Features and Management of Acute and Chronic Neuro Covid
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Marco Cascella Elvio De Blasio
IRCCS, Fondazione G. Pascale Emergency Unit
Istituto Nazionale Tumori Multidisciplinary Emergency Unit for
NAPOLI, Napoli COVID-19 Campania
Italy Napoli, Italy
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Dedicated to all colleagues and friends who
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Foreword
At the beginning of the pandemic, in the middle of the night, I received a message
from Marco asking for my opinion on a clinical case of COVID-19. He was excited
because the patient’s conditions rapidly improved after he received one dose of
tocilizumab. As an immunologist, I understood that the pathophysiology of the dis-
ease was largely attributable to the cytokine storm and this evidence could be
exploited for therapeutic purposes. In other words, what we learned over the years
in immuno-oncology could be translated to the treatment of COVID-19, particularly
the host inflammatory response phase of the disease. In this critical situation, it was
evident that not only the lung, but all the organs were affected by the hyperinflam-
mation with subsequent damage. In this context, the acute and long-lasting neuro-
logical manifestations of COVID-19 configure a chapter of paramount importance.
The authors have comprehensively addressed all the problems related to neuro-
COVID, from the neuropathogenesis of SARS-CoV-2 infection, to the acute clinical
pictures, and diagnostic approaches, to the post-acute neurological, psychiatric, and
neurocognitive issue. The result is a book that is enjoyable to read and full of infor-
mation. I appreciated, for example, the authors’ choice to summarize the therapeutic
suggestions into highlights. This strategy facilitates rapid consultation by those who
may have difficulty navigating into the plethora of scientific literature on the subject
and search for rapid practical suggestions. The efforts of the authors will certainly
be rewarded, and I am sure that both experienced readers and those who intend to
deepen their knowledge in the field will appreciate this book.
Paolo A. Ascierto
Unit of Melanoma, Cancer Immunotherapy
and Development Therapeutics
Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
Naples
Italy
vii
Preface
Similar to other epidemic-induced coronaviruses, the SARS-CoV-2 seems to be
neuroinvasive, neurotropic, and neurovirulent. A Chinese study published in the
first weeks after the onset of the pandemic reported neurological symptoms were
present in 36% of COVID-19 patients. Subsequently, thanks to the growing number
of data reported in the literature, clinicians and researchers deduced that the neuro-
logical manifestations could represent a separate chapter of the disease. The term
“neuro-COVID” was coined. Nevertheless, further data must be produced to char-
acterize its profile and obtain a precise taxonomy. In the meantime, we realize that
neuro-COVID is an umbrella that collects disparate clinical manifestations. In this
set, neurological effects, psychological/psychiatric aspects, and neurocognitive
phenomena are included. The pathophysiology of these processes is very complex.
Besides a potential direct viral damage, other mechanisms, such as immune-
mediated reactions, hypoxia, effects of multiorgan dysfunction, could be involved.
Furthermore, the consequences of long-term intensive care treatment, such as psy-
chological sequelae derived from isolation in critically ill patients, should not be
underestimated. These arguments also concern non-hospitalized patients who have
been subjected to a high burden of psychological distress.
In neuro-COVID, a logical distinction concerns the acute forms from those that
occur at a distance (Fig. 1). Although for narrative aims this approach is valid, it has
many limitations. Most of the clinical pictures recognize pathophysiology that
determines a trigger in the acute phase and that can clinically manifest itself within
the acute manifestations of the disease, or at a distance. Therefore, there is an over-
lapping and difficulties in temporally placing most phenomena often arise. For
example, changes in taste and smell, pain, headache, and dizziness may begin when
COVID-19 explodes and persist as respiratory symptoms resolve. Nevertheless, the
same clinical manifestations can occur after a free interval. Since several diagnostic
and therapeutic aspects must necessarily be kept separate, in this book the distinc-
tion between acute and chronic forms is maintained.
Another issue concerns the correlation between the clinical expressions of neuro-
COVID and the features of the underlying pathology. Myalgia, joint pain, sore
throat, abdominal pain, chest pain, and headache usually accompany respiratory
symptoms but they can also occur as isolated clinical findings, or can be expressed
regardless of the severity of COVID-19. Research on pathophysiology will clarify
this and other doubts. The angiotensin-converting enzyme 2/renin–angiotensin
ix
x Preface
system pathway and the direct virus-induced damage, the exuberant immune-
mediated inflammation, and disease-related factors represent a thriving field of
research that borders on the fields of neurology and embraces multiple disciplines.
The diagnostic phase plays a very important role. Given that the different expres-
sions of neuro-COVID can have a deleterious impact on the patient’s prognosis, a
high index of clinical suspicion for neurological complications is mandatory. Thus,
every effort should be done to reach a definitive diagnosis. In this contest, besides a
complete clinical evaluation, it is often necessary to utilize a battery of neuroimaging,
laboratory, and electrodiagnostic tests. Nevertheless, organizing diagnostic pathways
can be very difficult. For example, in the case of in-hospital patients, some diagnostic
procedures, such as neuroimaging techniques or electrophysiological tests, could be a
challenge due to the increased risk of virus transmission to other patients and staff.
A chapter of enormous interest in COVID-19 concerns the post-acute effects of
the disease. The implications, in fact, are manifold and range from the need to accu-
rately and urgently characterize the spectrum of clinical conditions that are involved,
to the healthcare needs, and obviously to the health costs associated with them. An
amount of scientific evidence is showing that COVID-19 is not only a pathology
that affects the physical health of those who contracted it, but it can induce a series
of non-negligible psychological consequences. Some symptoms related to the con-
tracted infection such as fatigue, weakness, and pain rarely disappear immediately
once the critical phase of the disease is overcome but also occur in the periods fol-
lowing COVID-19, impacting the quality of life of patients who have contracted the
SARS-CoV-2 infection. In particular, symptoms such as fear, mood changes, states
of anxiety, depression, sleep disorders, and insomnia can occur alone or in combina-
tion by structuring a variety of psychological syndromes. In the context of long-
COVID, risk factors should be carefully addressed. It seems, for instance, that
middle-aged women are more prone to develop debilitating long-term symptoms.
The therapy of many clinical forms of neuro-COVID is often addressed by the
individual specialist according to the type of symptom, or clinical manifestation,
Neuro-COVID
ACUTE CONDITIONS LONG-TERM EFFECTS
Central Nervous System
Neurological sequelae Psychological
• Headache Peripheral Nervous Skeletal muscle effects
• Fatigue and muscle
• Dizziness System manifestations
weakness • Anxiety
• Acute encephalopathy • Hypo/anosmia, • Depression
• Headache
• Posterior reversible dysgeusia/ageusia • Seizures • Affective
encephalopathy syndrome • Guillain-Barré Psychological • Smell and taste disorders
• Seizures syndrome and psychiatric • Sleep issues
disorders
• Acute cerebrovascular (and subtypes) acute problems
• Guillain Barré • PTSD
diseases • Pain syndrome
• Meningitis/encephalitis • Cranial nerve • Chronic pain Neurocognitive
• Acute myelitis injuries • Post-acute stroke issues
Fig. 1 Neuro-COVID: Synopsis
Preface xi
who follows the rules of good clinical practice. Very often, however, this approach
is not enough and a multidisciplinary, or preferably interdisciplinary, strategy is
desirable. It is a further challenge that launches the disease. It seems appropriate to
create synergies between medical and non-medical branches that are apparently
distant and to intensify efforts in the field of translational medicine.
Since research on SARS-CoV-2 and COVID-19 is advancing at unprecedented
speed, much data reported in this book on the pathophysiology, clinic, diagnosis,
and therapy will soon become obsolete. However, another lesson this pandemic has
taught us is to speed up the timing of science disclosure. It provides the implementa-
tion of translational research and building of research programs starting from syn-
thetic, but exhaustive, pathways, on specific topics. It is the real purpose of this
manuscript. To write it, we raced against time for providing an agile and useful book
to be consulted by clinicians, researchers, and even non-expert readers.
Napoli, Italy Marco Cascella
Napoli, Italy Elvio De Blasio
Acknowledgments
The list of people we should thank is particularly long. They are all those doctors,
nurses, health workers who, since the beginning of the pandemic, have thrown all of
themselves into the arena fighting against this indomitable beast. This book is dedi-
cated to all of them, and from them, we have obtained a wealth of data, suggestions,
most of which are not collected in scientific publications, but are an integral part of
a wealth of experience that will remain indelible. This wonderful inspiration
enhanced our determination and creativity.
We are especially grateful to colleagues who materially assisted us in drafting
the text, especially when we faced topics that went beyond our areas of competence.
In particular, we have to extend our heartfelt thanks to two doctors and researchers
of the San Pio Hospital (Benevento, Italy). Dr. Marco Sparaco, a neurologist from
the Division of Neurology and Stroke Unit performed an excellent revision of the
chapter on clinical features of neuro-COVID. Moreover, Dr. Carmine Franco
Muccio, neuroradiologist from the Division of Neuroradiology of the same hospital
has offered an invaluable contribution in drafting the chapter on diagnostics.
We thank Dr. Andrea Ridolfi, Editor Clinical Medicine Books, Responsible
Editor, Intensive Care Medicine, Anesthesiology, Neurology at Springer for his
kind and professional coordination. The experience accumulated in the field of sci-
entific publications allows us to affirm that his competence is far above the average.
He provided us with valuable advice at each stage of our project development.
These requirements are what an author expects when the best publisher to entrust
his/her manuscript is sought.
Finally, special thanks go to Laura and Vincenzo Cascella, medical students.
They have critically read the text and provided us with important suggestions to
make it accessible not only to expert readers, but also to those who are confronted
with these issues for the first time.
xiii
Contents
1 Pathophysiology of COVID-19-Associated Neurotoxicity���������������������� 1
1.1 Introduction���������������������������������������������������������������������������������������� 1
1.2 Overview on Neurological Manifestations ���������������������������������������� 3
1.3 Pathophysiology of COVID-19-Associated Neurotoxicity���������������� 4
1.3.1 The Issue of SARS-CoV-2 Neurotropism������������������������������ 5
1.3.2 Mechanisms of Diffusion Towards the Nervous Tissue���������� 12
1.3.3 Immune-Mediated Neurological Processes���������������������������� 17
1.3.4 Gut–Brain Axis Involvement�������������������������������������������������� 22
1.3.5 Effects of Multiorgan Dysfunction ���������������������������������������� 23
1.4 Potential Mechanisms for Long-Term Neurotoxicity ������������������������ 23
1.5 Pain and COVID-19: The COVID-Pain Issue������������������������������������ 25
1.5.1 Acute Clinical Manifestations������������������������������������������������ 25
1.5.2 Long-Term Painful Clinical Manifestations �������������������������� 27
1.6 Ongoing Clinical Research ���������������������������������������������������������������� 28
1.7 Research Perspectives ������������������������������������������������������������������������ 30
1.8 Conclusions���������������������������������������������������������������������������������������� 33
References���������������������������������������������������������������������������������������������������� 35
2 Acute Manifestations of Neuro-COVID�������������������������������������������������� 43
2.1 Introduction. Overview on Clinical Manifestations
of the Disease�������������������������������������������������������������������������������������� 43
2.2 Pathogenic Mechanisms���������������������������������������������������������������������� 46
2.3 Classification Approaches������������������������������������������������������������������ 47
2.4 Central Nervous System Manifestations�������������������������������������������� 49
2.4.1 Headache and Dizziness �������������������������������������������������������� 51
2.4.2 Acute Encephalopathy������������������������������������������������������������ 53
2.4.3 Posterior Reversible Encephalopathy Syndrome�������������������� 55
2.4.4 Seizures ���������������������������������������������������������������������������������� 57
2.4.5 Acute Cerebrovascular Diseases�������������������������������������������� 59
2.4.6 Meningitis and Encephalitis���������������������������������������������������� 67
2.4.7 Acute Myelitis������������������������������������������������������������������������ 71
2.5 PNS Manifestations���������������������������������������������������������������������������� 73
2.5.1 Hypo/Anosmia and Dysgeusia/Ageusia �������������������������������� 74
2.5.2 Guillain-Barré Syndrome and Variants ���������������������������������� 75
xv
xvi Contents
2.5.3 Pain ���������������������������������������������������������������������������������������� 80
2.6 Skeletal Muscle Manifestations���������������������������������������������������������� 81
2.6.1 Asthenia and Myalgia ������������������������������������������������������������ 81
2.6.2 Skeletal Muscle Injury������������������������������������������������������������ 81
2.7 Psychiatric Manifestations������������������������������������������������������������������ 82
2.8 Conclusions���������������������������������������������������������������������������������������� 87
References���������������������������������������������������������������������������������������������������� 87
3 Diagnostic Approaches to Acute Neuro-COVID ������������������������������������ 95
3.1 Introduction���������������������������������������������������������������������������������������� 95
3.2 Neuroimaging ������������������������������������������������������������������������������������ 96
3.2.1 Stroke�������������������������������������������������������������������������������������� 96
3.2.2 Cerebral Hemorrhagic Lesions ���������������������������������������������� 98
3.2.3 Mixed Pictures������������������������������������������������������������������������ 99
3.2.4 Posterior Reversible Encephalopathy Syndrome�������������������� 100
3.2.5 Encephalitis���������������������������������������������������������������������������� 102
3.2.6 Myelitis ���������������������������������������������������������������������������������� 105
3.2.7 Peripheral Nervous System and Muscular Disorders ������������ 106
3.2.8 Clinical and Neuroimaging Correlation���������������������������������� 108
3.2.9 The Role of Brain Positron Emission Tomography���������������� 111
3.2.10 Other Diagnostic Approaches ������������������������������������������������ 112
3.3 Electrodiagnostic Tests ���������������������������������������������������������������������� 113
3.3.1 EEG: Indications, Approaches, Features,
and Limitations ���������������������������������������������������������������������� 113
3.3.2 ICU-Acquired Weakness in COVID-19 Patients�������������������� 120
3.3.3 Mixed CNS/PNS Pictures ������������������������������������������������������ 122
3.4 Laboratory Tests���������������������������������������������������������������������������������� 123
3.5 Neuropathological Findings���������������������������������������������������������������� 127
3.6 Conclusions���������������������������������������������������������������������������������������� 130
References���������������������������������������������������������������������������������������������������� 130
4 Neurological, Psychological, and Cognitive Manifestations of Long-
COVID�������������������������������������������������������������������������������������������������������� 137
4.1 Introduction���������������������������������������������������������������������������������������� 137
4.2 The Long-COVID Phenomenon in Numbers ������������������������������������ 139
4.3 Neurological Symptoms���������������������������������������������������������������������� 141
4.3.1 Mechanisms���������������������������������������������������������������������������� 141
4.3.2 Clinical Features �������������������������������������������������������������������� 142
4.4 Psychological Sequelae of Long-COVID ������������������������������������������ 147
4.4.1 Disease-Related or Pandemic-Induced Effects? �������������������� 147
4.4.2 From Acute to Chronic Psychiatric Problems������������������������ 148
4.5 Potential Long-Term Cognitive Issues������������������������������������������������ 151
4.6 Conclusions���������������������������������������������������������������������������������������� 154
References���������������������������������������������������������������������������������������������������� 154
Abbreviations
F-FDG
18
F-fluorodeoxyglucose
18
ACE Angiotensin-converting enzyme
ADC Apparent diffusion coefficient
ADEM Acute disseminated encephalomyelitis
AHLE Acute hemorrhagic leukoencephalomyelitis
AIDP Acute inflammatory demyelinating polyradiculoneuropathy
AMAN Acute motor axonal neuropathy
AMSAN Acute motor and sensory axonal neuropathy
ANE Acute necrotizing encephalitis
Ang Angiotensin
ANM Acute necrotizing myelitis
ARDS Acute respiratory distress syndrome
ASL Arterial spin labelling
AT Ang type
BBB Blood-–brain barrier
BBE Bickerstaff brainstem encephalitis
BCSFB Blood–cerebrospinal fluid barrier
BDNF Brain-derived neurotropic factor
BFP Bilateral facial palsy with paresthesia
BMS Brain midline shift
CAM Confusion assessment method
CAR-T Chimeric antigen receptor T
CBF Cerebral blood flow
CBV Cerebral blood volume
CendR C-end rule
CNS Central nervous system
COVID-19 Coronavirus-induced disease 2019
CRP C-reactive protein
CRS Cytokine release syndrome
CSF Cerebrospinal fluid
CT Computed tomography
CTA CT-Angiography
CTP CT perfusion
DCE Dynamic contrast enhancement
xvii
xviii Abbreviations
DPP4 Dipeptidylpeptidase 4
DRG Dorsal root ganglia
DSC Dynamic susceptibility contrast
DWI Diffusion weighted imaging
EEG Electroencephalography
EMG Electromyography
FLAIR Fluid-attenuated inversion recovery
GBS Guillain-Barré syndrome
GCS Glasgow Coma Score
GFAp Glial fibrillary acidic protein
GM-CSF Granulocyte-macrophage colony-stimulating factor
HCoV Human coronavirus
HEV Hemagglutinating encephalomyelitis virus
HIV Human immunodeficiency virus
ICH Intracerebral hemorrhage
ICP Intracranial pressure
ICU Intensive care unit
IFN Interferon
IL Interleukin
IP10 Interferon gamma inducible protein-10
IVIG Intravenous IG
MCP1 Monocyte chemoattractant protein 1
MERS Middle East respiratory syndrome
MFS Miller Fisher Syndrome
MHV Murine hepatitis virus
MIP1A Macrophage inflammatory protein 1A
MIS-C Multisystem inflammatory syndrome in children
MMP Matrix metalloproteinase
MRI Magnetic resonance imaging
mRS Modified Rankin scale
nEVs Neuronal-enriched extracellular vesicles
NICE National Institute for Health and Care Excellence
NIHSS National Institutes of Health Stroke Scale
NIRS Near-infrared spectroscopy
NK Natural killer
NRP Neuropilin
OB Olfactory bulb
ORN Olfactory receptor neuron
PAG Periaqueductal gray
PD Parkinson’s disease
PET Positron emission tomography
PICS Post-intensive care syndrome
PNC Polyneuritis cranialis
PNS Peripheral nervous system
PP2A Protein phosphatase 2A
Abbreviations xix
PRES Posterior reversible encephalopathy syndrome
PTSD Post-traumatic stress disorder
RAS Renin–angiotensin system
ROS Reactive oxygen species
RT-PCR Reverse transcriptase-polymerase chain reaction
SAH Subarachnoid hemorrhage
SARS Severe acute respiratory syndrome
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
SSE Shannon’s spectral entropy
STIR Short tau inversion recovery
SWI Susceptibility weighted imaging
TCCD Transcranial color-coded duplex
TCD Transcranial cerebral Doppler
TF Tissue factor
TLR Toll-like receptors
TMPRSS Transmembrane serine protease
TNF-α Tumor necrosis factor α
US United States
WBC White blood cell count
Pathophysiology of COVID-19-
Associated Neurotoxicity 1
1.1 Introduction
The clinical spectrum of COVID-19 (coronavirus induced disease 2019), the pan-
demic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2), varies from paucisymptomatic forms to clinical conditions ranging from
different degrees of respiratory insufficiency to multiorgan/systemic manifestations
such as sepsis, septic shock, until multiorgan failure.
Similar to SARS-CoV which is another member of the family Coronaviridae
and responsible for the severe acute respiratory syndrome (SARS) outbreak, from
2002 to 2003, SARS-CoV-2 can spread through active pharyngeal viral shedding. In
turn, extrapulmonary manifestations of COVID-19 are encompassed among the
clinical features of the disease. Nevertheless, a key aspect of the COVID-19 patho-
physiology is understanding whether this extrapulmonary involvement is produced
by damage from viral spreading (direct damage). Moreover, it should be advisable
to distinguish alterations produced by an aberrant inflammatory response to the
viral attack (indirect damage) from organ damage that is the expression of advanced
disease with multiorgan dysfunction or failure. The latter picture has complex
pathophysiology including invasive therapies, drugs, severe hypoxia, and
other causes.
Regardless of the precise underlying pathogenic mechanisms, it is remarkable
that in COVID-19 several extrapulmonary manifestations frequently occur [1].
Evidence suggests that hematologic [2], cardiovascular [3], renal [4], gastrointesti-
nal, hepatobiliary, and pancreatic [5] systems, and other organs [6–8] can be affected
by the disease.
Within the context of the COVID-19-related extrapulmonary manifestations, the
neurologic aspects of the disease represent a special chapter [9, 10]. The term
“neuro-COVID” is useful for encompassing these neurological manifestations.
Notably, neurological issues were also described in other coronavirus-induced dis-
eases including the SARS and the Middle East respiratory syndrome (MERS), in
© The Author(s), under exclusive license to Springer Nature 1
Switzerland AG 2022
M. Cascella, E. De Blasio, Features and Management of Acute and Chronic
Neuro-Covid, https://doi.org/10.1007/978-3-030-86705-8_1
2 1 Pathophysiology of COVID-19-Associated Neurotoxicity
2012 [11]. It was demonstrated, for instance, that SARS-CoV can provoke a wide
range of lesions to the neurons, such as demyelination, and glial cells, mostly
expressed as glial hyperplasia; these lesions were localized in several brain areas
[12]. Previously, in 1993, and thus before the emergence of SARS and MERS, some
authors conducted in vitro and in vivo experiments for evaluating the neurotoxicity
of the human coronavirus HCV-229E on oligodendrocytes [13]. Later, it was also
proved that primary cultures of human neural cells, adult astrocytes, and adult
microglia can be infected by coronaviruses [14]. Interestingly, the awareness that
many coronaviruses, not just human coronaviruses (HCoVs), can infect the central
nervous system (CNS) of animals has long been known. In 1962, Greig et al. [15]
isolated the hemagglutinating encephalomyelitis virus (HEV), which is a
β-coronavirus, in the brains of pigs. Furthermore, in the early 1980s, two different
coronaviruses were detected in autopsy neural tissues of two patients suffering from
multiple sclerosis. The viruses, generically indicated with the initials of the patients
and not further characterized, were also isolated in their cerebrospinal fluid
(CSF) [16].
Thus, similar to other epidemic-induced coronaviruses, the SARS-CoV-2 seems
to be neuroinvasive, neurotropic, and neurovirulent. Nevertheless, given the magni-
tude of the COVID-19 pandemic, these phenomena can have considerable
importance.
Despite the great interest of the scientific community in the neuropathogenesis of
SARS-CoV-2 infection, there are many open questions. The potential route of entry
of the virus to the nervous tissue, the ability to damage cells, and the induction of
immune-mediated processes are all issues that must necessarily be well elucidated.
As mentioned above, the question is whether the clinical manifestations of neuro-
COVID are the effect of direct viral damage or they are caused by an excessive
immune-mediated response of the host. Is it possible an association between both
mechanics? Similarly, it would be appropriate to distinguish between events that
characterize acute damage to central and peripheral nervous tissue from processes
that could clinically manifest at a distance. The pathophysiology of the latter could
be very complex to explain. In addition to direct viral damage, other mechanisms
such as immune-mediated reactions, hypoxia, effects of multiorgan dysfunction,
could be involved. Furthermore, the consequences of long-term intensive care treat-
ment, such as psychological sequelae derived from isolation in critically ill patients,
should not be underestimated.
On these premises, a worrying scenario is opened and further research is needed
to better clarify if the neurotoxicity can induce long-term sequelae probably mani-
fested in terms of post-infectious neurodegenerative and neuroinflammatory com-
plications. Previous studies, indeed, suggested that coronaviruses can provoke
processes of demyelination, neurodegeneration, and cellular senescence. These
changes could also accelerate brain aging and/or exacerbate neurodegenerative con-
ditions [17].
Starting from experimental elements that come from different branches such as
molecular biology, virology, neurophysiology, the study of pathophysiology must
1.2 Overview on Neurological Manifestations 3
be able to arrive at an overall vision, as it happens for the construction of a mosaic.
Although we are a long way from this goal, the road seems to have been drawn.
Moreover, the vast spectrum of neurological manifestations involves two types
of problems. The former concerns the need for clinical care of patients who can be
extremely complex to treat. On the other hand, the latter issue concerns the need to
strengthen the preclinical research aimed at identifying the pathogenic mechanisms
underlying the pulmonary and extrapulmonary involvement of the disease for offer-
ing clinicians better therapeutic choices [18–21].
This chapter is aimed at dissecting the pathologic mechanisms of COVID-19-
associated neurotoxicity. The issue of pain mechanisms (COVID-pain) is dis-
cussed and updates on preclinical findings, ongoing clinical investigations, as
well as perspectives for conducting preclinical and clinical investigations are
also proposed.
1.2 Overview on Neurological Manifestations
The neuro-COVID chapter encompasses clinical manifestations of varying severity,
incidence, and significance. They can manifest before fever and respiratory symp-
toms, or be the unique clinical manifestation of COVID-19. Additionally, clinical
manifestations may also occur after the resolution of the acute phase (long-COVID).
Although in most cases there are isolated neurological symptoms (e.g., headache,
dizziness), complex scenarios can occur. Therefore, the term neuro-COVID is an
oversimplification as it appears to be a great umbrella that collects disparate clinical
conditions.
According to the location of symptoms, neurologic manifestations of
COVID-19 can be grouped into three categories including central nervous sys-
tem (CNS) manifestations, peripheral nervous system (PNS) manifestations, and
skeletal/muscular clinical expressions. Furthermore, the onset time of the clini-
cal presentations can help differentiate infective (acute) from post-infective com-
plications. A classification based on the pathophysiology of the symptoms seems
to be more appropriate. It should differentiate clinical conditions produced by
direct damage from others related to indirect injury (e.g., neuroinflammation and
cytokine-related injury), or disease-related (e.g., ischemic, multiorgan impair-
ment) damage. Nevertheless, it is often difficult to separate the mechanisms and
overlap phenomena exist.
Headache is one of the most common signs of COVID-19 (often associated
with fever). It usually has a non-specific meaning. Clinically it is manifested as
tension-type or migraine without aura, migraine-like headache (less com-
monly), with long-lasting duration and analgesic resistance. Dizziness is fre-
quently combined with headache (and tinnitus), and is often observed
in the earlier disease.
Data from literature and clinical experience suggest that olfactory and gusta-
tory dysfunction is considered an early manifestation of COVID-19 infection [1].