , Zhang JY , Soike KF , Cabirac GF (1992) Coronavirus infects and causes demyelination in primate central nervous system. Virology 188, 274–284.


Wege H , Winter J , Korner H , Flory E , Zimprich F , Lassmann H (1990) Coronavirus induced demyelinating encephalomyelitis in rats: Immunopathological aspects of viral persistency. Adv Exp Med Biol 276, 637–645.


Bergmann CC , Lane TE , Stohlman SA (2006) Coronavirus infection of the central nervous system: Host-virus stand-off. Nat Rev Microbiol 4, 121–132.


Yang L , Han Y , Nilsson-Payant BE , Gupta V , Wang P , Duan X , Tang X , Zhu J , Zhao Z , Jaffré F , Zhang T , Kim TW , Harschnitz O , Redmond D , Houghton S , Liu C , Naji A , Ciceri G , Guttikonda S , Bram Y , Nguyen D-HT , Cioffi M , Chandar V , Hoagland DA , Huang Y , Xiang J , Wang H , Lyden D , Borczuk A , Chen HJ , Studer L , Pan FC , Ho DD , tenOever BR , Evans T , Schwartz RE , Chen S (2020) A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27, 125–136.e127.


McGeer PL , McGeer EG (2004) Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 10(Suppl 1), S3–7.


Samii A , Etminan M , Wiens MO , Jafari S (2009) NSAID use and the risk of Parkinson’s disease: Systematic review and meta-analysis of observational studies. Drugs Aging 26, 769–779.


Gao X , Chen H , Schwarzschild MA , Ascherio A (2011) Use of ibuprofen and risk of Parkinson disease. Neurology 76, 863–869.


Brown GC (2019) The endotoxin hypothesis of neurodegeneration. J Neuroinflammation 16, 180.


Clark IA (2007) The advent of the cytokine storm. Immunol Cell Biol 85, 271–273.


Deneyer L , Albertini G , Bentea E , Massie A (2019) Systemic LPS-induced neuroinflammation increases the susceptibility for proteasome inhibition-induced degeneration of the nigrostriatal pathway. Parkinsonism Relat Disord 68, 26–32.


Qin L , Wu X , Block ML , Liu Y , Breese GR , Hong JS , Knapp DJ , Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453–462.


Sadasivan S , Zanin M , O’Brien K , Schultz-Cherry S , Smeyne RJ (2015) Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus. PLoS One 10, e0124047.


Tansey MG , Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37, 510–518.


Rohn TT , Catlin LW (2011) Immunolocalization of influenza A virus and markers of inflammation in the human Parkinson’s disease brain. PLoS One 6, e20495.


Limphaibool N , Iwanowski P , Holstad MJV , Kobylarek D , Kozubski W (2019) Infectious etiologies of parkinsonism: Pathomechanisms and clinical implications. Front Neurol 10, 652.


Duvoisin RC , Yahr MD (1965) Encephalitis and Parkinsonism. Arch Neurol 12, 227–239.


Jang H , Boltz DA , Webster RG , Smeyne RJ (2009) Viral parkinsonism. Biochim Biophys Acta 1792, 714–721.


Buzzard EF (1919) Encephalitis lethargica. Proc R Soc Med 12, 56–64.


Hoffman LA , Vilensky JA (2017) Encephalitis lethargica: 100 years after the epidemic. Brain 140, 2246–2251.


McCall S , Vilensky JA , Gilman S , Taubenberger JK (2008) The relationship between encephalitis lethargica and influenza: A critical analysis. J Neurovirol 14, 177–185.


Hawkes CH , Del Tredici K , Braak H (2007) Parkinson’s disease: A dual-hit hypothesis. Neuropathol Appl Neurobiol 33, 599–614.


Braak H , Rub U , Gai WP , Del Tredici K (2003) Idiopathic Parkinson’s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110, 517–536.


Mao L , Jin H , Wang M , Hu Y , Chen S , He Q , Chang J , Hong C , Zhou Y , Wang D , Miao X , Li Y , Hu B (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology 77, 683–690.


Helms J , Kremer S , Merdji H , Clere-Jehl R , Schenck M , Kummerlen C , Collange O , Boulay C , Fafi-Kremer S , Ohana M , Anheim M , Meziani F (2020) Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 382, 2268–2270.


Romero-Sanchez CM , Diaz-Maroto I , Fernandez-Diaz E , Sanchez-Larsen A , Layos-Romero A , Garcia-Garcia J , Gonzalez E , Redondo-Penas I , Perona-Moratalla AB , Del Valle-Perez JA , Gracia-Gil J , Rojas-Bartolome L , Feria-Vilar I , Monteagudo M , Palao M , Palazon-Garcia E , Alcahut-Rodriguez C , Sopelana-Garay D , Moreno Y , Ahmad J , Segura T (2020) Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry. Neurology 95, e1060–e1070.


Adams DR , Wroblewski KE , Kern DW , Kozloski MJ , Dale W , McClintock MK , Pinto JM (2017) Factors associated with inaccurate self-reporting of olfactory dysfunction in older US adults. Chem Senses 42, 223–231.


Lechien JR , Chiesa-Estomba CM , De Siati DR , Horoi M , Le Bon SD , Rodriguez A , Dequanter D , Blecic S , El Afia F , Distinguin L , Chekkoury-Idrissi Y , Hans S , Delgado IL , Calvo-Henriquez C , Lavigne P , Falanga C , Barillari MR , Cammaroto G , Khalife M , Leich P , Souchay C , Rossi C , Journe F , Hsieh J , Edjlali M , Carlier R , Ris L , Lovato A , De Filippis C , Coppee F , Fakhry N , Ayad T , Saussez S (2020) Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): A multicenter European study. Eur Arch Otorhinolaryngol 277, 2251–2261.


Giacomelli A , Pezzati L , Conti F , Bernacchia D , Siano M , Oreni L , Rusconi S , Gervasoni C , Ridolfo AL , Rizzardini G , Antinori S , Galli M (2020) Self-reported olfactory and taste disorders in SARS-CoV-2 patients: A cross-sectional study. Clin Infect Dis 71, 889–890.


Spinato G , Fabbris C , Polesel J , Cazzador D , Borsetto D , Hopkins C , Boscolo-Rizzo P (2020) Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA 323, 2089–2090.


Hjelmesaeth J , Skaare D (2020) Loss of smell or taste as the only symptom of COVID-19. Tidsskr Nor Laegeforen 140, doi: 10.4045/tidsskr.20.0287


Heidari F , Karimi E , Firouzifar M , Khamushian P , Ansari R , Mohammadi Ardehali M , Heidari F (2020) Anosmia as a prominent symptom of COVID-19 infection. Rhinology 58, 302–303.


Hopkins C , Surda P , Whitehead E , Kumar BN (2020) Early recovery following new onset anosmia during the COVID-19 pandemic - an observational cohort study. J Otolaryngol Head Neck Surg 49, 26.


Wehling E , Nordin S , Espeseth T , Reinvang I , Lundervold AJ (2011) Unawareness of olfactory dysfunction and its association with cognitive functioning in middle aged and old adults. Arch Clin Neuropsychol 26, 260–269.


Welge-Lussen A , Wolfensberger M (2006) Olfactory disorders following upper respiratory tract infections. Adv Otorhinolaryngol 63, 125–132.


Ansari KA , Johnson A (1975) Olfactory function in patients with Parkinson’s disease. J Chronic Dis 28, 493–497.


Haehner A , Boesveldt S , Berendse HW , Mackay-Sim A , Fleischmann J , Silburn PA , Johnston AN , Mellick GD , Herting B , Reichmann H , Hummel T (2009) Prevalence of smell loss in Parkinson’s disease–a multicenter study. Parkinsonism Relat Disord 15, 490–494.


Braak H , Del Tredici K , Rub U , de Vos RA , Jansen Steur EN , Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24, 197–211.


Doty RL , Deems DA , Stellar S (1988) Olfactory dysfunction in parkinsonism: A general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38, 1237–1244.


Domellof ME , Lundin KF , Edstrom M , Forsgren L (2017) Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson’s disease. Parkinsonism Relat Disord 38, 41–47.


White LD , Cory-Slechta DA , Gilbert ME , Tiffany-Castiglioni E , Zawia NH , Virgolini M , Rossi-George A , Lasley SM , Qian YC , Basha MR (2007) New and evolving concepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 225, 1–27.


Yoo HS , Chung SJ , Lee YH , Ye BS , Sohn YH , Lee PH (2019) Olfactory anosognosia is a predictor of cognitive decline and dementia conversion in Parkinson’s disease. J Neurol 266, 1601–1610.


Huang YH , Jiang D , Huang JT (2020) SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis. Brain Behav Immun 87, 149–149.


Moriguchi T , Harii N , Goto J , Harada D , Sugawara H , Takamino J , Ueno M , Sakata H , Kondo K , Myose N , Nakao A , Takeda M , Haro H , Inoue O , Suzuki-Inoue K , Kubokawa K , Ogihara S , Sasaki T , Kinouchi H , Kojin H , Ito M , Onishi H , Shimizu T , Sasaki Y , Enomoto N , Ishihara H , Furuya S , Yamamoto T , Shimada S (2020) A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 94, 55–58.


Benameur K , Agarwal A , Auld SC , Butters MP , Webster AS , Ozturk T , Howell JC , Bassit LC , Velasquez A , Schinazi RF , Mullins ME , Hu WT (2020) Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020. Emerg Infect Dis 26, 2016–2021.


Paniz-Mondolfi A , Bryce C , Grimes Z , Gordon RE , Reidy J , Lednicky J , Sordillo EM (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92, 699–702.


Politi LS , Salsano E , Grimaldi M (2020) Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia. JAMA Neurol, doi: 10.1001/jamaneurol.2020.2125


Dorsey ER , Sherer T , Okun MS , Bloem BR (2018) The emerging evidence of the Parkinson pandemic. J Parkinsons Dis 8, S3–S8.


Albrecht DS , Granziera C , Hooker JM , Loggia ML (2016) In vivo imaging of human neuroinflammation. ACS Chem Neurosci 7, 470–483.


Lee CS , Samii A , Sossi V , Ruth TJ , Schulzer M , Holden JE , Wudel J , Pal PK , de la Fuente-Fernandez R , Calne DB , Stoessl AJ (2000) In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 47, 493–503.


Scherman D , Desnos C , Darchen F , Pollak P , Javoy-Agid F , Agid Y (1989) Striatal dopamine deficiency in Parkinson’s disease: Role of aging. Ann Neurol 26, 551–557.


Scally G , Jacobson B , Abbasi K (2020) The UK’s public health response to covid-19. BMJ 369, m1932.


Gaiottino J , Norgren N , Dobson R , Topping J , Nissim A , Malaspina A , Bestwick JP , Monsch AU , Regeniter A , Lindberg RL , Kappos L , Leppert D , Petzold A , Giovannoni G , Kuhle J (2013) Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 8, e75091.


Berg D , Postuma RB , Adler CH , Bloem BR , Chan P , Dubois B , Gasser T , Goetz CG , Halliday G , Joseph L , Lang AE , Liepelt-Scarfone I , Litvan I , Marek K , Obeso J , Oertel W , Olanow CW , Poewe W , Stern M , Deuschl G (2015) MDS research criteria for prodromal Parkinson’s disease. Mov Disord 30, 1600–1611.


Abdullahi A , Candan SA , Abba MA , Bello AH , Alshehri MA , Afamefuna Victor E , Umar NA , Kundakci B (2020) Neurological and musculoskeletal features of COVID-19: A systematic review and meta-analysis. Front Neurol 11, 687.


Chen X , Laurent S , Onur OA , Kleineberg NN , Fink GR , Schweitzer F , Warnke C (2020) A systematic review of neurological symptoms and complications of COVID-19. J Neurol, doi: 10.1007/s00415-020-10067-3


Agosti E , Giorgianni A , D’Amore F , Vinacci G , Balbi S , Locatelli D (2020) Is Guillain-Barre syndrome triggered by SARS-CoV-2? Case report and literature review. Neurol Sci, doi: 10.1007/s10072-020-04553-9


Xiong W , Mu J , Guo J , Lu L , Liu D , Luo J , Li N , Liu J , Yang D , Gao H , Zhang Y , Lin M , Shen S , Zhang H , Chen L , Wang G , Luo F , Li W , Chen S , He L , Sander JW , Zhou D (2020) Newonset neurologic events in people with COVID-19 infection in three regions in China. Neurology, doi: 10.1212/WNL.0000000000010034


Elgamasy S , Kamel MG , Ghozy S , Khalil A , Morra ME , Islam SMS (2020) First case of focal epilepsy associated with SARS-coronavirus-2. J Med Virol, doi: 10.1002/jmv.26113


Mukherjee D , Sarkar P , Dubey S , Ray BK , Pandit A , Lahiri D (2020) Ataxia as a presenting manifestation of COVID-19: Report of a single case. medRxiv, 2020.2005.2024.20103648.


Balestrino R , Rizzone M , Zibetti M , Romagnolo A , Artusi CA , Montanaro E , Lopiano L (2020) Onset of Covid-19 with impaired consciousness and ataxia: A case report. J Neurol, doi: 10.1007/s00415-020-09879-0


Bernard-Valnet R , Pizzarotti B , Anichini A , Demars Y , Russo E , Schmidhauser M , Cerutti-Sola J , Rossetti AO , Du Pasquier R (2020) Two patientswith acutemeningoencephalitis concomitant with SARS-CoV-2 infection. Eur J Neurol, doi: 10.1111/ene.14298


Dogan L , Kaya D , Sarikaya T , Zengin R , Dincer A , Akinci IO , Afsar N (2020) Plasmapheresis treatment in COVID-19-related autoimmune meningoencephalitis: Case series. Brain Behav Immun 87, 155–158.


Efe IE , Aydin OU , Alabulut A , Celik O , Aydin K (2020) COVID-19-associated encephalitis mimicking glial tumor: A case report. World Neurosurg 140, 46–48.


Karimi N , Razavi A , Rouhani N (2020) Frequent convulsive seizures in an adult patient with COVID-19: A case report. Iran Red Crescent Med J, doi: 10.5812/ircmj.102828


Lu L , Xiong W , Liu D , Liu J , Yang D , Li N , Mu J , Guo J , Li W , Wang G , Gao H , Zhang Y , Lin M , Chen L , Shen S , Zhang H , Sander JW , Luo J , Chen S , Zhou D (2020) New onset acute symptomatic seizure and risk factors in coronavirus disease 2019: A retrospective multicenter study. Epilepsia 61, e49–e53.


Pilotto A , Odolini S , Stefano Masciocchi S , Comelli A , Volonghi I , Gazzina S , Nocivelli S , Pezzini A , Foca E , Caruso A , Leonardi M , Pasolini MP , Roberto Gasparotti R , Francesco Castelli F , Ashton NJ , Blennow K , Zetterberg H , Padovani A (2020) Steroid-responsive encephalitis in Covid-19 disease. Ann Neurol, doi: 10.1002/ana.25783


Poyiadji N , Shahin G , Noujaim D , Stone M , Patel S , Griffith B (2020) COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 296, E119–E120.


Wong PF , Craik S , Newman P , Makan A , Srinivasan K , Crawford E , Dev D , Moudgil H , Ahmad N (2020) Lessons of the month 1: A case of rhombencephalitis as a rare complication of acute COVID-19 infection. Clin Med (Lond) 20, 293–294.


Abalo-Lojo JM , Pouso-Diz JM , Gonzalez F (2020) Taste and smell dysfunction in COVID-19 patients. Ann Otol Rhinol Laryngol 129, 1041–1042.


Beltran-Corbellini A , Chico-Garcia JL , Martinez-Poles J , Rodriguez-Jorge F , Natera-Villalba E , Gomez-Corral J , Gomez-Lopez A , Monreal E , Parra-Diaz P , Cortes-Cuevas JL , Galan JC , Fragola-Arnau C , Porta-Etessam J , Masjuan J , Alonso-Canovas A (2020) Acute-onset smell and taste disorders in the context of COVID-19: A pilot multicentre polymerase chain reaction based case-control study. Eur J Neurol, doi: 10.1111/ene.14273


Gelardi M , Trecca E , Cassano M , Ciprandi G (2020) Smell and taste dysfunction during the COVID-19 outbreak: A preliminary report. Acta Biomed 91, 230–231.


Gudbjartsson DF , Helgason A , Jonsson H , Magnusson OT , Melsted P , Norddahl GL , Saemundsdottir J , Sigurdsson A , Sulem P , Agustsdottir AB , Eiriksdottir B , Fridriksdottir R , Gardarsdottir EE , Georgsson G , Gretarsdottir OS , Gudmundsson KR , Gunnarsdottir TR , Gylfason A , Holm H , Jensson BO , Jonasdottir A , Jonsson F , Josefsdottir KS , Kristjansson T , Magnusdottir DN , le Roux L , Sigmundsdottir G , Sveinbjornsson G , Sveinsdottir KE , Sveinsdottir M , Thorarensen EA , Thorbjornsson B , Love A , Masson G , Jonsdottir I , Moller AD , Gudnason T , Kristinsson KG , Thorsteinsdottir U , Stefansson K (2020) Spread of SARS-CoV-2 in the Icelandic population. N Engl J Med 382, 2302–2315.


Haehner A , Draf J , Draeger S , de With K , Hummel T (2020) Predictive value of sudden olfactory loss in the diagnosis of COVID-19. medRxiv, 2020.2004.2027. 20081356.


Hornuss D , Lange B , Schroter N , Rieg S , Kern WV , Wagner D (2020) Anosmia in COVID-19 patients. Clin Microbiol Infect, doi: 10.1016/j.cmi.2020.05.017


Lee Y , Min P , Lee S , Kim SW (2020) Prevalence and duration of acute loss of smell or taste in COVID-19 patients. J Korean Med Sci 35, e174.


Levinson R , Elbaz M , Ben-Ami R , Shasha D , Levinson T , Choshen G , Petrov K , Gadoth A , Paran Y (2020) Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection. medRxiv, 2020.2004.2011.20055483.


Menni C , Valdes AM , Freidin MB , Sudre CH , Nguyen LH , Drew DA , Ganesh S , Varsavsky T , Cardoso MJ , El-Sayed Moustafa JS , Visconti A , Hysi P , Bowyer RCE , Mangino M , Falchi M , Wolf J , Ourselin S , Chan AT , Steves CJ , Spector TD (2020) Real-time tracking of self-reported symptoms to predict potential COVID-19. Nat Med 26, 1037–1040.


Paderno A , Schreiber A , Grammatica A , Raffetti E , Tomasoni M , Gualtieri T , Taboni S , Zorzi S , Lombardi D , Deganello A , Redaelli De Zinis LO , Maroldi R , Mattavelli D (2020) Smell and taste alterations in Covid-19: A cross-sectional analysis of different cohorts. Int Forum Allergy Rhinol 10, 955–962.


Speth MM , Singer-Cornelius T , Obere M , Gengler I , Brockmeier SJ , Sedaghat AR (2020) Olfactory dysfunction and sinonasal symptomatology in COVID-19: Prevalence, severity, timing, and associated characteristics. Otolaryngol Head Neck Surg 163, 114–120.


Vaira LA , Deiana G , Fois AG , Pirina P , Madeddu G , De Vito A , Babudieri S , Petrocelli M , Serra A , Bussu F , Ligas E , Salzano G , De Riu G (2020) Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck 42, 1252–1258.


Wee LE , Chan YFZ , Teo NWY , Cherng BPZ , Thien SY , Wong HM , Wijaya L , Toh ST , Tan TT (2020) The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19. Eur Arch Otorhinolaryngol 277, 2389–2390.


Yan CH , Faraji F , Prajapati DP , Boone CE , DeConde AS (2020) Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol 10, 806–813.


Yan CH , Faraji F , Prajapati DP , Ostrander BT , DeConde AS (2020) Self-reported olfactory loss associates with outpatient clinical course in Covid-19. Int Forum Allergy Rhinol 10, 821–831.


Lechien JR , Chiesa-Estomba CM , Hans S , Barillari MR , Jouffe L , Saussez S (2020) Loss of smell and taste in 2013 European patients with mild to moderate COVID-19. Ann Intern Med, doi: 10.7326/M20-2428


Lechien JR , Cabaraux P , Chiesa-Estomba CM , Khalife M , Hans S , Calvo-Henriquez C , Martiny D , Journe F , Sowerby L , Saussez S (2020) Objective olfactory evaluation of self-reported loss of smell in a case series of 86 COVID-19 patients. Head Neck 42, 1583–1590.


Moein ST , Hashemian SMR , Mansourafshar B , Khorram-Tousi A , Tabarsi P , Doty RL (2020) Smell dysfunction: A biomarker for COVID-19. Int Forum Allergy Rhinol 10, 944–950.


Vaira LA , Hopkins C , Salzano G , Petrocelli M , Melis A , Cucurullo M , Ferrari M , Gagliardini L , Pipolo C , Deiana G , Fiore V , De Vito A , Turra N , Canu S , Maglio A (2020) Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study. Head Neck 42, 1560–1569.


Mar 18, 2013
USA / Europe
You can get Parkinsonism from almost any viral infection since serotonin overload is required for any viral infection to take hold, and Parkinson turned out to be a condition of serotonin excess and not so much dopamine deficiency (even though serotonin excess would suppress dopaminergic functions in the brain). Again, any viral infection, especially in metabolically compromised people, can cause this and it is not unique to COVID-19.
Serotonin Excess, Not Dopamine Deficiency, May Be The Cause Of Parkinson
Tremor In Parkinson Disease (PD) Is Due To High Serotonin

It is not a coincidence that anti-serotonin drugs like cinanserin have been found to be therapeutic in COVID-19 and I think blocking serotonin before / during / after the infectious event may be therapeutic for the Parkinsonism, if it develops as a complication. It does not have to be cinanserin, cyproheptadine, Benadryl, famotidine, etc may also work and the last one has already been found to be therapeutic for COVID-19.
Cinanserin - Wikipedia

Tristan Loscha

Thread starter
Dec 18, 2018
@haidut @LeeLemonoil

I am still undecided myself, and consider everything. Toxicity of serotonin is well documented and will play it's part in covid-19 pathology. I liked the references and the notion of endotoxin LPS, which also locates in the mouth. Maybe we need to step up our mouthwash game for the covid critters!


Sep 24, 2016
Is aspiring high social status and material wealth a strategy to avoid LPS?
Are the Rich healthier because they live in clean buildings? Are the poor sick because they dwell in dirty corners, water damaged buildings full of bacteria?

Exaggerating of course, but maybe another piece of the puzzle.

Tristan Loscha

Thread starter
Dec 18, 2018
Is aspiring high social status and material wealth a strategy to avoid LPS?
Are the Rich healthier because they live in clean buildings? Are the poor sick because they dwell in dirty corners, water damaged buildings full of bacteria?

Exaggerating of course, but maybe another piece of the puzzle.

It is indeed. If i recall correctly, the physician Virchow was delegated by the rulers of the day to screen for causes of increased occurrence of pandemia - like concentration of common illnesses in particular quarters of neighborhoods, and he reported the causes as decreased access to hygiene and lower quality of the foodsupply.
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