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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5221_Библиотеки_им_академика_М_И_Перельмана.pdf
Infectious Disease and Neurocognition
there is no evidence to suggest that the cognitive dysfunction found in children and
adolescents diers from that found in adults.
In addition to suggesting what might cause cognitive dysfunction, there are suggestions of what does not cause it. One or more studies support each of the following
conclusions: cognitive dysfunction is not related to the fatigue of the patient at the
time of testing (Josev et al., 2020; Michiels & Cluydts, 2001), cognitive dysfunction
is not related to the presence or the degree of depression in the patient (Michiels &
Cluydts, 2001; Robinson et al., 2019), and the severity of cognitive dysfunction is not
proportional to the duration of the patient’s illness (Santamarina- Perez et al., 2011).
Our findings in context
FM and ME/ CFS are examples of illnesses that are associated with either antecedent
or comorbid infection aer which cognitive dysfunction ensues.
We would be remiss were we not to mention and perhaps include long Covid patients because they can satisfy the diagnostic criteria of ME/ CFS and develop cognitive dysfunction. A relatively recent estimate of long Covid patients places their
number at 145 million people worldwide (Hanson et al., 2022).
A search of the PubMed database using the search terms (long Covid) and (cognitive function) and (domains) resulted in 42 citations. We found one meta- analysis of
papers that studied the cognitive dysfunctions associated with long Covid (Biagianti
et al., 2022). Moreover, in an examination of 1.9 million mild Covid cases by Larkin
(2023), cognitive dysfunction was found to be among the long Covid symptoms endured by these patients suggesting that acute, mild cases of Covid- 19 are capable of
producing cognitive dysfunction beyond the active phase of infection.
Larkin’s (2023) meta- analysis search strategy retrieved 711 articles, of which
only 19 were included in his review. One of his ndings relevant to our subject is
that cognitive function assessment tools dier in their ability to detect the severity of the various domains of cognitive dysfunction. For example, the Montreal
Cognitive Assessment is better at detecting mild decits while the Mini- Mental State
Examination is better at detecting moderate- to- severe decits (Liew et al., 2015).
us, we are cautioned that it is dicult to compare or combine studies when different instruments of cognitive assessment are used. We agree. Our approach in
Table 22.6 is to provide the reader with a sampling of the studies in the literature,
indicating the place or places where the studies were conducted, the number of patients included in the study as an approximation of the reliability of the ndings, the
cognitive assessment instruments used in the studies, and a brief summary of the
authors’ ndings. e reader can then appreciate the diculties involved in drawing
conclusions from this heterogeneous group of studies. Based on our interpretation
of the available research ndings, we conclude that (1) overall, the cognitive dysfunction confronting long Covid patients is similar to those confronting FM and
ME/ CFS patients; (2) there is a need for larger studies employing more uniform
Fibromyalgia and Chronic Fatigue 389
Table 22.6 Summary of cognitive impairments in long Covid
Ref. Country Number of
Patients
1 UK 81,337 recovered
patients
2 Spain 136 recovered
patients with
cognitive
complaints
3 Spain 50 patients
reporting no
complaints 6–
9 months aer
To o ls Results
Spatial problem- solving; spatial
planning; working memory; spatial
short- term memory capacity;
spatial visual attention; spatially
manipulate objects; semantic
reasoning; identify the correct
denitions of words; identify and
discern between emotions
T- MoCA, Conners Continuous
Performance Test II (CPT- II), Rey’s
Auditory Verbal Learning Test
(RAVLT), Rey– Osterrieth Complex
Figure Test (ROCFT), Digit Span
Forward and Backward, Boston
Naming Test (BNT), Block Design,
Coding, Symbol Search, TMT Parts
A and B, Stroop task, and verbal
uency tasks
Forward and backward digit span,
Corsi block- tapping test, Symbol
Digit Modalities Test, Boston
Naming Test, Judgment Line
Orientation (JLO), Rey– Osterrieth
Complex Figure (copy and recall at
3, 30 min, and recognition), Free
and Cued Selective Reminding Test,
verbal uencies (animals and words
beginning with “p” and “m” in 1
minute each one), Stroop Color–
Word Interference Test, and the
Visual Object and Space Perception
Battery
People who had
recovered from
Covid- 19, including
those no longer
reporting symptoms,
exhibited signicant
cognitive decits
Executive
functioning and
attention were
shown to be crucial
cognitive factors
related to fatigue
Diminished
performance on
several tests evaluating
attention and executive
function. Alterations
in processing speed,
divided attention,
selective attention,
visual vigilance,
intrinsic alertness,
working memory,
inhibition, episodic
memory, and
visuospatial processing
4 Canada 478 self- reported
Covid- 19 positive
Covid- 19- positive cohort compared
to normative data on ve composite
scores (i.e., domains) of cognitive
performance, instead of testing each
of the 12 cognitive tasks separately
Participants
performed
signicantly
worse than prepandemic norms on
cognitive measures
of processing
speed, reasoning,
verbal, and overall
performance, but not
short- term memory,
suggesting domainspecic decits.
Cognitive dierences
are even observed
in participants who
did not require
hospitalization
(continued)
Infectious Disease and Neurocognition
Table 22.6 Continued
Ref. Country Number of
Patients
5 Italy 76 hospitalized
patients
To o ls Results
e Brief Repeatable Battery of
Neuropsychological Tests which
assess verbal and visuospatial long‐
term memory, attention, working
memory, processing speed, language.
e Serial Recall Test— a test of
verbal memory composed of three
sub- scores: (i) long‐term storage, an
index of eciency in verbal long‐
term memory storage processes;
(ii) consistent long‐term retrieval,
which reects the consistency of
unaided retrieval from verbal long‐
term memory storage; (iii) delayed
recall, an index of long‐term verbal
recall ability. e Spatial Recall Test
evaluates visuospatial memory and
produces two sub scores: (i) SPART,
a measure of visuospatial learning;
(ii) SPART‐D, a measure of delayed
visuospatial recall. e Symbol‐Digit
Modalities Test is a measure of
processing speed and visual attention.
e Paced Serial Additions Test
evaluates working memory and
attention and consists of two tests,
one in which numbers are presented
with an interval of 3 seconds and
one with an interval of 2 seconds.
Lastly, the Word List Generation
test represents an index of language
functioning and specically of
semantic verbal uency
Verbal memory,
attention, and
processing
speed improved
signicantly aer
1 year, whereas
visuospatial memory
did not. e most
aected domains
aer 1 year were
processing speed
(28.3 percent) and
long- term visuospatial
(18.1 percent) and
verbal (15.1 percent)
memory
6 Spain 152 patients
90– 120 days aer
hospital discharge
e California Verbal Learning
Test, the Free and Cued Selective
Reminding Test for verbal episodic
memory, Boston Naming Test
for denomination capacity,
Rey Complex Figure Test for
visuospatial episodic memory, and
Digit Retention Test of Wechsler
Adult Intelligence Scale for working
memory and memory reserve
Impairment in episodic
verbal memory
was observed in
34.7– 38.5 percent
of patients. Working
memory w as a ect ed
in 26.4– 36.7 percent
of the sample. Other
types of memory such
as semantic memory
seemed less aected.
e impairment of
executive functions was
substantial. Variables
related to attention,
were abnormal for
34.2 percent of the
sample
Table 22.6 Continued
Fibromyalgia and Chronic Fatigue 391
Ref. Country Number of
Patients
7 Canada
Spain
8 Finland 213: ICU, ward,
63 post- Covid19 patients with
complaints
home- treated
To o ls Results
MoCA, CPT‐II, RAVLT, ROCFT,
Digit Span Forward and Backward,
BNT, Block Design, Coding, Symbol
Search, TMT, Stroop, verbal uency
tasks, and the 15‐Objects Test
Wechsler Adult Intelligence
Scale- IV coding, Continuous
Performance Test, and Stroop
Naming, executive functions with
TMT Part B, Stroop Interference,
and Frontal Assessment Battery,
and memory with WMS- III word
list, delayed recall, WMS- III logical
memory, delayed recall, and Rey
Complex Figure, delayed recall
Patients suered from
pervasive impact on
attention abilities,
both as the singularly
aected domain
(19 percent of singledomain impairment)
as well as coupled
with decreased
performance in
executive functions,
learning, and longterm memory. Decits
are unrelated to
clinical factors such as
hospitalization, disease
duration, biomarkers,
or aective measures
e groups diered
in the total cognitive
score, calculated
in three domains
(attention, executive
functions, and
memory). Both
patients treated in the
intensive- care unit and
ward- treated patients
performed worse than
home- isolated patients
9 USA 72 Remotely administered BrainCheck
including the TMT for executive
function (cognitive exibility), the
Digit Symbol Substitution Test for
attention and processing speed, the
Stroop Test for executive function
(response inhibition), and the List
Learning Test for immediate and
delayed verbal memory
e frequency of
objective cognitive
impairment was
40 percent. 24 percent
of participants showed
impairment on a
measure of executive
functioning. Attention
and processing speed
were more impaired
in males. Younger
age was correlated
with impairment.
A greater number of
Covid- 19 symptoms
was correlated with
lower subjective
cognitive function.
Moderate Covid- 19
severity was associated
with attention- and
processing- speed
impairment
Infectious Disease and Neurocognition
Table 22.6 Continued
Ref. Country Number of
Patients
10 South
Korea
Abbreviations: BNT, Boston Naming Test; CPT II, Conners’ Continuous Performance Test II; ICU, intensive care
unit; JLO, Judgment Line Orientation; RAVLT, Rey Auditory Verbal Learning Test; Ref., reference; ROCFT, Rey–
Osterrieth Complex Figure Test; SPART, Spatial Recall Test; TMT, Trail Making Test; T- MoCA, Telephone interviewed Montreal Cognitive Assessment; WMS- III, Wechsler Memory Scale third edition.
Reference citation key: 1. Hampshire et al., 2021; 2. Calabria et al., 2022; 3. Delgado- Alonzo et al., 2022; 4. Wild
et al., 2022; 5. Ferrucci et al., 2022; 6. Serrano- Castro et al., 2022; 7. García- Sánchez et al., 2022; 8. Ollila et al., 2022;
9. Henneghan et al., 2022; 10. Chang et al., 2022.
40 post- Covid- 19 Digit Span Forward (attention/
To o ls Results
72 percent
processing speed) and Backward
(working memory) tests, the TMT
Part A (attention/ processing speed)
and Part B (executive functioning),
and the Stroop Word– Color
Interference Test (executive
functioning)
(n = 29) of subjects
had impairments
in at least one
cognitive domain.
e most frequent
impairment was in
executive function
(64.9 percent)
followed by
impairments in
processing speed
and attention
(52.5 percent) and
working memory
(42.5 percent)
patient selection criteria and utilizing the same cognitive assessment instruments;
and (3) that for the purposes of advocating for research into the relationship between infectious agents and cognitive dysfunction, long Covid patients should be
added to the group of patients so impaired.
Other infectious diseases associated
with cognitive impairment
In addition to possible associations between ME/ CFS and FM and infectious diseases, a variety of other infectious diseases as discussed throughout this volume
have been associated with cognitive impairment. To provide a general overview of
such diseases and to place the associations between ME/ CFS and FM in a broader
context, we searched PubMed utilizing the search terms (infectious diseases) AND
(cognitive dysfunction), which resulted in the 16 diseases listed in Table 22.7. To
determine the extent to which each of these diseases has been investigated for cognitive dysfunction, we searched each individual disease and cognitive dysfunction. If
the resultant number of identied studies permitted further renement, we searched
that individual disease and cognitive dysfunction and domains as text words. e
results appear in the Table 22.7.
Fibromyalgia and Chronic Fatigue 393
Table 22.7 Number of articles that examine the relationship of infectious
diseases and general and domain- specific cognitive dysfunction
Number of articles
Disease General Domain specic
Chikungunya virus 2
Coccidioidal meningitis 2
Covid- 19 or long Covid 538 39
Dengue virus 4
Ebola 2
Epstein– Barr virus 16
Hepatitis C virus 122 16
Human immunodeciency virus (HIV) 153
Human T- cell lymphotropic virus (HTLV) 10
Human herpesvirus 62 7
Malaria 43
Murine typhus 1
Neuroborreliosis (Lyme disease) 14
Neurosyphilis 29 2
Varicella zoster virus 7 2
Zika virus 11
e relationship of human immunodeciency virus (HIV) to cognitive dysfunction is complex (Saylor et al., 2016) with the burden of neurocognitive disorders ranging from 7.3 percent to 85 percent (Zenebe et al., 2022), thereby
making the estimation of the number of patients experiencing cognitive dysfunction dicult.
While the infectious origin and cognitive dysfunction associated with tickborne illness is beyond the scope of this chapter but in view of the increasing public
and personal awareness of tick- borne diseases, we briey address the chronic diseases and cognitive dysfunction associated with tick bites. Despite there being a
multitude of tick species, Cutler et al. (2021) report that only 32 tick species bite
humans. Much of the available research ndings is focused on Lyme disease,
chronic Lyme disease, and post- treatment Lyme disease syndrome, all of which
are generated by Borrelia burgdorferi. ese infections are transmitted to humans
by infected Ixodes ticks (K. H. Wong et al., 2022). Lindquist and Vapalahti (2008)
describe an encephalitis caused by a avivirus that is also transmitted to humans
Infectious Disease and Neurocognition
by Ixodes ticks and is signicant because of its expansive geographic range from
western Europe to the east coast of Japan. Several species of avivirus are known
to cause cognitive impairment (Zucker et al., 2017). A third infection resulting
from tick bites, described by Neto et al. (2014), is Brazilian human borreliosis,
also known as Baggio– Yoshinari syndrome. Baggio– Yoshinari syndrome can produce oligoarthritis, cognitive impairment, meningoencephalitis, and erythema
nodosum.
Alzheimer’s disease has been associated with various pathogens including
viruses, bacteria, fungi, and parasites (Vigasova et al., 2021). Damiano et al.
(2022) and Hernandez- Ruiz et al. (2022) suggest that herpes, cytomegalovirus,
HIV, varicella zoster, Epstein– Barr, and hepatitis C viruses may be associated
with Alzheimer’s disease. In addition, Treponema pallidum and Chlamydia
pneumonia also have been associated with Alzheimer’s disease (Breijyeh &
Karaman, 2020).
Another infectious disease associated with cognitive dysfunction is malaria, where
cognitive dysfunction has been found in both adults (Chaudhary et al., 2022) and
children (Itzhaki & Wozniak, 2007).
Helminthiases such as Ascaris lumbricoides, Trichuris trichiura, Ancylostoma
duodenale, and Necator americanus may aect up to one- third of the world’s population (Pabalan et al., 2018) and have been associated with decreased cognitive function in children ages 7– 18 years in four domains: learning, memory, verbal uency,
and nonverbal intelligence (Ezeamama et al., 2005).
The association between infectious diseases and cognitive dysfunction is an
underexplored research area, particularly in view of the likely large population
of patients who have cognitive dysfunction subsequent to infection. It would be
difficult to calculate or estimate the world population burdened with cognitive
difficulties associated with precedent or comorbid infectious diseases. We can,
however, estimate the combined number of ME/ CFS, FM, and long Covid patients. We do so here because it has been noted that some long Covid patients
satisfy the diagnostic criteria for ME/ CFS. As FM is thought to occur in an estimated 2– 4 percent of the general population (Häuser & Fitzcharles, 2018), and
based on the United Nation’s current estimate of the world population of 8 billion people (United Nations, 2023), we estimate a disease burden of FM of between 160 and 320 million people. Similarly, the global prevalence of ME/ CFS is
estimated to be between 17 and 24 million people (Marshall- Gradisnik & EatonFitch, 2022). Summing the two estimates produces an estimated worldwide
number of people with FM or ME/ CFS of approximately 200 million patients.
Adding the estimated 145 million people globally with long Covid (Hanson et al.,
2022) to the estimated number of patients with ME/ CFS and FM brings the total
to 345 million. The hypothesis that these three diseases belong to a larger group
of infectious diseases associated with cognitive dysfunction, namely post- active
phase of infection syndromes (PAPIS) has been published elsewhere (Friedman
et al., 2022).
Fibromyalgia and Chronic Fatigue 395
Conclusion
Querying PubMed for literature supporting prior or comorbid infections in patients
diagnosed with ME/ CFS or FM yielded reports of such relationships from numerous
countries sustained over decades. ese results lead us to the conclusion that such
relationships exist. Moreover, we found that the infections associated with ME/ CFS
usually dier from those associated with FM. We cannot state, however, that a prior
or comorbid infection is mandatory for the onset of all cases of ME/ CFS or FM.
We similarly found that querying PubMed for literature supporting cognitive impairment as a sequel to ME/ CFS and FM shows such reports from numerous countries occurring over decades. We conclude that both ME/ CFS and FM have a high
probability of resulting in, or being followed by, cognitive impairment. e literature
we examined did not provide sucient detail for us to be able to parse dierences
between the cognitive impairment(s) associated with ME/ CFS from those of FM.
Additional literature searching has led us to conclude that the infective and inammatory processes associated with ME/ CFS and FM are by no means unique to
these two diseases. Nor are the cognitive impairments that develop subsequently.
We were able to identify 16 other diseases (Table 22.7) to which we would propose
adding HIV, tick- borne illnesses, Alzheimer’s disease, malaria, helminthiases, and
long Covid, bringing the total of such diseases we have identied to 22. Our ndings
suggest that there is a need to consider cognitive dysfunction as a sequel to chronic
infection and to determine the pathophysiology that causes its onset and sustains it.
Treatments and cures for these diseases and their cognitive impairments are needed.
To underscore the magnitude of disability created by the cognitive impairment
associated with chronic diseases, we estimated the number of people cognitively
impaired by three of these diseases: ME/ CFS, FM, and long Covid. We estimate
that 245 million people worldwide have cognitive impairment resulting from ME/
CFS, FM, and long Covid: an estimated 85– 95 percent of ME/ CFS patients suer
cognitive impairment (Chaudhury, 2014); an estimated 60 percent of FM patients
demonstrate neuropsychological impairment (Dick et al., 2002), and 21 percent
of post- Covid patients were found to have cognitive impairment (Perrottelli et al.,
2022). Because Covid is now endemic, with new variants spontaneously being generated sporadically, the number of long Covid patients will likely increase with the
numbers of cognitively impaired patients also likely increasing unless treatment,
cure, disease prevention mechanisms can be found.
In 2021, Friedman and colleagues put forward the hypothesis that the similarity
and overlap of ME/ CFS and long Covid symptoms suggest similar pathological processes with similar underlying biochemical pathways and pathophysiological processes despite the dierence in initiating triggers (Friedman et al., 2021). ose
symptoms included cognitive impairment. Here, we propose to extend that hypothesis to all 22 diseases discussed above underscoring the importance of an increased worldwide eort to understand the underlying pathophysiology and to
Infectious Disease and Neurocognition
develop treatments and create cures. Friedman et al. (2021) proposed to call such
diseases “post- active phase of infection syndromes” (PAPIS). We propose that the
cognitive impairments associated with the diseases mentioned in this chapter satisfy
the PAPIS classication and that these diseases should be considered PAPIS.
Our hope is that additional PAPIS research will be forthcoming. To assist the re-
searcher in publishing PAPIS- related manuscripts, and to assist the reader in nding
the journal Healthcare (Papis Topical Collection, 2021). While research articles in
the PAPIS Topical Collection are being published immediately upon satisfying peer
review, articles belonging to the collection will be republished in monographs for
subsequent ease of access and historical purposes.
Acknowledgments
e authors gratefully acknowledge the work and support of the Interlibrary Loan
teams of the Alvin Sherman Library of Nova Southeastern University, and the
Rowan University Library for providing access to cited articles not available through
online access.
e authors gratefully acknowledge the nancial support of the New Jersey
Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Association and its Research
Fund for covering the nancial costs of obtaining some of the publications needed to
write this manuscript and ensure its accuracy.
Fibromyalgia and Chronic Fatigue 397
APPENDIX 1
Chronological Summary of Popular
Myalgic Encephalomyelitis/ Chronic
Fatigue Syndrome Case Definitions
1. Centers for Disease Control and Prevention, 1988
(Holmes et al., 1988)
Major criteria:
• Onset of persisting or relapsing fatigue or easy fatigability with no previous history.
• Exclusion of other clinical conditions producing similar symptoms.
• Specic laboratory tests or clinical measurements are not required.
• Abnormal tests should result in searching for other conditions causing such a result.
Minor criteria (symptom must be present for a minimum of 6 months):
• Mild fever
• Sore throat
• Painful lymph nodes
• Unexplained, generalized muscle weakness
• Muscle discomfort of myalgia
• 24 hours of greater generalized fatigue aer exercise previously tolerated
• Generalized headaches dierent from previous, premorbid headaches
• Migratory arthralgia without joint swelling or redness
• Neuropsychological complaints (photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, diculty thinking, inability to concentrate, depression)
• Hypersomnia or insomnia.
Physical criteria must be documented on two occasions 1 month apart:
• Low- grade fever
• Non- exudative pharyngitis
• Palpable or tender anterior or posterior cervical or axillary lymph nodes.
2. Straus et al. (1988)
Overview: “A case must fulll major criteria 1 and 2, and the following minor criteria: (a) 6 (or more)
of the 11 symptom criteria and 2 (or more) of the 3 physical criteria; or (b) 8 (or more) of the symptom
criteria.”
Major criterion #1:
• New onset of persistent or relapsing, debilitating fatigue or easy fatigability.
• Has no previous history of similar symptoms.
• Does not resolve with bed rest.
• Serious enough to reduce or impair average daily activity below 50 percent of the patient’s premorbid activity level for a period of at least 6 months.