Embryology and bony malformations of the craniovertebral junction

During resegmentation, the caudal half of somite 5 and the cranial half of somite 6 combine to produce the first cervical sclerotome; likewise, the second cervical sclerotome is made up of corresponding parts of somites 6 and 7. In the axial region of these sclerotomes destined to form vertebral centra, dense and loose zones appear in regular succession as in the lower cervical sclerotomes. The loose prevertebral zone of the first cervical sclerotome gives rise to the basal segment of the dens, and that of the second cervical sclerotome becomes the body of the axis (Fig. 14). Unlike in the more caudal sclerotomes, however, where the dense IBZ ultimately becomes the annulus and nucleus pulposus of an intervertebral disc, the dense zones in the first two cervical sclerotomes do not form true intervertebral discs and soon disappear [65]. Their intervertebral boundary mesenchyme gradually turns into the upper and lower dental synchondroses that ultimately cement the apical to the basal dens and the basal dens to the body of C₂, respectively (Fig. 14).

Thus after resegmentation, the human membranous axis consists of three median constituents that have been designated the apical dental segment from the caudal proatlas, the basal dental segment from the first cervical sclerotome, and the body of the axis from the second cervical sclerotome [6, 7, 36, 78, 82]. These three constituents chondrify simultaneously around 6 weeks of gestation but remain segregated by the more cellular upper and lower dental synchondroses. Ossification of the cartilaginous axis occurs in three chronological waves (Fig. 16). The first wave appears as a single ossification centre within the axial body around 4 months of gestation. The second wave begins at 6 months of gestation as two separate ossification centres on each side of the basal dental segment [69, 75, 95, 100]. At birth, these two centres integrate and fuse, and the main component of the dens should at least have begun to show bony fusion with the axis body, even though a clear rarification may still be discernible at the lower synchondrosis till the fifth or sixth post-natal year (Figs. 16 and 17). Occasionally, the basal dens remains bifid (dens bicornis) when the third wave of ossification arrives within the apical dens around 3 to 5 years of age [6, 53, 75] (Figs. 16, 17, and 18). Ossification of the dental tip and bony fusion of the upper synchondrosis are not completed until adolescence [55, 56, 94, 96].

Lastly, the apical ligament is almost certainly derived from the axial proatlas, and the alar and transverse atlantal ligaments are from the axial component of the first cervical sclerotome in association with the basal dental segments [65].

The lateral dense zone of the first cervical sclerotome develops into the posterior arch of the atlas, whilst the lateral dense zone of the second cervical sclerotome forms the arch of the axis. Their respective loose zones promote outgrowths of the second and third cervical nerves and segmental arteries. The hypochordal bow of the first cervical sclerotome ventral to the notochord subsequently forms the anterior arch of the atlas (Fig. 14, middle and right) [63‐65, 82]. No definite hypochordal bows are seen caudal to this level and equivalent cells in the lower segments appear to play no role in the formation of the vertebral column.

Abrogation of the IBZ during early resegmentation such as in the transgenic mutant mice undulated causes exuberant fusion between sclerotomal units rather than lack of fusion [83, 99]. Thus, when there is non-fusion of discrete individual dental components as in os odontoideum and ossiculum terminale persistens, one may safely assume that the respective IBZ between the proatlas and the first two cervical sclerotomes were initially demarcated but subsequent development of the upper and lower dental synchondroses was unconsummated.

There are endless debates in the literature about whether os odontoideum is truly a developmental anomaly or an un-united odontoid fracture. Proponents for the traumatic theory argue that the inferior surfaces of most os odontoideum are above the “expected base” of the normal dens, which is supposed to be below the level of the C₂ lateral masses [15, 17, 34‐36, 58, 61, 94], and that there is often a “cupola” bulging cranially from the axis stump that represents the bottom half of a fractured dens [94]. In countering, the developmentalists point out that transgenic mutant experiments repeatedly show that vertebral primordia that have undergone aberrant development seldom evolve into the orthodox configuration of the normal phenotype, but instead become oddly shaped due to over-, under- or even erratic growth depending on the activities of local inducers [75, 83, 99]. The often expanded roundness of the os odontoideum with its corrugated horn-like corners (Fig. 26a) can hardly be the expected visage of an unhealed odontoid fracture, with its compromised blood supply. In addition, os odontoideum has been found in identical twins [46] and families [62], as well as amongst children with collagenopathies, and it frequently co-exists with other developmental bony anomalies of the skull base, all reinforcing the congenital theory. We believe that what has been called os odontoideum is a heterogeneous designation of both the congenital and post-traumatic varieties, but there may also be cases with mixed aetiologies. For example, the mesenchyme at the IBZ may have failed to chondrify and therefore cannot ultimately undergo ossification and fusion. As the two dental components ossify on opposite sides of the IBZ and gain mechanical leverage, the persisting mesenchymal tissue could no longer withstand the stress caused by foetal movements, and the upper part separates as the loose os odontoideum. The evidence for either theory is selectively circumstantial although the clinical implications are the same.

There is little dispute about the developmental origin of ossiculum terminale persistens. The ossiculum represents an unfused and detached apical dental segment, which comes from the proatlas centrum [18, 19, 36, 94] (Fig. 27). The detachment is probably due to upper dental synchondrosis failure although late disturbance of the third wave of odontoid ossification may be responsible. The ossiculum is usually non-syndromic although cases are seen with Morquio’s disease.

Because the TAL straps around the basal segment of the dens, os odontoideum is at least potentially unstable (Fig. 28). Symptoms vary from persistent neck pain, torticollis, transient quadriparesis, lower cranial neuropathies, to recurrent brain stem strokes caused by stretching of the vertebral arteries and basilar artery embolism (Fig. 26b).

Although most ossiculum terminales are stable anomalies [17, 94] because the TAL’s anchorage is not affected, we have encountered cases in which the basal dental segment is hypoplastic and the dental pivot is short. Some of these are conducive to atlantoaxial subluxation and high cord compression (Fig. 29a, b). Posterior C₁–C₂ fusion is adequate treatment if complete reduction is achievable. If there is persistent anterior dislocation of C₁, its posterior arch may have to be removed for decompression, in which case occipital C₂–C₃ fusion is necessary (Fig. 29c).

A 10-year-old girl presented with intermittent quadriparesis and neck pain. Dynamic sagittal CT reconstruction shows an ossiculum terminale with anterior subluxation and only partial reduction on extension and persistent cord compression by the posterior arch of C₁ (Fig. 30a). The nearly spherical ossiculum forms a synovial joint with the posterior aspect of the anterior C₁ arch, and the two structures move together (Fig. 30a). Sagittal MRI shows an extremely narrow spinal canal at C₁ (Fig. 30b). C₁ laminectomy and instrumentation fusion of occiput to C₂–C₃ was performed. Her occiput had a robust midline keel so that a regular cruciate occipital plate was secured to the skull with three 6-mm screws (Fig. 30c) and then to two upright rods contoured to the region. The rods were affixed by interlocking links to bilateral C₁–C₂ transarticular screws and C₃ lateral mass screws (Fig. 30d).

In human malformations, it is not uncommon to find errant ontogeny reverting to a morphological pattern reminiscent of an organ’s phylogenetic past. As case in point, a separate bone between the dens and the basioccipital resembling the attached ossiculum in the human anomaly is found in some fish and reptiles and many birds [29, 31, 39, 75, 76, 85, 100]; hence, our terminology os avis. In higher vertebrates, this bone, the primordium of the apical dens, normally becomes detached from the basioccipital rim, which shares with it a common origin in the proatlas centrum. Lack of proper resegmentation of the proatlas centrum, in essence negating the necessary cleavage, prevents descent and subsequent joining of the apical segment with the centrum of the first cervical sclerotome to complete the dental pivot. The reason for this failure is unknown, but since proatlas resegmentation normally occurs at the transitional zone between somites 4 and 5, a caudal shift of this transitional zone along the body axis may affect the resegmentation process. In transgenic mouse mutant in which Hox a-7 is expressed earlier and more rostrally in its anterior domain, the last occipital somite (O₄) is transformed (posteriorly) to become the atlas, bearing a “proatlas” centrum that remains attached to the basioccipital. C₁ then becomes C₂ and acquires a complete centrum whilst C₂ is deleted of its normal dens [24]. This extra “proatlas” bone in the murine mutant very much resembles the os avis in the human malformation and suggests that a Hox gene mutation causing posterior homeotic transformation of segmental identity may indeed underlie the genesis of the os avis.

An os avis tends to be associated with neurological deterioration. The two patients with os avis described by Wollin [100] amongst seven others with “loose” ossiculum terminale and os odontoideum are the only ones with symptoms, and both had a hypoplastic dental pivot. Both cases of os avis described by Menezes and Fenoy are symptomatic due to posterior dislocations of C₁ on C₂ [60]. Of the two cases in our series, one had a hypoplastic dens and the atlantoaxial complex is extremely unstable on extension; the TAL is strapped against the os and therefore moves with the skull (Fig. 31). Our other case is associated with other CVJ anomalies such as multiple hyposegmentation of vertebral bodies, short clivus, basilar impression and a stenotic foramen magnum, even though the dens pivot is tall and sustaining for the TAL. The patient does not have instability but develops compressive symptoms (Fig. 32). In Wollin’s cases, associated anomalies include a large median (third) occipital condyle (see below) and a hyperplastic anterior C₁ arch.

Treatment of os avis depends on the other anomalies. Pure instability can be remedied with C₁–C₂ fusion. An absent posterior C₁ arch or an occipitalized atlas would mandate inclusion of the occiput into the fusion. Concomitant neural compression due to basilar impression or invagination of the opisthion may require simultaneous decompression.

A completely bifid dens is an extremely rare entity. It is different from the “dens bicornis” described by von Torklus and Gehle in which only the tip of the dens is bicornuate and the function of the otherwise well-formed dental pivot is unaffected [94]. Dens bicornis results from aberrant distal ossification late in development. In true dental bifidity, the partition in the basal dental segment goes full length of the process to the lower synchondrosis. In one example, the bifid dens is accompanied by a dislocated ossiculum terminale (Fig. 33). In two others, one half of the split dental base is unattached to the centrum of C₂ and is floating free, whilst the body of C₂ is fused with that of C₃, which is itself bifid. The anterior C₁ arch is also unfused in the midline (see “Illustrative case 2”). These examples suggest that the lack of midline integration occurs very early in development, probably in the mesenchymal prevertebral stage or during chondrification. The lack of midline integration in the primordium of the basal dental segment appears to interfere with fusion of the adjacent synchondrosis leading to a detached “hemi-os” in two and an ossiculum terminale in the other. Also, faulty midline integration in the second example given here is not confined to the basal dens but also extends to the primordium of the C₃ centrum and the hypochordal bow of the first cervical sclerotome, which forms the anterior C₁ arch. The multiplicity of primordial abnormalities occurring around resegmentation would make it unlikely for a truly bifid dens to be a result of anomalous ossification, which occurs much later.

Our entire experience of three cases suggests that the bifid dens is associated with atlantoaxial instability because the central pivot is hypoplastic when bifid. In our first case, the hypoplastic dens is aggravated by the dislocated ossiculum terminale, negating any possibility for TAL anchorage (Fig. 33b, c). In our second and third case, the hypermobile “hemi-os” pops backwards during flexion and accentuates the cord compression (see “Illustrative case 2”).

Stabilization for case 1 had to include the occiput into the fusion because of an incomplete posterior arch of C₁. In the other two cases, occipital–cervical fusion is combined with a transoral resection of both halves of the dens to relieve the anterior compression.

A 6-year-old boy presented with intermittent quadriplegia and somnolence whenever he flexed his neck to study. CT showed a bifid odontoid with the right half unfused to the axis body (Fig. 34a) so that on flexion the mobile “hemi-os” popped backwards against the lower brainstem. A previous occipital–cervical fusion failed to relieve neural compression from the anterior vector (Fig. 34b). Because the boy also had congenital microstomia and micrognathia, which prevented a conventional transoral approach to the odontoid, we split the mandible, tongue, mylohyoid muscle and soft palate to access and resect the hemi-os and odontoid (Fig. 34c–g). The child recovered with complete abatement of symptoms (Fig. 34h).

Congenital basilar impression, which concerns us here, is less a result of active upward indentation of the dens against the brainstem, as the word “impression” implies, than a drop of the posterior fossa contents on to the erect dens due to a shallow occipital “box” and flattened skull base. The causative occipital dysplasia is due to deformed growth of all three parts of the occipital primordium: the basioccipital (pars basilaris) and the exoccipital (pars lateralis including the condyles and the foramen magnum rim), which enlarge by endochondral ossification, are primarily hypoplastic; and the supraoccipital, the squama, which expands by membranous ossification and therefore depends on growth of the chondrocranial molds of the other two parts, is obligatorily constricted.

Three types of congenital basilar impression can be distinguished. Anterior basilar impression is caused by changes in the basioccipital complex, which derives from the axial (median) occipital sclerotomes. The most dramatic change is platybasia, when the nasion–tuberculum–basion angle (NTB angle of Welcker) is increased and the sphenoclival block appears severely flattened. Platybasia is often accompanied by a shortened basioccipital or clivus, which normally measures more than 3.2 cm from the spheno-occipital synchondrosis to the basion. The summated effect of a short and flattened clivus is that the basion, which normally lies below the nasion–opisthion line (of Boogaard), is raised way above it and moves cranially (Fig. 37). This forces the plane of the foramen magnum to tilt upwards in a lordotic angle and with it the planes of the occipital condyles and of the condyle–atlas articulations (Fig. 38).

The fusion and chondrification of the basioccipital and the exoccipital sclerotomes occur slightly earlier than the resegmentation of the C₁–C₂ sclerotomes. A severely lordotic skull base angle consequently forces the emerging upper cervical sclerotomal column to bend backwards “in sympathy”, especially its centra complex that will ultimately form the dens–axis (Fig. 39). This explains why platybasia and short clivus are frequently associated with a retroflexed and lordotic dens, that, in severe cases, points sharply and wickedly backwards into the brainstem (Fig. 39). Clinical studies have indeed shown that patients with basilar impression have a significantly shorter clivus than control groups [67].

In the posterior form of basilar impression, the exoccipitals, derived from the lateral sclerotomes of the proatlas, rise up towards the foramen magnum, bringing with them the occipital condyles and opisthion. Alternatively, the exoccipital bones may be thin and the condyles flat and hypoplastic. In either case, the dens is secondarily elevated towards the cranial cavity without being lordotic or retroflexed. The opisthion, however, often invaginates into the cranial aperture (basilar invagination).

A 12-year-old girl of normal intelligence presented with occipital headache, neurogenic dysphagia, nasal voice and right arm and hand clumsiness. CT showed a steeply elevated occipital condyle (exoccipital), basilar (opisthion) invagination and C₁ assimilation (Fig. 40a). There is no platybasia, and the dens, though migrated cranially into the foramen magnum, was not retroflexed (Fig. 39a, right). MR showed severe brainstem and upper cord compression mainly from the invaginating opisthion (Fig. 40b). At surgery, the posterior lip of the foramen was removed by careful drilling under microscopy (Fig. 40c). The thin occipital bone and the bizarre shapes of C₂ and C₃ precluded the use of regular occipital screw plates and intraaxial cervical screws. We used instead the inside–outside occipital screw plate system affixed to the C₂ and C₃ laminae with sublaminar cables (Fig. 40d–h). Onlaid autogenous iliac crest grafts were put in place (Fig. 40i–k).

In the combined anterior and posterior form, severe basilar impression by a retroflexed dens is accompanied by posterior invagination of the opisthion, causing neural compression from both front and back.

A 12-year-old girl presented with occipital headache, hemi-sensory loss and tongue fasciculation. CT shows an essentially flat nasion–tuberculum–basion line and severe platybasia, an acute Wackenheim angle (basilar kyphosis), an elevated retroflexed dens and severe basilar (opisthion) invagination (Fig. 41).

The upward migration of the anterior and posterior occiput in severe basilar impression in essence reduces the posterior fossa volume, estimated by the index of Klaus, which measures the distance between the tip of the dens and the tuberculo-cruciate line (between the tuberculum sellae and the internal occipital protuberance) (Fig. 36). This index should exceed 30 mm [94]. With significant reduction to below 25 mm, the developing cerebellum and brainstem are desperately crowded and herniate downwards, accounting for the common association of ectopic cerebellar tonsils (Chiari I malformation) with severe basilar impression, platybasia, shortened clivus and retroflexed dens (Fig. 42). Occasionally, the lower brainstem also lies well below the plane of the foramen magnum (“Chiari 1.5”) [89]. It is our impression that the truly congenital form of Chiari I malformation often includes skull base dysplasia, and the much debated acquired Chiari I malformation consists only of ectopic cerebellar tonsils. Studies have shown that patients with hindbrain herniation and basilar impression have a higher brain to posterior fossa volume ratio than those with just hindbrain herniation, and both groups have higher ratios than controls [67, 87, 90].

Platybasia without basilar impression is asymptomatic (Fig. 43). Indentation of the anterior medulla by the dens, however, produces brainstem dysfunction and lower cranial neuropathies more frequently than “pure” cerebellar ectopia without an anterior compression vector. The brainstem deficits include neurogenic dysphagia [70, 71], nasal or hoarse voice due to paresis of the palatal levator and vocal cords, sleep apnea and intermittent or progressive spastic quadriparesis. Tussive headaches, syncope and gait discoordination are also common complaints.

Posterior decompression for Chiari I malformation with coexisting basilar impression carries a much higher late complication rate than for pure cerebellar ectopia. Even if the anterior vector is not initially symptomatic, the slightest amount of post-operative cranial settling after nullification of the dorsal tension band will deliver the brainstem straight on to the pointing dens to cause rapid onset of new brainstem signs [32]. In addition, platybasia and a decrease in the clivus–axis angle (of Wackenheim) (basilar kyphosis) accentuate the forward bending moment acting on the clivus–dens pivot point and accelerate the forward “folding” of the cranio-cervical axis (see “Illustrative case 5” below). It is our distinct impression that this type of post-operative instability occurs far more commonly in the associative type of Chiari I malformation. We therefore avoid removing the C₂ lamina during the decompression, if necessary at the expense of resecting the tips of the tonsils.

If symptomatic post-decompression cranial settling does occur despite precautions, calipers skull traction with the neck in slight extension should be rendered under muscle relaxation and sedation for a few days, aiming at reversing the kyphotic deformity and telescoping effect at the foramen magnum. Occiput–C₁–C₂ fusion should be done after reduction. If brainstem indentation persists, transoral resection of the dens may be necessary.

A 10-year-old girl presented with neck pain, diminished gag reflex, hand clumsiness and poor truncal coordination. MRI and CT showed cerebellar ectopia, basilar impression, a retroflexed dens and mild platybasia. The pre-operative clival–axis angle was 130° (Fig. 44a). The child improved after suboccipital craniectomy and C₁–C₂ laminectomy. Six weeks after surgery, the child presented with rapid onset of nasal food regurgitation, nasal voice, loss of gag reflex and aspiration. MRI and CT showed cranial settling, extreme basilar kyphosis with the Wackenheim angle now reduced to 110° and a shortened dens–basion interval (DBI) (Fig. 44b). Reduction with skull calipers traction and subsequent occipital C₁–C₂ fusion (Fig. 44c) promptly reversed her neurological defects. Post-fusion MRI and CT showed relief of the anterior basilar impression, straightening of Wackenheim’s angle to 130° and restoration of the initial DBI (Fig. 44d).

The hypochordal bow is an arcual strip of mesenchyme ventral to the axial sclerotome. In humans, only the hypochordal bows of the proatlas and C₁ resegmented sclerotome persist [65]. The hypochordal bow of the proatlas normally forms a small midline osseus tubercle attached to the ventral surface of the basioccipital below the rim of the foramen magnum (Fig. 14). Rarely, it remains as a fully ossified structure distinct from the basioccipital bone. If the entire arc is preserved, it is called a pre-basioccipital arch, which looks like a U-shaped bony valance on the underside of the anterior rim of the foramen magnum [75, 92, 94] (Fig. 45). If only the paramedian arch persists, two parasagittal spikes project downwards from the clivus, called the basilar processes [75, 92, 94]. Neither of these bony excrescences encroach on the foramen magnum and are thus harmless. Occasionally, however, the median portion of the proatlas hypochordal bow becomes exuberantly hyperplastic and forms a prominent bone spur that juts obliquely backwards from the basioccipital tip, that does cause neural compression. This median bony process is firmly attached to the basion and, elongating it, frequently forms true synovial joints with the anterior arch of C₁ and the odontoid apex (Fig. 46) [92]; it is thus rather aptly termed a median or third occipital condyle (condylus tertius) [48] [74, 77, 92, 94]. These articulations, though bizarre, are not surprising if one remembers that the anterior arch of C₁ comes from the hypochordal bow of the first cervical sclerotome directly subjacent to the hypochordal bow of the proatlas, and the dental apex develops from the proatlas centrum; joint formation between corresponding components of adjacent sclerotomes is “normal” in the lower vertebral levels.

A third occipital condyle may be mistaken for an os avis on radiographs since both are osseous appendages of the clival tip. However, it is important to distinguish them because of their very different implications of stability. In os avis, the dental pivot has lost its top and becomes perilously hypoplastic, whereas the dental pivot in the case of the third occipital condyle has normal height and therefore remains solid anchor for the TAL; instability is unlikely. Although some third condyles are short and protrude along the contour of the clivus or even curl forward away from the brainstem (Fig. 47), others can be enormous backward pointing cantilevers [48, 60, 77, 94] producing serious neurological deficits. Because there is no instability, transoral, transclival resection of the third condyle is an adequate treatment.

A 6-year-old boy was born with a fixed torticollis. At age 5, he began complaining of worsening neck pain and loss of rotation. He presented after a gentle fall on his back with right arm and leg weakness. CT and MRI showed a severe lateral tilt of the craniocervical junction, gnarly hypertrophy of the right occipital condyle and compression and lateral distortion of the C₁ cord (Fig. 48). A right far lateral approach was used to resect the condyle–C₁ joint followed by occiput–C₁–C₂ fusion.

It has already been mentioned that inactivation of Hox d-3 gene expression in mice results in anterior homeotic transformation at the CVJ such that the C₁ vertebra takes on an occipital identity and the head–neck transitional zone moves caudally to the C₁–C₂ junction (Fig. 21). All mutants have assimilation of C₁ to the basiocciput [13, 24]. It is therefore tempting to ascribe human cases of isolated C₁ assimilation to similar mutations of the human Hox gene homologues. However, in cases of combined C₁ assimilation and Klippel–Feil syndrome in which multiple levels of cervical fusion are seen below C₂, the Hox gene theory will require multiple Hox mutations and alterations of multiple Hox codes, which is highly improbable. Since Pax-1 expression is involved in resegmentation of all levels of the embryonic axis, inappropriate repression of Pax-1 at the proatlas–C₁ sclerotome interphase and other vertebral levels may be involved in associative cases of atlas assimilation.

Assimilation of the atlas to the occiput means that the first mobile segment between the skull and spine has been transferred to the C₁–C₂ junction, as are all the motion stresses including that of flexion–extension, normally of restricted range at this level and for which the local joint anatomy is ill suited. This also means the supporting myoligamentous structures are more likely to suffer “over-stretch” failure. Almost 60% of Gholve et al.’s patients with C₁ assimilation has C₁–C₂ instability defined as an atlantal–dens interval (ADI) greater than 4 mm in adults and 5 mm in children [30]. McRae and von Torklus and Gehle had similar findings [55‐57, 93]. More than half of Gholve et al.’s patients with instability also had C₂–C₃ fusion, which adds to the burden of stresses at C₁–C₂.

The symptoms of C₁–C₂ instability range from persistent neck pain and stiffness to frank myelopathy. Typically, the neurological deficits begin in the third or fourth decade of life [55] and tend to worsen with age [56]. We have also seen concomitant hypertrophy of the posterior arch of C₂, which accentuates the neural compromise. Management for symptomatic cases is stabilization between occiput and C₂–C₃ in concert with treatment for the other associated malformations.