**1. Introduction**

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 (CCI). 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 decided to look at this avenue. So here I am, with this new blog post. In paragraph 2, I 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 5-10). In paragraph 11, I describe CCI. In paragraph 12, I discuss the possible link between craniocervical instability and ME/CFS. In paragraph 13, there is a collection of measures from the supine MRIs of some ME/CFS patients. In the last paragraph, I propose an alternative definition of CCI, with the introduction of Euler’s angles.

**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).

**3. Points**

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.

**4. Lines**

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 measure and the clival-canal angle.

*Clival slope*(CS). It connects CP to vCMD. It is also called the Wackenheim Clivus Baseline (Smoker W.R.K. 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 according to (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). A clival canal angle below 125° is considered to be predictive of CCI according to (Joaquim A.F. et al. 2018). In a study on 33 normal subjects employing standard MRI, CXA was measured in the sagittal section of each subject: this group had a mean value of 148° with a standard deviation of 9.88°; the minimum value was 129° and the maximum one was 175° (Botelho R.V. et al. 2013). The reader may have noted that the mean CXA in this study is below the cutoff for neurological deficits according to the 1987 book. This might be due to the fact that there is a difference between the measure taken on an MRI sagittal section and the one taken on radiographic images.

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). When using MRI, it is assumed that values above 9 mm is abnormal (R) but I have not been able to find statistical data on this measure in MRIs of healthy individuals. Moreover, the study by Grabb was mainly on a pediatric population (38 children and two adults) with Chiari malformation. So it is unclear if these measures can be used to assess the CCJ in adults. The measure was made on sagittal sections of MRIs.

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.

**7. Horizontal Harris measure
**

Another measure that has been introduced to check the anatomical relationship between the skull and the Atlas is the distance between PAL and point B (figure 5). This measure has been introduced in (Harris J.H. e al. 1993) where it was performed in 400 adults and with a normal cervical spine and in 50 healthy children. In the first group, 96% of the individuals had a distance of the basion from PAL longer than 1-4 mm and shorter than 12 mm. All the children had a distance below 12 mm. This measure has been used recently to assess craniocervical instability in hypermobile patients (Henderson F.C. et al. 2019), along with the Grabb’s measure and the clival-canal angle. We will refer to this measure as HHM. It is important to mention that the study by Harris was based on radiographs, so it is unclear if they can be used for a comparison of measures taken from MRI sagittal sections. Yet a measure below 12 mm was considered normal in a study employing MRI (Henderson F.C. et al. 2019).

**8. Distance between Chamberlain’s line and the odontoid process
**

Another measure that has been introduced to determine whether occipitovertebral relationship is normal or not is the distance between the Chamberlain’s line and the closest point of the tip of the odontoid process (also called *dens*) (figure 6). The Chamberlain’s line extends between the posterior pole of the hard palate and the posterior margin of the foramen magnum (called *opisthion*) (Smoker W.R.K. 1994). In a study on 200 healthy European adults employing standard MRI, this measure was taken from the T1 weighted sagittal section of each subject. Measures start from the cortical bone, i.e. from the dark signal. The mean was -1.2 mm with a standard deviation SD = 3 mm (Cronin C.G. et al. 2007). The minus before the number indicates that the mean position of the selected point of the dens is below the line.

**9. Distance between McRae’s line and the odontoid process**

McRae’s line is drawn from the anterior margin of the foramen magnum (basion) to its posterior border (opisthion). It was introduced in 1953 to assess normality at the level of the CCJ (McRae D.L. et Barnum A.S. 1953). The distance between McRae’s line and the closest point of the tip of the dens can be used, as in the case of Chamberlain’s line, to assess abnormality of the CCJ along the z-axis (figure 7). In a study on 200 healthy European adults employing standard MRI, this measure was taken from the T1 weighted sagittal section of each subject. Measures start from the cortical bone, i.e. from the dark signal. The mean was -4.6 mm with a standard deviation SD = 2.6 mm (Cronin C.G. et al. 2007). The minus before the number indicates that the mean position of the selected point of the dens is below the line. In normal individuals, the dens is always below the McRae’s line (McRae D.L. et Barnum A.S. 1953), (Cronin C.G. et al. 2007).

**10. Distance between basion and odontoid process
**

It is the distance between the basion and the tip of the dens. It is also called basion-dental interval (BDI) and it has been proposed that a value greater of 10 mm is abnormal and predicts occipito-atlantal instability. Moreover, the average value is 5 mm, according to (Handerson F. 2016). I have not been able to find statistical data for BDI measured in MRI sagittal sections of healthy subjects. Moreover, I do not have a cutoff for the minimum value.

**11. Craniocervical instability
**

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).

In one study on craniocervical junction stabilization by surgery in five patients with Chiari I malformation or basal invagination (Henderson FC. et al. 2010), inclusion criteria, beside abnormal Grabb’s measure and CXA, were:

- signs of cervical myelopathy (sensorimotor findings, hyper-riflexia);
- signs of pathology at the level of the brainstem, collected in this table;
- severe head and/or neck pain, improved by the use of a neck brace for at least a 2 weeks period.

The same inclusion criteria were adopted in another similar study on patients with hereditary hypermobile connective tissue disorders (Henderson F.C. et al. 2019).

Several mechanisms are believed to play a role in the genesis of the clinical picture described in CCI: stretch of the lower cranial nerves (vagus nerve is among them) and of the vertebral arteries; deformation of the brainstem and of the upper spinal cord (Handerson F. 2016).

**12. Craniocervical instability and ME/CFS**

CCI has been described in Ehlers-Danlos syndrome hypermobile type (Henderson F.C. et al. 2019), although the prevalence of CCI in EDSh has not been established, yet (to my knowledge). At the same time, an overlapping between EDSh and ME/CFS has been reported in some studies: most of EDSh patients met the Fukuda Criteria, according to (Castori M. et al. 2011) and it has been proposed that among patients with ME/CFS and orthostatic intolerance, a subset also has EDS (Rowe P.C. et al. 1999), (Hakim A. et al. 2017). So, it might seem not unreasonable to find CCI in a subgroup of ME/CFS patients.

Moreover, both in CCI and in ME/CFS there is an involvement of the brainstem. Briefly, hypoperfusion (Costa D.c: et al. 1995), hypometabolism (Tirelli U. et al. 1998), reduced volume (Barnden L.R. et al. 2011), microglial activation (Nakatomi Y et al. 2014), and loss of connectivity (Barnden L.R. et al. 2018) have been reported in the brainstem of ME/CFS patients. 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. Recently, brainstem pathology in ME/CFS (midbrain serotoninergic neurons alteration, in particular) has been theorized as part of a mathematical model on disrupted tryptophan metabolism (Kashi A.A. et al. 2019), (R). So, one might argue that CCI could in some cases lead to a clinical picture similar to the one described in ME/CFS because in both these conditions there is a pathology in the same anatomical district (figure 8).

We know that in most of the cases ME/CFS starts after an infection (Chu L. et al. 2019). That said, how could CCI be linked to this kind of onset? The presence of CCI in rheumatoid arthritis (Henderson F.C. et al. 1993) might be a clue for a causal role of the immune system in this kind of hypermobility. In fact, a link between hypermobility and the immune system has been found also in a condition that is due to the duplication/triplication of the gene that encodes for tryptase (a proteolytic enzyme of mast cells) (Lyons JJ et al. 2016).

A piece of evidence against a link between CCI and ME/CFS is perhaps represented by the results of a study on EDSh patients with CCI who underwent surgery for their craniocervical junction abnormalities. Before surgery, all the 20 patients reported fatigue among their symptoms and two years after surgery the improvement in this symptom was not statistically significant, despite improvement in the craniocervical joint measures (CXA and Grabb’s measure) and improvement in overall functioning (Henderson F.C. et al. 2019). This seems to be a clue against the role of CCI in fatigue, at least in this patient population.

**13. Craniocervical measures in a few ME/CFS patients
**

I have collected standard MRIs of the head of seven ME/CFS patients and I have performed the measures described in this article, using the sagittal section of T1 weighted series. Data are collected in table 1.

GM stands for Grabb’s measure and the cutoff for this value has been taken from an MRI study on children with Chiari malformation (Grabb P.A. et al. 1999). I have not been able to find a study on adult normal subjects, so I don’t have any reliable statistical data on that measure. Yet, the reported cutoff of 9 mm is what is commonly indicated for GM (R), (Handerson F. 2016), (Joaquim A.F. et al. 2018). HHM stands for horizontal Harris measure and the cutoff was deduced from (Henderson F.C. et al. 2019), but again, I have not found statistical data on this measure from MRIs sagittal sections of an adult healthy population. BDI is the basion-dens interval and the cutoff comes from (Handerson F. 2016) and no statistical data available on a suitable population. CDD and MDD are the distances of the tip of the dens from the Chamberlain’s line and the McRae’s line, respectively and I got the statistical data from an MRI study on adult healthy subjects (Cronin C.G. et al. 2007). CXA is the clival-canal angle: statistical data were from an MRI study on 33 healthy adults (Botelho R.V. et al. 2013), while the cutoff was indicated in (Henderson F.C. et al. 2019).

The only abnormal values found are the distance between the tip of the dens and both Chamberlain’s line and McRae’s line in P2 and the Grabb’s measure in P7, with the caveat that I don’t have suitable statistical data for comparison, in the latter case. And of course, I don’t know what the meaning of these slightly abnormal values is. Of notice, none of these patients would fit the criteria proposed in (Henderson F.C. et al. 2019) for surgery of the craniocervical junction.

Patient 4 should probably be excluded from this table: she had a documented B12 deficiency at the onset of her disease; she was treated with vitamin B12 injections. After some months she has substantially improved. So it might have been a case of vitamin B12 deficiency. She also has a problem with iron, which tends to be low and has to be supplemented; since vitamin B12 and iron are both absorbed in the small intestine, this patient may have some pathology in that area. In fact, signs of inflammation were found in a sample of her duodenum, but it was not possible to define a specific diagnosis (celiac disease was ruled out, as well as Crohn’s disease). Interesting enough, this patient had a diagnosis of POTS (by tilt table test) and vitamin B12 deficiency has been linked to POTS (Öner T. et al. 2014). As mentioned, she is in remission now.

Let’s try now a statistical analysis for the values of the clival canal angle reported in Table 1, using as control group the one published in (Botelho R.V. et al. 2013). We can use Cantelli’s inequality (see Eq. 2, paragraph 15) and extend it to a random vector. We get for the p value:

In our case m = 8, µ = 148, σ = 9.88. By using the following very simple code we calculate a p value < 0.03, which is statistically significant. The problem here is that the measure of the CXA in the control group has been made by someone else than me, so this might be a source of error. Moreover, the sample is very small. All that said, a tendency towards a reduction of the clival canal angle among ME/CFS patients might be further proof of increased mobility of the cranio-cervical joint in this patient population, in agreement with previous studies on other joints (Rowe P.C. et al. 1999), (Hakim A. et al. 2017).

clear all mu = 148 ds = 9.88 m = 8 p = 1.; x = [142, 146, 142, 142, 135, 140, 140, 139]; for i=1:m p = p*( 1/( 1 + ( ( (mu-x(i))/ds )^2 ) ) ); endfor p

**14. Craniocervical instability and Euler’s angles**

A more sound definition of CCI might perhaps be obtained with the introduction of the angles that are used to describe the orientation of a rigid body with respect to a fixed coordinate system. To simplify our analysis, we assume here that atlas (C1) and axis (C2) are fixed one to the other. Then, consider the coordinate system (O; *x, y, z*) in figure 1 to be fixed to C1-C2 and then let’s introduce a second coordinate system (Ω; *ξ, η, ζ*), fixed to the skull. The orientation of (Ω; *ξ, η, ζ*) with respect to (O; *x, y, z*) is given by the angles *ψ, φ, θ, *called Euler’s angle (figure 7). The angle θ is the one between *z *and* ζ. *In order to define the other two angles, we have to introduce the *N* axis, known as *line of nodes*, which is the intersection between plane *xy* and plane *ξη. *That said, *ψ* is the angle between *x* and *N, *while *φ *is the angle between *ξ *and* N. *

All that said, craniocervical hypermobility may be defined as follows.

Def.We have CCI when there is an increase in the physiological range of Euler’s angles and/or when |ΩO|≠0.

In this definition, we have assumed that in physiological conditions the length of the vector **ΩO** is nought. The length of **ΩO **is indicated as** |ΩO|**. The condition |**ΩO|≠**0 means that at least one of the components of **ΩO** along the axises *x, y, z *is different from zero*. *

The reader can easily recognize now that:

- the clival-canal angle is a measure of instability in the angle
*θ*; we can also say that clival-canal angle measures instability around*N;* - Grabb’s measure and Horizontal Harris measure both indicate instability along the
*x*-axis; they are a measure of the*x*component of vector**ΩO**; - Chamberlain’s line gives a measure of instability along the
*z*-axis; the same applies to McRae’s line and to BDI.

**15. Cantelli’s inequality
**

To assess the statistical significance of the experimental data in Table 1 we have used Cantelli’s inequality, also known as one-tailed Chebyshev’s inequality. Given the random variable X whose distribution has mean E[X] and variance Var[X], then Cantelli’s inequality states that:

for any η>0. The importance of these two inequalities is that they are true whatever the distribution is. In the case of our patient’s MRS data, we only knew mean values and standard deviations (which is the square root of variance) of the distributions of the metabolic values of the control group. So one way to assess significance was to use this inequality (the other way would be to use the less precise Chebyshev’s inequality). To prove Eq. 1 and Eq. 2 we have first to prove Markov’s inequality, which states that

for any *a*>0. In order to prove that, consider that for the probability on the left of the inequality we can write

At the same time, the expectation (or mean) of the distribution can be written

Thus we have

and Markov’s inequality is proved. Let’s now come back to the proof of Cantelli’s inequality. If we consider the random variable *Y = X – E[X]* we have that *P(Y≥η) = P(Y+t≥η+t) *and assuming that *η+t > 0 *we have

That said, Markov’s inequality gives

For the expectation on the right we have

and knowing that E[Y²] = Var[X] and that E[Y] = 0, we can write

The function on the right of the inequality is represented in Figure 4. It is easy to recognize that it assumes its lower value for *t = Var(X)/η *and this proves Eq. 1. The other inequality (Eq. 2) can be proved in the same way, considering the random variable Z* = E[X] – X. *

Hello Paolo

My name is Libby and I work with the ME/CFS Association in New Zealand (ANZMES)

I wanted you to know that we published your blog post in our quarterly publication called “Meeting Place.”

I am not the editor, but she is a friend and a colleague. It is a modest publication which only goes out to ME patients in New Zealand.

Would you like us to send you a copy electronically? We are able to send it this way. It may take us some time because we don’t have much money and at the moment, we need to find a new secretary and coordinator.

But I thought you would like to know how much we appreciate your work.

Libby

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Hello Libby,

thank you for publishing my blog post, I do appreciate that.

Please send me a copy at the following e-mail: macpa@tiscali.it

Thank you,

Paolo

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Gracie, Paolo. I will forward this to our editorial committee with ANZMES.

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Gracie, Paolo. I will forward this to our editor.

Libby

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how does having inflammation in the duodenum preclude there being CCI? intestinal inflammation could easily be a downstream affect of brain stem / spinal cord compression

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Hi sue!

This blog post was – among other things – an attempt at searching for the prevalence of CCI among ME/CFS patients.

But since P4 (table 1) had an initial B12 deficiency and she recovered after B12 supplementation (and of course, we can’t say for sure what really happened, why she recovered) she should perhaps be excluded from our cohort of ME/CFS patients.

This is what I was trying to say in the article.

By the way, none of the measurements I took on her T1-weighted sagittal section is abnormal, which rules out CCI in her case, at least if we consider the definition I used in this article.

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Henderson, Gilette, and others do these measurements using an upright MRI with extension and flexion. I was diagnosed by Henderson based on abnormal CXA and Grabb Oakes in flexion. I’m “borderline” in extension. CXA of 135 or below is considered abnormal (by these NSs). 136-149 is “borderline.”

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Hi Rhea!

Yes, there is some paper in which the upright imaging has been used, but most of the literature is on the use of standard MRI. The very recent paper by Handerson (see below) in which they diagnosed CCI in EDS patients, was based on standard MRIs. I used it as a reference.

https://pubmed.ncbi.nlm.nih.gov/30627832/

I’ll extend the analysis to upright imaging in a future blog post.

It is worth mentioning that in normal subjects the CXA angle can range from 129° to 175° (see reference below) even when measured while the patient is supine.

https://pubmed.ncbi.nlm.nih.gov/23640096/

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