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. 2022 Oct 10;11(1):20210033. doi: 10.1515/em-2021-0033

Orthostatic intolerance and neurocognitive impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Caroline L Gaglio 2, Mohammed F Islam 1,3, Joseph Cotler 1, Leonard A Jason 1,✉
PMCID: PMC9550273  PMID: 36310761

Abstract

Objectives

The Institute of Medicine (IOM 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington: The National Academies Press) suggested new criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which requires an endorsement of either neurocognitive impairment or orthostatic intolerance (OI) in addition to other core symptoms. While some research supports the inclusion of OI as a core symptom, others argue that overlap with neurocognitive impairment does not justify the either/or option. The current study assessed methods of operationalizing OI using items from the DePaul Symptom Questionnaire (DSQ-1 and -2) as a part of the IOM criteria. Evaluating the relationship between OI and neurocognitive symptoms may lead to a better understanding of diagnostic criteria for ME/CFS.

Methods

Two-hundred and forty-two participants completed the DSQ. We examined how many participants met the IOM criteria while endorsing different frequencies and severities of various OI symptoms.

Results

Neurocognitive impairment was reported by 93.4% of respondents. OI without concurrent neurocognitive symptoms only allowed for an additional 1.7–4.5% of participants to meet IOM criteria.

Conclusions

Neurocognitive symptoms and OI overlap in ME/CFS, and our results do not support the IOM’s inclusion of neurocognitive impairment and OI as interchangeable symptoms. Furthermore, our findings highlight the need for a uniform method of defining and measuring OI via self-report in order to accurately study OI as a symptom of ME/CFS.

Keywords: diagnostic criteria, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, neurocognitive impairment, orthostatic intolerance

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex illness with core symptoms of post-exertional malaise, cognitive impairment, unrefreshing sleep, and other symptoms (Carruthers et al. 2003). One aspect of this illness, which has amplified the complexity, is the disagreement regarding case definitions and the development of standardized diagnostic approaches (Brurberg et al. 2014; Jason, Zinn, and Zinn 2015a). The Institute of Medicine (IOM 2015) issued a report outlining new criteria for the diagnosis of ME/CFS. These new criteria require substantial reduction in pre-illness levels of activity, post-exertional malaise, unrefreshing sleep, and either neurocognitive impairment or orthostatic intolerance (OI). Furthermore, the IOM generally indicates that it is essential to assess for moderate or greater frequency and severity of symptoms, as it is required to distinguish ME/CFS from other illnesses (IOM 2015). While the definition captures some of the same core symptoms as other ME/CFS criteria (Carruthers et al. 2003, 2011; Fukuda et al. 1994), concerns exist regarding the utilization of neurocognitive impairment and OI as interchangeable symptoms (Jason et al. 2015d).

While neurocognitive impairment has been recognized as a core symptom of ME/CFS (Bedree, Sunnquist, and Jason 2019; Brown and Jason 2014; Jason et al. 2014; Jason et al. 2015c), there is less consensus for the inclusion of OI in ME/CFS as a core symptom. OI is defined by an inability to tolerate an upright position and is relieved by rest and recumbence (Lambert and Lambert 2014). Common symptoms of OI include dizziness, lightheadedness, and syncope, amongst others. OI can result in significant impairment, but it is not as frequently reported in patients with ME/CFS (Jason et al. 2014). Schondorf et al. (1999) reported that only 40% of their participants with ME/CFS had a positive tilt test (indicative of OI), while Timmers et al. (2002) reported 27.8%. Moreover, LaManca et al. (1999) found no significant differences in presyncope symptoms or heart rate and blood pressure changes (also indicative of OI challenges) between participants with ME/CFS and healthy control groups. The aforementioned findings suggest that OI might not be a core symptom of ME/CFS.

The IOM’s criteria (2015), which allows OI symptoms to be interchangeable with neurocognitive symptoms, has been evaluated against other criteria for ME/CFS. Using the first version of the DePaul Symptom Questionnaire (DSQ-1), Jason et al. (2015d) found only 67% of patients with ME/CFS report OI, while 93% report cognitive impairment. The endorsement of OI was qualified by reporting of one of the following symptoms at a “moderate severity” experienced about half of the time within the past six months: feeling unsteady on feet, shortness of breath, dizziness or fainting, or irregular heartbeats. The option of having OI instead of neurocognitive impairment allowed for 2% more participants to meet IOM criteria than if the criteria had only required cognitive impairment. Chu et al. (2017) conducted a similar study to examine the IOM criteria. In lieu of using a frequency and severity threshold as used by Jason et al. (2015c), Chu and colleagues utilized a categorical response of “yes” and “no” to measure items that included feeling sick, uncomfortable, or fainting while standing. The results indicated that 92% of participants reported OI and 87% of participants endorsed cognitive impairment. Chu and colleagues’ operationalization of OI allowed for 13% more participants to meet IOM criteria than if participants were required to endorse cognitive impairment alone. Chu and colleagues hypothesized the discrepancy in findings from Jason et al. (2015d) may be due the researchers’ use of “less common symptoms” to represent OI (shortness of breath and irregular heartbeats). Additionally, Chu and colleagues argued that minimum frequency and severity thresholds are not required by the IOM to meet the criteria.

These discrepancies warrant further investigation to more accurately identify those with OI. The present study evaluated different methods in which OI can be measured to examine the IOM’s interchangeable criteria for cognitive impairment and OI. By determining the advantages and disadvantages of ways to measure OI as a symptom of ME/CFS through self-report, researchers and clinicians can better define this symptom and then more reliably classify patients as having the illness.

Methods

Participants

In the current study, 242 participants were analyzed from a convenience sample of adults living with chronic illnesses collected as a part of another study (Ohanian et al. 2016). Participants were recruited online via research forums, support groups, and social media platforms. Additionally, participants were required to self-report a diagnosis of ME/CFS and complete the neurocognitive and orthostatic items on the DSQ-2 (Bedree, Sunnquist, and Jason 2019). A majority of the sample was female (85.5%) and white (96.3%), with an average age of 50.2 years (SD=13.8). Participants were screened using Fukuda et al. (1994) criteria in efforts to replicate Chu et al. (2017).

Measures

The DePaul Symptom Questionnaire-2: Participants completed the second iteration of the DePaul Symptom Questionnaire (DSQ-2; Bedree, Sunnquist, and Jason 2019), a 132 item self-report questionnaire assessing symptomatology, demographics, and medical, occupational, and social history. The DSQ-2 includes all items from the DSQ-1 with an additional five items addressing OI. The DSQ-1 has evidenced strong test-retest reliability (Jason et al. 2015b), and the DSQ-2 has high content validity in assessing the eight ME and CFS symptom domains (Bedree, Sunnquist, and Jason 2019).

Participants rated the frequency and severity of each symptom item on the DSQ-2 over the past six months on a 5-point Likert scale. The frequency was rated as: 0=none of the time, 1=a little of the time, 2=about half of the time, 3=most of the time, and 4=all of the time. Similarly, severity was rated: 0=symptom not present, 1=mild, 2=moderate, 3=severe, and 4=very severe.

Medical outcomes study 36-item short-form health survey (SF-36 or RAND questionnaire): The SF-36 (Ware and Sherbourne 1992) is a 36-item self-report survey of functional health status across eight domains: (1) physical functioning; (2) bodily pain; (3) role physical (limitations due to physical health problems); (4) role emotional (limitations due to emotional problems); (5) mental health; (6) social functioning; (7) vitality; and (8) general health. Domains are measured on 100-point scales, where higher scores indicate better health or less impact of health on functioning. Test construction studies have shown high internal consistency, significant discriminant validity among subscales, and substantial differences between patient and non-patient populations (Ware and Sherbourne 1992).

Case definitions

IOM criteria: To meet IOM criteria (2015), participants needed to indicate six or more months of fatigue which resulted in a reduction of pre-illness levels of occupational, educational, social, or personal activities. Participants also needed to endorse two of the following three criteria on the SF-36 to meet the requirement for substantial reduction from previous levels of functioning: role physical<50, social functioning<62.5, or vitality<35. To meet post-exertional malaise criteria, participants needed to have a frequency and severity ≥2 on at least one of five post-exertional malaise items from either DSQ: dead heavy feeling after exercise, next day soreness or fatigue after non-strenuous, everyday activities, mentally tired after the slightest effort, physically tired from minimum exercise, or physically drained or sick after mild activity. To meet unrefreshing sleep, a frequency and severity score ≥ 2 was required for at least one of the following: unrefreshing sleep, problems falling asleep, problems staying asleep, needing to nap daily, or sleeping all day and staying awake all night.

Participants also needed to have either cognitive impairment or OI. A frequency and severity score of ≥2 on at least one of the following items was required to meet cognitive impairment: problems remembering, difficulty paying attention, difficulty expressing thoughts, difficulty understanding things, difficulty focusing on more than one thing, slowness of thought, or absent mindedness.

Methods of operationalizing OI

In the current study, we aimed to compare new OI items from the DSQ-2 with previous findings using OI items from the DSQ-1 (Jason et al. 2015d). Additionally, we assessed a broader version of OI that was used by Chu et al. (2017), where “mild” severity and less frequent OI items would meet IOM criteria. Finally, we evaluated these outcomes with a narrower version that involved at least “moderate” severity and frequency OI items to meet the IOM criteria. Seven methods to measure OI were used.

Four of the seven methods defined “mild” OI symptoms as measured at a 1/1, indicating that a participant endorsed a DSQ symptom frequency and severity score of 1 on one item (minor severity and a little of the time; See Table 1). The first four categories were meant to identify the number of patients meeting broad criteria.

  • (1)

    4 DSQ-1 items. This is a basic comparison of a very broad threshold.

  • (2)

    4 DSQ-items plus 5 additional items from DSQ-2. This is also a broad threshold but introduces a more comprehensive group of OI items.

  • (3)

    2 DSQ-1 items, excluding 2 DSQ-1 items criticized by Chu et al. (2017), plus 5 additional items from DSQ-2. This is a comparison of a larger set of OI items that excludes those Chu and colleagues suggested were not good measures of this domain.

  • (4)

    Another mild measurement used methods that best matched the items utilized by the Chu et al. (2017) investigation. For Chu and colleagues’ participants to meet OI, they responded “yes” to one of the following items: “Have you felt sick or uncomfortable standing still, for example, while waiting in line?” or “Have you fainted or felt like you were going to faint while standing”. The two items on the DSQ-2 that most closely resembled these items asked about a participant’s dizziness or fainting and feeling unsteady on their feet within the past six months. To meet OI criteria that closely matches Chu and colleagues’ “yes” or “no” responses to items, participants in the current study had to report either dizziness or fainting and feeling unsteady on their feet within the past six months with a frequency and severity of 1 (both are DSQ2 items). Due to this frequency and severity rating, we categorized these symptoms as mild OI.

Table 1:

Orthostatic intolerance related items across different measures.

Orthostatic intolerance 4 DSQ-1 4 DSQ-1 plus 2 DSQ-1 plus 2 items from
items items 5 DSQ-2 items 5 DSQ-2 items Chu et al. (2017)
Feeling unsteady on feet X X X X
Shortness of breath X X
Dizziness or fainting X X X X
Irregular heartbeats X X
Feeling disoriented X X
Inability to tolerate an upright position X X
Graying or blacking out after standing X X
Blurred or tunnel vision after standing X X
Heart beats quickly after standing X X
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The next three comparisons captured a narrower depiction of OI, which we call “moderate” OI. It is measured with at least a 2/2 frequency/severity score (moderate severity and at least half the time). That is, participants needed to respond to the following OI DSQ items with a frequency and severity ≥2 on one item:

  • (5)

    4 DSQ-1 items at higher frequency and severity OI than measured in the first comparison.

  • (6)

    4 DSQ-1 items plus 5 DSQ-2 items. This added more comprehensive OI items that are in the moderate degree of impairment.

  • (7)

    2 DSQ-1 items minus the 2 DSQ-1 items critiqued by Chu et al. (2017) plus the 5 DSQ-2 items. This includes more moderately impairing OI items but deleting 2 items that Chu et al. (2017) had critiqued.

Thus, there are four methods of measuring “mild” OI and three methods of measuring “moderate” OI.

Results

Findings of the study can be found in Table 2, which shows frequency of people who endorsed neurocognitive symptoms and OI using the different methods of operationalization. Regarding neurocognitive impairment, 226 (93.4%) participants reported these symptoms.

Table 2:

Frequency of participants endorsing neurocognitive and various orthostatic intolerance symptoms of mild and moderate severity.

Domain Participants who endorsed symptom % (n)
Cognitive impairment 93.4 (226)
Orthostatic intolerance
 Mild: 1/1 frequency/Severity
 4 DSQ-1 plus 5 DSQ-2 items 99.6 (241)
 2 DSQ-1 plus 5 DSQ-2 items 98.8 (239)
 4 DSQ-1 items 98.3 (238)
 2 items from Chu et al. (2017) 91.7 (222)
 Moderate: 2/2 frequency/severity
 4 DSQ-1 and 5 DSQ-2 items 85.1 (206)
 2 DSQ-1 and 5 DSQ-2 items 81.0 (196)
 4 DSQ-1 items 69.8 (169)
Total participants 100 (242)
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Mild OI

Nearly all participants endorsed mild OI: 238 (98.3%) using the 4 DSQ-1 items, 241 (99.6%) with the 4 DSQ-1 plus 5 DSQ-2 items, and 239 (98.8%) with the 4 DSQ-1 items (excluding 2 DSQ-1 critiqued items) plus 5 DSQ-2 items. Moreover, 222 (91.7%) persons endorsed mild OI with items that most closely matched Chu and colleagues’ (2017). This finding is similar to the 92% that was found by Chu et al. (2017).

Moderate OI

Fewer participants endorsed moderate OI: 169 (69.8%) using 4 items from the DSQ-1; findings consistent with Jason and colleagues’ (2015d) reported 67%. Additionally, 206 (85.1%) endorsed moderate OI when using 4 DSQ-1 plus 5 DSQ-2 items, and 196 (81.0%) with the 4 DSQ-1 items but excluding the 2 DSQ-1 critiqued items plus 5 DSQ-2 items.

IOM using either cognitive impairment or OI: mild or moderate OI

We next assessed how many participants would meet IOM criteria (2015) when they had either cognitive impairment or OI, which is the specified algorithm in the IOM case definition (See Table 3). Measuring mild OI allowed for most of the sample to meet criteria. Most participants met IOM criteria when cognitive symptoms or mild OI symptoms occurred: 4 DSQ-1 items (n=218, 90.1%), 4 DSQ-1 plus 5 DSQ-2 items (n=218, 90.1%), 4 DSQ-1 plus 5 DSQ-2 (n=217, 89.7%), and DSQ items matched with items used by Chu and colleagues (2017; n=212, 87.6%). Similarly, most participants met IOM when either cognitive symptoms or moderate OI symptoms occurred: 4 DSQ-1 items (n=211, 87.2%), 4 DSQ-1 plus five DSQ-2 (n=214, 88.4%), and 2 DSQ-1 plus 5 DSQ-2 items (n=214, 88.4%).

Table 3:

Frequency of participants who met IOM (2015) criteria across different types of OI.

Ways of operationalizing Participants who met Participants who met Participants who
OI within IOM criteria with either criteria with cognitive met criteria with
Criteria cognitive symptoms or OI % (n) symptoms exclusively % (n) OI exclusively % (n)
Mild: 1/1 frequency/severity
 4 DSQ-1 and 5 DSQ-2 items 90.1 (218) 85.5 (207) 90.1 (218)
 2 DSQ-2 and 5 DSQ-2 items 89.7 (217) 85.5 (207) 89.3 (216)
 4 DSQ-1 items 90.1 (218) 85.5 (207) 88.8 (215)
 2 Items from Chu et al. (2017) 87.6 (212) 85.5 (207) 83.1 (201)
Moderate: 2/2 frequency/severity
 4 DSQ-1 and 5 DSQ-2 items 88.4 (214) 85.5 (207) 78.9 (191)
 2 DSQ-1 and 5 DSQ-2 items 88.4 (214) 85.5 (207) 75.6 (183)
 4 DSQ-1 items 87.2 (211) 85.5 (207) 65.3 (158)
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IOM using cognitive impairment or OI exclusively: mild OI symptoms

Rather than having to endorse either cognitive or OI symptoms to meet IOM criteria, as occurred in the section above, we next wanted to evaluate who met IOM criteria if we set it as just meeting cognitive symptoms or, in a different analysis, set the IOM criteria as just meeting OI symptoms. In this way, we could determine how many additional people would qualify for criteria with either symptom alone. This comparison would show the unique numbers of patients that might be brought into the IOM by just the OI criteria of either the mild or moderate threshold.

Table 3 also shows the frequency of participants who met IOM criteria (2015) with either cognitive symptoms or OI symptoms exclusively. Two-hundred and seven participants (85.5%) met IOM criteria with cognitive symptoms exclusively. Participants met IOM criteria with mild OI without concurrent cognitive symptoms qualified by: 4 DSQ-1 items (n=215, 88.8%), 4 DSQ plus 5 DSQ-2 items (n=218, 90.1%), 2 DSQ-1 plus 5 DSQ-2 items (n=216, 89.3%), and DSQ items matched with items used by Chu and colleagues (2017) (n=201, 83.1%). Measuring these mild OI symptoms allowed for 4.5%, 4.5%, 4.1%, and 2.1% of our participants who did not have cognitive impairment to meet IOM criteria, respectively.

IOM using cognitive impairment or OI exclusively: moderate OI symptoms

Regarding moderate OI, fewer participants met the IOM criteria when OI symptoms were exclusive and qualified by: 4 DSQ-1 items (n=158, 65.3%), 4 DSQ-1 and 5 DSQ-2 items (n=191, 78. 9%), and 2 DSQ-1 and 5 DSQ-2 items (n=183, 75.6%). Measuring moderate OI symptoms allowed for 1.7%, 2.9%, and 2.9% of participants without concurrent cognitive impairment to meet IOM criteria, respectively.

Discussion

Our results suggest that the discrepancies in prevalence of OI between the Jason et al. (2015d) study and the Chu et al. (2017) study were not due to the use of less common symptoms (i.e., critiqued items). When removing such critiqued items (shortness of breath and irregular heartbeats) from the criteria, moderate OI allowed for an additional 2.9% of participants to meet IOM criteria who did not have cognitive impairment. Even when measuring mild OI and removing the critiqued items, OI symptoms alone allowed for only and additional 4.1% of participants to meet IOM criteria. Measuring all DSQ-1 mild OI items allowed the most participants to meet criteria, and even then, only allowed for 4.5% more participants without cognitive impairment to meet IOM criteria. All methods of assessing OI without concurrent neurocognitive symptoms allowed considerably fewer participants to meet criteria than the 13% reported by Chu et al. (2017).

The few participants who met IOM criteria (2015) with OI alone using any method of measurement can be attributed to the overlap between OI and neurocognitive symptoms. Most of our sample (93.4%) had cognitive impairment, matching the findings of Jason et al. (2015d). Neurocognitive deficits can often occur as a symptom of orthostatic intolerance in ME/CFS (Ocon et al. 2012; Stewart et al. 2011). Given this connection, participants who endorsed orthostatic intolerance are likely to also endorse cognitive dysfunction. Changing the criteria for OI in the current study, such as including or removing fewer common symptoms of OI, did not substantively or meaningfully change the prevalence of OI or affect how many participants are able to meet IOM criteria.

The overlap between OI and neurocognitive impairment does not support the IOM’s (2015) decision of including OI and cognitive impairment as interchangeable symptoms. It should be acknowledged that OI is a serious symptom for people with ME/CFS which can cause significant distress for patients. Nonetheless, OI has often been considered a secondary symptom. Factor analysis and principal component research has found neurocognitive impairment to be a core symptom of ME/CFS; however, none have identified orthostatic intolerance as such (Arroll and Senior 2009; Brown and Jason 2014; Conroy, Islam, and Jason 2022; Friedberg et al. 2000; Hickie et al. 2009; Jason, Corradi, and Torres-Harding 2007; Nisenbaum et al. 1998; Nisenbaum et al. 2004). Symptom domains such as neurologic, vascular and neuroendocrine, autonomic, and immune dysfunction, which address some components of OI, have been identified as important symptoms (Brown and Jason 2014; Friedberg et al. 2000; Jason, Corradi, and Torres-Harding 2007). However, OI itself does not occur at a high enough frequency within the literature to consider it a primary symptom, and it has been suggested that a more general domain of autonomic dysfunction be considered a secondary symptom or a subtype (Jason, Zinn, and Zinn 2015a; Jason et al. 2014).

Our results also highlight the importance of selecting appropriate frequency and severity thresholds when using self-report. The IOM does not require a minimum frequency or severity threshold for OI when diagnosing ME/CFS; however, it would be reasonable to employ a minimum frequency and severity threshold in order to assess OI via self-report. A 1/1 frequency/severity of a symptom on the DSQ-1 or -2 (i.e., identifying mild symptoms that occur a little of the time) may allow more people to endorse OI even when they do not experience regular impairment associated with orthostatic challenge. Similarly, the language of Chu et al. (2017) items may also result in a higher prevalence rate. “Yes” or “no” responses to their items may not provide complete evidence as to whether a participant is experiencing acute or chronic symptoms. Therefore, participants who do not experience OI as a core symptom of ME/CFS may be included in OI analysis. These issues in operationalizing OI affects research into its prevalence in ME/CFS and can make it difficult to define the illness and assess existing criteria.

Limitations of this study involve replicating Chu et al. (2017) procedures for case definitions. Chu and colleagues excluded participants if they were treated with antiviral or antibiotic medication for less than two weeks within the past 30 days, or antiretroviral medication within the past year. However, the DSQ does not include questions about this type of medication use and we were unable to exclude these participants. Furthermore, we could not completely replicate the items that Chu and colleagues used to measure OI. While we made efforts to include DSQ items that best captured the same symptoms, the different items could have caused us to capture different participants than would be selected using Chu and colleagues’ items. However, our results yielded similar prevalence rates to their original study (2017), so the discrepancies are expected to be minimal.

A further limitation includes our sampling. Our sample was not diverse in terms of ethnicity and gender, but this has also characterized most existing studies in this area. Lastly, the use of self-report data may be considered a limitation. However, recent study on the DSQ found that self-report measures of orthostatic intolerance in child and adolescent populations with ME/CFS correlated with formal, physician assessed measures (Schultz et al. 2019). It may be expected that the use of self-reported symptoms on the DSQ-1 and -2 would be similarly accurate. However, other studies have found that clinical symptoms may not be enough to diagnose OI, as patients may deny OI symptoms while sill exhibiting cerebral blood flow reduction (van Campen et al. 2020). Given that symptomatology of OI is diverse and that current methods of operationalizing orthostatic intolerance can be inconsistent across studies, we, again, suggest a uniform method of self-report be developed in agreement with objective biological data, as is supported by the literature.

The results of the current study provide further evidence for the overlap between neurocognitive symptoms and orthostatic intolerance. Because these symptoms often occur simultaneously, the IOM’s (2015) decision to require either symptom as a core feature is not supported by our findings. However, these results underscore the importance of creating a uniform way of operationalizing OI. By using appropriate items, researchers may be able to more accurately identify cases of orthostatic intolerance in ME/CFS through survey data.

Acknowledgments

The authors would like to thank Karl E. Conroy for his assistance in the preparation of this manuscript.

Footnotes

Research funding: The authors appreciate the funding provided by the National Institute of Neurological Disorders and Stroke (project number 1R01NS111105-01A1)

Author contribution: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

Informed consent: Informed consent was obtained from all individuals included in this study.

Ethical approval: The local Institutional Review Board deemed the study exempt from review.

Contributor Information

Caroline L. Gaglio, Email: CarolineLGaglio@gmail.com.

Leonard A. Jason, Email: LJASON@depaul.edu.

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