Recently there have been some anecdotal reports of patients with a diagnosis of ME/CFS who met the criteria for a diagnosis of craniocervical instability. After surgical fusion of this joint, they reported improvement in some of their symptoms previously attributed to ME/CFS (R, R). After some reluctance, given the apparently unreasonable idea that there could be a link between a mechanical issue and ME/CFS, I found some convincing arguments in favour of that link. So here I am, with this new blog post. In paragraph 2 I will introduce some basic notions about the anatomy of the neck. In paragraph 3 I describe three points that can be taken from the middle slice of the sagittal sections of the standard MR study of the brain. These points can be used to find four lines (paragraph 4) and these four lines are the basis for quantitative diagnosis of craniocervical instability (paragraph 5 and 6). In paragraph 7, I discuss the possible link between craniocervical instability and ME/CFS. Enjoy.
2. Basic anatomy
The craniocervical (or craniovertebral) junction (CCJ) is a complex joint that includes the base of the skull (occipital bone, or occiput), the first cervical vertebra (atlas or C1), the second cervical vertebra (axis or C2), and all the ligaments that connect these bones (Smoker WRK 1994). This joint encloses the lower part of the brainstem (medulla oblongata) and the upper trait of the spinal cord, along with the lower cranial nerves (particularly the tenth cranial nerve, the vagus nerve). Since the CCJ is included in the series of sagittal sections of every MR study of the brain, its morphology can be easily assessed (figure 1, left). It is worth mentioning that the CCJ is the only joint of the body that encloses part of the brain. The atlas and the axis are represented with more detail in figure 1 (right), where their reciprocal interaction has been highlighted. From a mechanical point of view, these two bones make up a revolute joint, with the rotation axis going through the odontoid process. This is only a simplification, though, because while it is true that the atlantoaxial joint provides mainly axial rotation, there are also 20 degrees of flexion/extension and 5 degrees of lateral bending, which means that spherical joint would be a more appropriate definition. Other degrees of freedom are provided at the level of the occipital atlantal joint, where 25 degrees of motion are provided for flexion/extension, 5 degrees of motion are provided for one side lateral bending and other 10 degrees are provided for axial rotation (White A. & Panjabi M.M. 1978).
The measurement of the Grabb’s line and of the clival-canal angle is based on a simple algorithm which starts with the identification of three points on the midline sagittal image of a standard MRI scan of the head (figure 2). In order to find this particular slice, search for the sagittal section where the upper limit of the odontoid process reaches its highest and/or the slice with the widest section of the odontoid process. This algorithm is mainly taken from (Martin J.E. et al. 2017). In looking at T1-weighted images, always keep in mind that cortical bone (and cerebrospinal fluid too) gives a low signal (black strips) while marrow bone gives a high signal (bright regions) (R).
- Clival point (CP). It is the most dorsal extension of the cortical bone of the clivus at the level of the sphenooccipital suture. This suture can’t be seen clearly in some cases (figure 3 is one of these cases). So another definition can be used for CP: it is the point of the dorsal cortical bone of the clivus at 2 centimetres above the Basion (see next point).
- Basion (B). It is the most dorsal extension of the cortical bone of the clivus. This is the easiest one to find!
- Ventral cervicomedullary dura (vCMD). This is the most dorsal point of the ventral margin of the dura at the level of the cervicomedullary junction. I find this point the most difficult to search for and somehow poorly defined, but this is likely due to my scant anatomical knowledge.
- Posteroinferior cortex of C-2 (PIC2). It is the most dorsal point of the inferior edge of C2.
Connecting the three points found in the previous paragraph allows us to define four lines (figure 3) that will be then used to calculate the Grabb’s mesure and the clival-canal angle.
- Clival slope (CS). It connects CP to vCMD. It is also called the Wackenheim Clivus Baseline (Smoker WRK 1994).
- Posterior axial line (PAL). It connects vCMD to PIC2.
- Basion-C2 line (BC2L). It connects B to PIC2.
- Grabb’s line (GL). It is the line from vCMD that is orthogonal with BC2L.
We now know all we need in order to take two of the most important measures for the assessment of craniocervical junction abnormalities.
5. The clival-canal angle and its meaning
The clival-canal angle (CXA) is the angle between CS and PAL. The value of this angle for the individual whose scan is represented in figure 4 is 142°. This angle normally varies from a minimum of 150° in flexion to a maximum of 180° in extension (Smoker WRK 1994). Ence, what we should normally see in a sagittal section from an MR scan of the brain is an angle between these two values. A value below 150° is often associated with neurological deficits (VanGilder J.C. 1987) and it is assumed that a CXA below 135° leads to injury of the brainstem (Henderson F.C. et al. 2019).
It has been demonstrated with a mathematical model that a decrease in the clival-canal angle produces an increase in the Von Mises stress within the brainstem and it correlates with the severity of symptoms (Henderson FC. et al. 2010). Von Mises stress gives an overall measure of how the state of tension applied to the material (the brainstem in this case) causes a change in shape. For those who are interested in the mathematical derivation of this quantity (otherwise, just skip the equations), let’s assume that the stress tensor in a point P of the brainstem is given by
Then it is possible to prove that the elastic potential energy due to change in shape stored by the material in that point is given by
where E and ν are parameters that depend on the material. Since in monoaxial stress with a module σ the formula above gives
by comparison, we obtain a stress (called Von Mises stress) that gives an idea of how the state of tensions contributes to the change of shape of the material:
In the brainstem, this parameter – as said – appears to be inversely proportional to the clival-canal angle and directly proportional to the neurological complaints of patients, according to (Henderson FC. et al. 2010). For a complete mathematical discussion of Von Mises stress, you can see chapter 13 of my own handbook of mechanics of materials (Maccalini P. 2010), which is in Italian though.
6. The Grabb’s measure and its meaning
The Grabb’s measure is the length of the segment on the Grabb’s line whose extremes are vCMD and the point in which the Grabb’s line encounters the Basion-C2 line. In figure 4 this measure is 0.8 centimetres. This measure has been introduced for the first time about twenty years ago with the aim of objectively measuring the compression of the ventral brainstem in patients with Chiari I malformation. A value greater or equal to 9 mm indicates ventral brainstem compression (Grabb P.A. et al. 1999). In a set of 5 children with Chiari I malformation and/or basal invagination (which is the prolapse of the vertebral column into the skull base) a high Grabb’s measure was associated with a low clival canal angle (Henderson FC. et al. 2010). The CXA only takes into account osseous structures (it depends on the reciprocal positions between the body of the axis and the clivus), so it can potentially underestimate soft tissue compression by the retro-odontoid tissue. This problem can be addressed with the introduction of the Grabb’s measure (Joaquim A.F. et al. 2018). Nevertheless, we can assume that they both measure the degree of ventral brainstem compression, and if you look at figure 3 you realize that as the angle opens up, the Grabb’s measure becomes shorter. Points and lines described in these paragraphs for two more patients are represented in figure 4, while the CXA and the Grabb’s measure for three ME/CFS patients (the one in figure 3 and the two in figure 4) are collected in the table below (OI stands for orthostatic intolerance).
7. Craniocervical instability and ME/CFS
According to some authors, the craniocervical junction is considered to be unstable (craniocervical instability, CCI) in the case of “any anomaly that leads to neurological deficits, progressive deformity, or structural pain”. A clival canal angle below 125° and/or a Grabb’s measure above 9 mm are considered to be predictive of CCI (Joaquim A.F. et al. 2018). Craniocervical instability has been described in congenital conditions like Down syndrome (Brockmeyer D 1999), Ehlers-Danlos syndrome (Henderson F.C. et al. 2019), and Chiari malformation (Henderson FC. et al. 2010) as well as in rheumatoid arthritis (Henderson F.C. et al. 1993).
There are some clues that can potentially link CCI to ME/CFS, as mentioned in the introduction. My interest in this topic aroused some weeks ago because of anecdotal reports of diagnosis of CCI (with subsequent successful surgery, apparently) among ME/CFS patients (R, R), in the absence of formal studies (to my knowledge, at least). And yet there is a substantial overlap between Ehlers-Danlos syndrome hypermobile type (EDS-HT) and ME/CFS, with about 80% of EDS-HT patients meeting the Fukuda criteria (Castori M. et al. 2011) and we know, as mentioned, that CCI is present in Ehlers-Danlos syndrome. Moreover, brainstem abnormalities are well known to be present in ME/CFS, where hypoperfusion (Costa D.c: et al. 1995), hypometabolism (Tirelli U. et al. 1998), reduced volume (Barnden L.R. et al. 2011), microglia activation (Nakatomi Y et al. 2014), and loss of connectivity (Barnden L.R. et al. 2018) in brainstem have been reported. Basal ganglia dysfunction has also been documented in ME/CFS (Miller AH et al. 2014), and this could be an indirect measure of midbrain abnormal functioning, given the connection between substantia nigra (midbrain) and basal ganglia, via the nigrostriatal tract. It is worth mentioning here that vagus nerve infection has been proposed as a feasible cause of ME/CFS (VanElzakker MB 2013) and vagus nerve (the tenth cranial nerve) has its origin in the lower part of the brainstem. Moreover, the presence of CCI in rheumatoid arthritis might be a clue for a causal role of the immune system in this kind of hypermobility. A link between hypermobility and the immune system has been found also in a condition due to the duplication/triplication of the gene that encodes for tryptase (a proteolytic enzyme of mast cells) (Lyons JJ et al. 2016). CCI can lead to orthostatic intolerance (OI), and OI is widely prevalent in ME/CFS.
So, it is not unreasonable to consider pathology of the craniocervical junction to be involved in some cases of CFS-like symptoms. It might be due to some degree of predisposition to hypermobility and/or to abnormal immune activity. These cases would then be aggravated or triggered by infections, as it is often the case in ME/CFS patients. How to properly classify these patients would be just a matter of nomenclature. But as we all know “A rose by any other name would smell as sweet”.