[From 2020] The pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is unknown. In this study, we test the hypothesis that hypermobility, signs of intracranial hypertension (IH), and craniocervical obstructions may be overrepresented in patients with ME/CFS and thereby explain many of the symptoms. Our study is a retrospective, cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS as defined by the Canada Consensus Criteria. The first 272 patients with ME/CFS were invited to participate, and 229 who provided prompt informed consent were included. Hypermobility was assessed using the Beighton Score. IH was assessed indirectly by the quotient of the optic nerve sheet diameter (ONSD)/eyeball transverse diameter on both sides as measured on magnetic resonance imaging (MRI) of the brain. We also included assessment of cerebellar tonsil position in relation to the McRae line, indicating foramen magnum. Craniocervical obstructions were assessed on MRI of the cervical spine. Allodynia was assessed by quantitative sensory testing (QST) for pain in the 18 areas indicative of fibromyalgia syndrome (FMS). A total of 190 women, mean age 45 years, and 39 males, mean age 44 years, were included. Hypermobility was identified in 115 (50%) participants. MRI of the brain was performed on 205 participants of whom 112 (55%) had an increased ONSD and 171 (83%) had signs of possible IH, including 65 (32%) who had values indicating more se...
...we hypothesize that hypermobility and craniocervical obstruction are overrepresented in patients with ME/CFS and that a large portion of these patients may have a degree of intracranial hypertension (IH), which may explain many of the ME/CFS symptoms.
[Intracranial hypertension = elevated CSF pressure]
The prevalence of permanent sick leave was 39% and, together with other forms of social welfare, 57% of the participants had their income covered by social insurance, 10% had no income at all, and 25% still worked to some degree. The education level was high as 40% of participants had previous or actual work with an academic background, and 10% had blue-collar work.
Correlation between the degree of joint hypermobility and the ONSD/ETD ratio as a marker for IH was calculated.
Spondylolisthesis (forward or backward slipping of a vertebral body), osteophytes (bone formations that may obstruct nerve and other soft tissue passages), spinal cysts, and syringomyelia were noted regardless of segment or severity. Spinal cord compression due to bulging or herniated discs or bones impinging upon the medulla spinalis was noted on axial and sagittal sections.
General joint hypermobility was identified in 115 participants or 50%. 192 or 85% marked pain in all four body quadrants—that is, widespread pain. Spondylolisthesis was identified in eight (6%) and osteophytes in 11 (9%) participants. Obstructions of different varieties were present in 100 participants (80%). More than one segment of C1–T2 was obstructed in 80 participants (64%). Spinal cord compressions were most frequent at C5–C6 (53%) and C6–C7 (28%).
Our hypothesis that general joint hypermobility and craniocervical obstructions is overrepresented in patients with ME/CFS and that many of these patients may have a degree of IH was supported by our findings outlined above. Based on these findings, we propose that joint hypermobility and craniocervical obstructions may be one pathway to develop ME/CFS. ME/CFS as defined by the large CCC umbrella may include subgroups with infectious, immunological, traumatic, and craniocervical origins. The complexity of ME/CFS and the difficulty faced in diagnosing this syndrome is reflected by the numerous healthcare contacts with 90 visits in the last 5 years although the mean in the general population, including those with chronic diseases, is <30. The many diagnoses our participants had encountered prior to admission at our clinic is also conspicuous.
[optic nerve sheath diameter] ONSD and the ONSD/ETD ratios are related to IH. Our results indicate that IH may contribute to ME/CFS symptoms. ONSD ratios indicating IH were significantly more common in our study cohort compared to that of the healthy adult population as described in a study by Kim et al. of 314 individuals.
[Our results suggest] that a portion of patients with ME/CFS may have more harmful intracranial pressure.
Low cerebellar tonsils that protrude into the foramen magnum may obstruct the flow of CSF and indirectly cause IH. The limit for what is considered a low position of cerebellar tonsils varies between investigators, and most argue that a position >5 mm below the McRae line bilaterally should be considered a Chiari 1 malformation.
Only a fraction (11%) of our participants with ME/CFS had a normal cerebellar tonsil position well above the McRae line. Symptom onset in our study population was greater in the 25–45 age range, when symptoms of Chiari syndrome usually also first present.
Interestingly, a high proportion of our participants with ME/CFS exhibited signs of IH, and the criteria for ME/CFS include many symptoms similar to those of IH, including cognitive dysfunction, headache, dizziness, and pain.
Also interesting is that 173 or 76% of participants had concomitant [Fibromyalgia Syndrome] FMS. The prevalence of allodynia was even higher at 96%. This finding, characteristic of widespread sensitization, is a strong argument for CNS engagement in ME/CFS. A shared pathophysiology between ME/CFS, IH, and FMS has also been hypothesized by Hulens.
Craniocervical obstructions were frequent in our study sample. Most of these were disc bulges and hernias, which were found in 80% of participants who underwent MRI of the cervical spine. These kinds of obstructions are increasingly frequent with increased age and may be asymptomatic. However, our study population was relatively young with a mean age of 45 years.
One of the surprisingly few studies on the normal prevalence of craniocervical obstructions is the still often cited work by Boden from 1990, in which 63 asymptomatic volunteers participated (23). Of the 40 participants with age <40 years, four participants or 10% had disc bulging or hernias; of the 23 participants with age >40 years, two participants or 9% had such findings. If we presume that all of our participants without a present MRI scan are free from findings of obstruction of this kind (which gives an underestimate of the true obstruction prevalence in our sample), we still find a significant overrepresentation compared with the groups in Boden's study. The prevalence of cervical hernias or disc bulging in our study with this presumption is 35% with such findings in 28 of altogether 79 participants <40 years of age. In the group >40 years of age, we find such obstructions in 48%, that is, in 72 of altogether 150 participants. Comparing these prevalence's with Boden's study using a Chi-square test shows a significant overrepresentation of craniocervical obstructions in our study, both in the age group <40 years (p = 0.003) and in those >40 years (p = 0.004).
Craniocervical obstructions causing changed CSF flow and neuronal dysfunction have been proposed as a possible vehicle to develop ME/CFS symptoms. In a recent study from Johns Hopkins University, three patients with cervical spinal stenosis and ME/CFS who underwent decompressive spine surgery were considerably improved and relieved from ME/CFS symptoms (25).
Another common observation in patients with ME/CFS is that they find relief from nausea, vertigo, and pain symptoms in a supine position. This observation prompts the hypothesis that an upright position may alter CSF and blood flow in the craniocervical area due to the weight of the head compressing cervical segments and gravity pulling cerebellar tonsils caudally/into the foramen magnum. This hypothesis is supported by a pilot study by Freeman et al. on 1,200 patients with neck pain in which they found that both cervical spine obstructions and tonsil position were more prominent in MRI exams conducted in the upright position (9). Consequently, in a future study, patients with ME/CFS should be examined with upright MRI of the craniocervical area and compared with the standard supine MRI.
Neuroinflammation of the CNS is a proposed consequence of craniocervical obstructions and IH. This idea was recently raised by articles on ME/CFS and IH (24, 25). Other mechanisms that may cause neuroinflammation in the CNS are also possible. For instance, the “glymphatic system,” a functional metabolic waste clearance system that engages the CNS, can contribute to IH, and obstructions or flow disturbances can compromise the glymphatic system (27). Komaroff recently expressed this view of ME/CFS pathophysiology (3). We have no ground to say that cervical obstructions cause neuroinflammation and ME/CFS; however, our observation that craniocervical obstructions were very frequent in our population of patients with ME/CFS prompts a question: Is there a substantial subgroup of patients, worldwide, with ME/CFS for whom findings of craniocervical obstructions are signs of undetected IH?
In this relatively large novel study on symptoms and signs of IH, hypermobility and craniocervical obstructions in patients with ME/CFS we found to have a significant overrepresentation in our cohort compared to the general population. These signs might explain some of the major clinical symptoms and signs of ME/CFS, such as brain fog, fatigue, orthostatic intolerance, PEM, preference for the supine position, widespread pain, CNS neuroinflammation, immunological reactivity, and autoimmunity mechanisms. If our findings are further validated, a paradigm shift in the diagnostic methods and treatments for patients with ME/CFS may occur.
