Degenerative Disc Disease (DDD) and Cervical Spondylotic Myelopathy (CSM)

The intervertebral discs (IVD) are composed of a collagen-rich outer ring called the anulus fibrosus and a proteoglycan-rich, hydrophilic and tumescent core, known as the nucleus pulposus. The IVD serves to bear axial compressive loads and to redistribute these forces along the vertebral endplates. Furthermore, owing to its viscoelastic nature, the nucleus pulposus provides a pivotal role in maintaining the IVD height. ^{Reference Roberts, Evans and Trivedi5} Wear and tear due to aging, excessive mechanical stress, and/or environmental and nutritional factors cause the nucleus pulposus to degenerate and lose its viscoelastic properties. ^{Reference Palepu, Kodigudla and Goel6,Reference Nixon7} As a result, the decreased IVD height alters the distribution of the axial forces leading to increased loads on the uncovertebral joints. Subsequently, the uncovertebral processes become flattened thereby increasing stress on the annulus and facet joints. ^{Reference Baptiste and Fehlings8,Reference Kalsi-Ryan, Karadimas and Fehlings9} This ultimately initiates a cascade of degenerative changes. These changes comprise alterations to the disc (such as annular tears, disc bulging, or disc herniation), the formation of osteophytic spurs in an attempt to stabilize the abnormal motion and increase the surface of the weight-bearing endplates, and ligamentous hypertrophy or calcification. ^{Reference Galbusera, van Rijsbergen and Ito10,Reference Badhiwala, Ahuja and Akbar11} Each individual degenerative change or a combination thereof contributes to the narrowing of the spinal canal and harbors the risk of spinal cord compression.

A static injury occurs through direct compressive forces or increased longitudinal stretching (caused by forcing the spinal cord over anterior bony spurs, protruded discs, or vertebral bodies in kyphotic deformities). ^{Reference Ames, Blondel and Scheer12} In addition, dynamic mechanisms can cause movement-dependent worsening of compressions to the spinal cord through instability, increased range of motion and minor trauma in the setting of pre-existing DCM. ^{Reference Nouri, Tetreault and Singh4} While neck flexion can potentiate the compressive effects of ventral osteophytes or disc herniations, hyperextension causes the ligamentum flavum (LF) to buckle and impinge the spinal cord posteriorly. ^{Reference Tracy and Bartleson13,Reference Tetreault, Goldstein and Arnold14} On that note, the most common form of incomplete traumatic SCI, also known as central cord syndrome, usually occurs in older patients with pre-existing degenerative changes after low-impact hyperextension injuries to the cervical spine and is characterized by an asymmetric motor weakness, more profound in the upper than lower extremities. ^{Reference Schneider, Cherry and Pantek15–Reference Ej, Mh and Gm17}

Ligamentous Aberrations

Spinal degeneration may also result in structural changes to the posterior longitudinal ligament (PLL) and the LF, which include hypertrophy and aberrant ectopic ossification or calcification. These alterations ultimately result in a reduction of the spinal canal diameter and contribute to spinal cord compression. ^{Reference Badhiwala, Ahuja and Akbar11}

While the loss of IVD height has been discussed to cause abnormal cervical spine biomechanics that eventually lead to hypertrophic degeneration and buckling of the ligamentum flavum, ^{Reference Baptiste and Fehlings8,Reference Kalsi-Ryan, Karadimas and Fehlings9} a nucleus pulposus prolapse has been proposed to be involved in the initiation of hypertrophic changes to the PLL. ^{Reference Inamasu, Guiot and Sachs18} However, the exact underlying pathomechanism in the development of ossification of the PLL (OPLL), ossification of the LF (OLF), and calcification of the LF (CLF) remains unclear. While incidences of OPLL among Germans and North Americans have been reported to be 0.1 %, increased incidences of OPLL (1.9-4.3%), OLF (up to 20% in >65 years of age) and CLF among the Japanese population suggest environmental and/or genetic factors contribute to the marked calcification and ossification of these ligaments. ^{Reference Baptiste and Fehlings8,Reference Matsunaga and Sakou19–Reference Matsunaga and Sakou21}

Congenital Disorders

Several congenital disorders result in altered cervical spine anatomy and accelerate degeneration of cervical structures, thereby promoting earlier development and clinical manifestation of DCM.

Patients with Down syndrome (DS) potentially suffer from a variety of congenital manifestations, which, from a cervical spine perspective, include a predisposition to atlantoaxial instability (AAI), cervical spondylosis, and developmental abnormalities of bony structures (such as the odontoid process or the posterior arch of C1). ^{Reference Ali, Al-Bustan and Al-Busairi22,Reference Bosma, Buchem and Voormolen23} The increased incidences of AAI among patients with DS have been numbered between 10–20%, of which however only 1–2% develop symptomatic myelopathy. ^{Reference Ali, Al-Bustan and Al-Busairi22}

Yet another hereditary disorder that renders the atlantoaxial joint at higher risk for instability is Ehlers-Danlos syndrome (EDS). ^{Reference Henderson, Austin and Benzel24,Reference Halko, Cobb and Abeles25} EDS is a clinically and genetically heterogenous group of connective tissue disorders affecting mainly the skin, joints, and ligaments. ^{Reference Steinmann, Royce and Superti-Furga26} The atlantoaxial joint is essentially dependent on the stabilizing properties of the transverse and alar ligaments, which in EDS show a proclivity to inefficiency thereby increasing the risk for AAI. ^{Reference Henderson, Austin and Benzel24,Reference Halko, Cobb and Abeles25} Furthermore, ligamentous laxity puts patients with EDS at an increased risk of developing segmental instabilities and kypho-scoliotic deformities. ^{Reference Henderson, Austin and Benzel24,Reference Steinmann, Royce and Superti-Furga26} As a result of a loss of physiologic cervical lordosis and increasing kyphosis, normal elongation of the spinal cord during neck flexion may worsen due to compression against the vertebral bodies and/or ventral spondylotic bars. ^{Reference Henderson, Austin and Benzel24,Reference Shedid and Benzel27}

KFS is a complex, congenital condition, which has been shown to present with a classical clinical triad of low posterior hairline, short neck and limited cervical range of motion in 34–74% of patients. ^{Reference Samartzis, Herman and Lubicky28,Reference Tracy, Dormans and Kusumi29} Although various neurologic and visceral abnormalities have been shown to be associated with KFS, the hallmark of this condition is the improper segmentation of cervical motion segments, resulting in congenitally fused vertebrae. ^{Reference Samartzis, Herman and Lubicky28,Reference Tracy, Dormans and Kusumi29} The abnormal vertebral fusion seen in KFS patients is mainly observed in the cervical spine and has been linked to facilitate similar degenerative processes as seen in patients who have undergone operative fusion of cervical motion segments. The effects, which have been discussed to occur as a result of increased biomechanical stress on adjacent nonfused segments, include the development of adjacent level disc degeneration, cervical spondylotic development, subluxation, bulging of the disc and/or LF, and loss of cervical alignment. ^{Reference Samartzis, Herman and Lubicky28,Reference Eck, Humphreys and Lim30,Reference Goffin, Geusens and Vantomme31}

Developmental narrowing of the cervical spinal canal, as seen in congenital spinal stenosis, has been shown to lower the threshold at which the cumulative effects of degenerative changes encroaching the spinal cord cause clinical signs and symptoms of DCM. ^{Reference Nouri, Tetreault and Singh4,Reference Baptiste and Fehlings8,Reference Bernhardt, Hynes and Blume32,Reference Yue, Tan and Tan33} While normal sagittal canal diameters have been reported to be 17–18 mm between C3 and C7, a sagittal diameter of <13 mm constitutes a risk factor for developing signs and symptoms of cervical myelopathy. ^{Reference Baptiste and Fehlings8,Reference Bajwa, Toy and Young34} Clearly, interindividual variabilities of what is considered a “normal” spinal canal diameter, variations in the thickness of the spinal cords, and imaging artifacts complicate the development of uniform thresholds when taking into account absolute values. The Torg-Pavlov method compares the spinal canal diameter with the corresponding vertebral body (spinal canal/vertebral body), whereby a ratio of 0.82 has been found to suggest significant cervical spinal stenosis. ^{Reference Pavlov, Torg and Robie35}

Clinical Signs and Symptoms

The early clinical signs of DCM can be subtle. Common presenting symptoms include upper extremity paresthesias, sphincter dysfunction, gait disturbances, and fine motor dysfunction. The clinical signs of DCM are encompassed by the mJOA (Table 1). ^{Reference Martin, De Leener and Cohen-Adad56} This scale can be used to assign a score to patients from their upper and lower extremity motor function, upper extremity sensory function and their sphincter function. Patients can then be stratified into mild, moderate, and severe disease based on their mJOA score. The physical exam signs of DCM are characterized by upper motor neuron signs (hyperreflexia, Babinski sign, Hoffman’s sign), focal motor deficits, sensory deficits, gait ataxia, and positive Romberg sign. A thorough exam and history taking is essential in the diagnosis and monitoring of DCM patients.

Table 1: The modified Japanese Orthopedic Association (mJOA) classification. The sum of the subscores from each of the four categories defines the severity of degenerative cervical myelopathy: mild (15–17); moderate (12–14); and severe (0–11) degenerative cervical myelopathy

The signs and symptoms of DCM are broad and can also be present in other neurological conditions. The differential diagnosis of DCM includes, radiculopathy, peripheral neuropathy, stroke, amyotrophic lateral sclerosis, diabetic neuropathy, Chiari malformation, and tumors. Patients with early DCM are often misdiagnosed with bilateral carpal tunnel given similar presentations. Whenever DCM is suspected, it is essential to carry out a thorough clinical and physical examination, as well as to obtain imaging and electrophysiological testing when appropriate. When the clinical diagnosis of DCM is uncertain, a referral to a neurologist or spinal surgeon is warranted.

Imaging Techniques

The diagnosis of DCM requires clinical signs and symptoms of cervical myelopathy and imaging evidence of cervical cord compression. Magnetic resonance imaging (MRI) is the imaging modality of choice for the diagnosis of DCM. In cases where an MRI cannot be obtained, CT myelography can be substituted. Patients with mild DCM can have subtle imaging findings. Any changes that cause the deformation of the cord can result in DCM. Cord signal change and circumferential compression of the cord are not required for the diagnosis of DCM. ^{Reference Nouri, Martin and Mikulis61}

The diagnosis of DCM can potentially be transformed with advancements in MRI modalities. There are emerging techniques that provide further granularity on the microstructural integrity of the spinal cord. One of these quantifying techniques is T2*-weighted imaging, which can provide a sensitive assessment of cord integrity and potentially be used in monitoring disease progression. ^{Reference David, Mohammadi and Martin1,Reference Martin, De Leener and Cohen-Adad62} With T2*-weighted imaging, one can compare the signature ratio of the white and gray matter as a biomarker of white matter injury (T2*WI WM/GM). With these advancements in MRI modalities and the ability to quantify the structural integrity of the cord, we can expect a transition to a personalized approach to the imaging diagnosis and monitoring of DCM. However, further research is required prior to widespread utilization of these emerging techniques.

Ancillary Tests

As the care of DCM continues to evolve, there is a need for personalized clinical assessment and diagnostic tools. ^{Reference Wilson, Badhiwala, Moghaddamjou, Martin and Fehlings63} Given the varied disease presentation, a single ancillary test is not feasible for the diagnosis of DCM. Specialized testing of cord function, including using the Timed Up and Go, ^{Reference Richardson64} GAITRite, ^{Reference Bilney, Morris and Webster65,Reference Van Uden and Besser66} and the Graded Redefined Assessment of Strength Sensibility and Prehension protocol (GRASSP), ^{Reference Kalsi-Ryan, Curt and Verrier67} can be used to provide further granularity in the clinical assessment of patients with DCM. Adopting these personalized measurement tools requires a multidisciplinary approach to care with an emphasis on a personalized approach that will allow for enhanced discovery of disease progression. ^{Reference Moghaddamjou, Wilson and Martin68}

The Role of Biomarkers

Ongoing research in the field of DCM biomarkers will provide us with tools aimed at tailoring patient-specific therapeutic approaches. This becomes all the more important, as the disease is usually accompanied by a subtle progression of neurologic deterioration in a particularly aged patient population. Biomarkers hold the potential to increase the accuracy of diagnosis, provide us with a tool to monitor disease progression, offer prognostic information for patients and their relatives, as well as aid in clinical decision-making.

Recently, circulating microRNAs have emerged as potential serum biomarkers for SCIs. One such microRNA, termed MIR21-5p, has been found to play a key role in the regulation of neuroinflammation in DCM. ^{Reference Laliberte, Karadimas and Vidal69} In human and rodent studies of DCM, MIR-21-5p upregulation has been shown to correlate with initial symptom severity and poor treatment outcomes, thereby providing a tool for outcome prediction. ^{Reference Laliberte, Karadimas and Vidal69} Other micro RNAs, such as MIR-10a, MIR-210, and MIR-563, have been shown to be potentially useful in diagnosing OPLL. ^{Reference Xu, Zhang and Zhou70} While the diagnosis of OPLL is particularly imaging-dependent, serum biomarkers might be useful as a fast and readily available, broadly applicable screening tool in high risk populations (i.e., Japanese >65 years of age) or where imaging is not available at hand.

Apolipoprotein E (APOE) has been suggested to play a critical role in repair and regeneration processes after lesions to the CNS with an impairment of this function in proteins with the isoform E4 coded by the ϵ4 allele. ^{Reference Setzer, Hermann and Seifert54} The presence of an ApoEϵ4 gene polymorphism, as detected by DNA analysis from venous blood samples, has been associated with an increased risk of developing myelopathy in patients with chronic cervical spinal cord compression as well as a lack of neurologic improvement after surgical cord decompression. ^{Reference Setzer, Hermann and Seifert54,Reference Setzer, Vrionis and Hermann71} A recent study investigated the effects of surgical decompression in a clinically relevant DCM model in genetically modified mice that possessed the human ApoE4 gene.(Article, PMID: 34369386) As compared to their ApoE3 counterparts, mice which were expressing human ApoE4 revealed delayed neurobehavioral recoveries post-decompression surgery. Notably, this was accompanied by an exacerbated pro-inflammatory response resulting in higher concentrations of TNF-α, IL-6, CCL3, and CXCL9. These exciting findings suggest that an at risk ApoE4-positive DCM patient population potentially benefits from personalized strategies in the treatment of DCM.

Ancillary technical tools, such as electrophysiology, have demonstrated promising results in improving diagnostic accuracy and providing prognostic information. ^{Reference Jutzeler, Ulrich and Huber72,Reference Holly, Matz and Anderson73} As delineated above, imaging characteristics can be correlated to disease severity. Further technical advancements as well as the field of artificial intelligence and machine learning hold the potential to substantially increase the sensitivity and prognostic value of imaging studies in the near future.

Clinical Decision-Making

The main decision surrounding the management of DCM is surgical vs. nonoperative management. According to the AO Spine clinical practice guidelines, patients with severe (mJOA < 12) and moderate (mJOA 12–14) myelopathy should be offered surgery unless contraindicated. ^{Reference Fehlings, Tetreault and Riew74} In patients with mild myelopathy without clinical progression, there is equipoise between operative managements and a structured supervised trial of conservative management.

Given the uncertainty in the management of mild DCM patients, a personalized approach to their care is required. A patient’s general health, co-morbidities, functional status, and occupational status can all be factored into the decision-making. Ultimately, a patient’s preference in management will often dictate their care. If a nonoperative approach to care is adopted, it is essential that patients are followed closely for clinical progression. Those patients with clinical progression should be re-considered for surgical intervention. Patients themselves are often not aware of disease progression, and early signs can be difficult to detect due to neuroplasticity, adaption and behavioral modifications. ^{Reference Martin, De Leener and Cohen-Adad56} These patients should have frequent follow-up and a multidisciplinary team with personalized functional ancillary testing in their monitoring.

Anterior Versus Posterior Surgical Approach

While in younger patients with ventrally located, focal pathologies (such as single- or two-level DDD), an anterior surgical approach is usually favored, ^{Reference Fehlings, Barry and Kopjar81} decision-making in other scenarios might not be as clear. The seemingly equipoise between anterior and posterior approaches in these cases has generated a source of vibrant debates about the optimal surgical approach. ^{Reference Fehlings, Barry and Kopjar81–Reference Kato, Nouri and Wu83} A prospective observational multicenter study of 264 patients demonstrated no significant differences in rates of complications and functional or quality of life outcomes as measured by the mJOA, Nurick Scale, Neck disability index (NDI), and SF36v2 scores. ^{Reference Fehlings, Barry and Kopjar81} These findings have been underscored by a propensity-matched analysis of a combined dataset of two large prospective multicenter AO Spine studies where anterior and posterior surgical decompression resulted in no significant differences in rates of complications and postoperative outcomes at 2 years. ^{Reference Kato, Nouri and Wu83} A recent quality outcomes database analysis of 245 patients undergoing three to five-level surgical decompression for DCM (Anterior = 163, Posterior =82) strengthened the previous findings of similar patient reported outcomes and found no significant differences in readmission and return to work rates. ^{Reference Asher, Devin and Kerezoudis82} Finally, the results of a North American multicenter RCT (n = 163; anterior surgery n = 63; dorsal surgery n = 100) have just recently been published confirming that an anterior surgical approach did not significantly improve patient-reported physical functioning at 1 or 2 years as indicated by the Physical Component Summary score of the SF-36v2. ^{Reference Ghogawala, Terrin and Dunbar84} However, patients undergoing anterior surgery had a significantly greater risk of complications than dorsal surgery (47.6% vs 24%; 95% CI, 8.7–38.5%; P = 0.002). Of particular note, most of the complications were minor, including dysphagia (41% vs. 0% for anterior vs posterior surgery, respectively), and resolved within one year after surgery.

In sum, the current evidence does not show superiority of one surgical approach over another. And yet, in order to provide optimal surgical treatment and move toward an individual, patient-tailored approach, several factors need to be considered including the underlying pathology, management of sagittal deformity as well as surgical expertise. ^{Reference Nouri, Martin and Nater85}

Considerations in Surgical Decision-Making

Several clinical factors have been shown to affect outcomes from DCM surgery including patient age, duration of symptoms, comorbidities, preoperative imaging characteristics and the restoration of sagittal alignment. ^{Reference Wilson, Jiang and Fehlings86}

Indeed, recent studies have ascribed increasing importance to the consideration of preoperative cervical alignment parameters (such as the C2–7 angle and the modified K-line method) in surgical decision-making. ^{Reference Shamji, Mohanty and Massicotte87} Cervical lordosis, for example, is commonly assessed from C2–C7 using the Cobb angle method. ^{Reference Ames, Blondel and Scheer12} In that regard, patients with a cervical kyphosis exceeding 13° have demonstrated improved neurologic recoveries when undergoing an anterior surgical approach or posterior surgery where the correction of local kyphosis is being addressed by instrumentation as compared to laminoplasty. ^{Reference Suda, Abumi and Ito88} Another helpful measurement tool attempting to predict residual anterior compression of the spinal cord after DCM surgery has been introduced with the modified-K line method. ^{Reference Taniyama, Hirai and Yamada89} On a mid-sagittal cervical MRI, the modified K-line represents a connecting line from the sagittal midpoints of the spinal cord at the levels of C2 and C7. The minimum interval distance (mINT) describes the distance between the anterior compressing elements and the modified K-line. Using this concept, the authors suggest a mINT of >4.4 mm as a cutoff for an optimal neurologic recovery in nonlordotic patients after laminoplasty. ^{Reference Taniyama, Hirai and Yoshii90} On the other hand, a mINT of <4 mm should direct the surgeon toward an anterior or combined anterior/posterior approach in order to avoid residual anterior compressive forces and achieve best possible neurologic outcomes. These data clearly stress the importance of cervical alignment parameters, which as a result should be incorporated into surgical decision-making.

Factors that guide the choice between the varied anterior or posterior surgical techniques have been recently reviewed in detail by Wilson et al. ^{Reference Wilson, Tetreault and Kim91} In brief, when an anterior surgical approach is chosen in the setting of minimal retrovertebral disease, a multilevel ACDF is recommended over an ACCF or a hybrid ACDF-ACCF approach. However, in the presence of significant retrovertebral disease, a hybrid discectomy-corpectomy approach is preferred over multiple corpectomies. ^{Reference Wilson, Tetreault and Kim91,Reference Shamji, Massicotte and Traynelis92}

In the setting of a posterior approach, the current body of evidence does not show superiority of one surgical procedure over the other (laminoplasty versus laminectomy and fusion) in terms of neurologic outcomes. ^{Reference Wilson, Tetreault and Kim91,Reference Fehlings, Santaguida and Tetreault93–Reference Yoon, Hashimoto and Raich96} This stresses the importance of having a high-quality RCT in order to provide final clarity on this subject.