a b c d Figure 1. Typical imaging findings a Endstage ankylosis of the sacroiliac joint (SIJ). b Dense sclerosis and irregularities of the SIJ at the iliac side. Note the osseous bridges crossing the SIJ. c STIR sequence showing increased signal intensity within the SIJ at the sacral side. Joint irregularities are less visible on MRI com- pared to CT. d Typical syndesmophyte with calcification of the longitudinal ligament and outer anulus fibrosus. Note the preserved disc height. 1064 Section Tumors and Inflammation Table 2. Radiologic grading of sacroiliac joint alterations Grade I suspicious Grade II evidence of erosion and sclerosis Grade III Grade II and ankylosis Grade IV complete ankylosis New York criteria [97] The radiologic hallmark is a sacroiliitis However, inflammatory processes in AS must be well differentiated from a septic sacroiliitis (e.g., Staphylococcus aureus, Streptococcus species). Septic sacroiliitis (SS) is a rare disease. Typically a septic sacroiliitis shows non-specific symptoms similar to AS such as low back pain, pain in the pelvic region, and related pain in varying locations (hip joints). Typical radiological changes of the spine indicative of AS are [20, 58]: bony erosions bony sclerosis syndesmophytes Andersson lesions (erosive discovertebral lesions) [61] ankylosis (bamboo spine) vertebral osteoporosis Syndesmophytes must be differentiated from osteophytes Syndesmophytes as a result of an ossification of outer anulus fibrosus (Sharpey’s fibers) must be differentiated from osteophytes by their shape and site ( Fig. 1d). Syndesmophytes exhibit a slow growth from the cervical to the lumbar spine [17] leading to a kyphotic deformation of the entire spine and often resulting in a pro- gressive sagittal imbalance. The kyphotic deformity is most pronounced in the thoracic spine. During the advanced stage of the disease, vertebral column alterations can include: severe kyphotic spinal deformity with sagittal imbalance spinal fractures (often occult) [42, 57, 75] atlanto-occipital instability Rule out spinal fractures in case of trauma Patients with AS are susceptible to fractures of the spinal column which are fre- quently overlooked. The fractures are atypical compared to fractures of the undis- eased bone [57] and frequently involve all three spinal columns [103]. Radiographs arestrongly recommended after each single trauma with pain symptoms. Persistent pain even after minor trauma should prompt a thorough imaging work-up. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) provides an excellent depiction in early stages of the inflammatory disease. Standard examinations searching for inflam- matory alterations are done in the coronal and sagittal plane using fluid sensitive sequences with fat signal suppression, e.g., short tau inversion recovery (STIR) sequence. The advantage is a better contrast of fat and water which results in a better sensitivity for inflammatory spinal lesions than in T1-weighted MRI after contrast enhancement [7, 8]. The STIR sequence is also helpful in diagnosing occult fractures of the vertebral column indicated by indirect signs of a bony edema or soft tissue ( Fig. 1c). MRI can demonstrate inflammatory alterations early Magnetic resonance imaging can demonstrate injuries to the ligaments or sequelae of spinal trauma, e.g., neural compromise and epidural hematoma. Therefore, especially at the level of the cervical column, MRI should be compul- Ankylosing Spondylitis Chapter 38 1065 Examination of AS patients in the MR magnet is difficult because of the spinal deformity sory [75]. MRI does not show fewer fractures for the whole spine than computed tomography (CT) [103]; however, a disadvantage of MRI is the difficult examina- tion of dorsal elements of the vertebral and cervical columns, e.g., facets. In these cases detection of fractures with MRI can be difficult [57]. Characteristic findings of MRI suggestive of AS are [17, 105]: discitis erosions syndesmophytes partial fusion ankylosis Signs of an inflammatory lesion are: Differentiate inflammatory and septic sacroiliitis subchondral sclerosis without increased signal after contrast enhancement edema-like bone marrow abnormalities (by STIR and/or contrast enhanced sequences) fatty replacement of subchondral bone marrow of SI joints Magnetic resonance imaging allows the differentiation of inflammatory and sep- tic sacroiliitis. Signs indicative of a septic origin are [91]: anterior and/or posterior subperiosteal infiltrations transcapsular infiltrations of juxta-articular muscle layers Computed Tomography The spine can be precisely visualized with 3D CT imaging, particularly the dorsal elements (posterior longitudinal ligament, spinous process and facet joints), which are more difficult to visualize with MRI [57, 103]. A spiral CT with multi- planar reconstruction can improve the image resolution, which makes identifica- tion of bone fractures easier and thus helps inelucidating “occult” fractures [46]. CT scan is helpful in the detection and localization of spinal fractures The domain of the CT is the diagnosis of fractures. Patients with AS can sus- tain fractures after minor trauma [42, 57, 75, 78, 103] or even without recalling a trauma [77]. Furthermore, CT can be utilized for preoperative planning of cor- rective spinal osteotomies. Bone Scan Bone scan remains a screening tool for inflammatory processes Bonescansstillplayaroleasasupraregional screening modality for inflamma- tory reactions. The scintigraphy is less sensitive than an MRI scan for detecting a sacroiliitis (61% vs. 55%) [48]. The specificity of a sacroiliac joint scintigraphy is reduced due to a high bone turnover metabolism [20]. However, the scintigra- phy is a good alternative method for diagnosing AS in the early stages, at the time when typical radiological changes of SI joints are missing in standard radio- graphs [48, 83]. A scintigraphy can also be useful in the search for inflammatory lesions or aseptic discitis. The location of the spine pathology is important for differentiation between a fracture, metastasis, inflammatory lesions or discitis. Diagnostic Criteria The diagnosis is difficult at an early stage The diagnosis of AS is difficult at an early stage because of non-specific clinical symptoms and a lack of radiological signs. Therefore, AS often remains undiag- nosed for several years. The most frequent clinical symptom in AS is a sacroilii- tis, whichis present in 90% of all chronic cases. However, in the early stages a sac- roiliitis can be absent in 70–90% of all cases [81]. Other typical clinical symp- toms and signs are inflammatory back pain, progressive spinal stiffness and 1066 Section Tumors and Inflammation reduced chest expansion. At the level of the spinal column inflammatory lesions appear mainly at the thoracic level [8, 17, 105]. Chronic inflammatory alterations appear at all levels of the vertebral column. Mainly affected are spinous processes and facet joints [105]. The modified New York criteria allow the diagnosis of AS ( Table 3)[97]: Table 3. Modified New York criteria for ankylosing spondylitis Clinical criteria Radiologic criterion low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest sacroiliitis grade 2 bilaterally, or sacroiliitis grade 3–4 unilaterally limitation of motion of the lumbar spine in both the sagittal and frontal planes limitation of chest expansion relative to normal values corrected for age and sex Definite AS is present if the radiological criterion is associated with at least one clinical criterion [97] Diagnosisisstilldifficultand based on the presence of multiple findings The modified New York criteria differentiate non-active and active stages of AS. An active stage is defined as persisting clinical symptoms for a minimum of 6months. Non-operative Treatment Ankylosing spondylitis is a chronic, systemic disease which cannot be cured. All treatment measures remain palliative, i.e., can reduce clinical symptoms and slow disease progression and ankylosis. The general objectives of treatment are ( Table 4): Table 4. General objectives of treatment control of inflammatory processes pain relief prevention of disease progression preservation of spinal balance preservation of spinal mobility improvement of quality of life Natural History Ankylosing spondylitis is a chronic inflammatory disorder with a varying level of disease Ankylosing spondylitis is a chronic inflammatory disorder with varying disease progressions and accordingly mild to severe clinical symptom intensity. How- ever, in less than 1% of all patients a long term remission has been described [52]. Progr ession of ankylosing spondylitis is usually linear [22] and affects either isolated structures or a combination of them [106]: sacroiliac joints axial skeleton peripheral joints extra-articular structures In spondylarthopathies in general, several prognostic factors have been identi- fied which correlate with disease severity [1]: hip arthritis high erythrocyte sedimentation rate (>30 mm/h) poor efficacy of non-steroidal anti-inflammatory drugs limitation of lumbar spine sausage-like finger or toe onset 16 years Ankylosing Spondylitis Chapter 38 1067 Hip involvement is a strong predictor of poor outcome If none of these factors is present at entry, a mild outcome can be predicted with a high sensitivity (92.5%) and specificity (78%). If a hip is involved or if three factors are present, a severe course is predictable (sensitivity: 50%) and a mild disease practically excluded (specificity: 97.5%) [1]. In particular, hip involve- ment has been demonstrated as a predictor of poor outcome [22]. There is an increase in the prevalence of spinal fracture with age [40], which has been associ- ated with a decreased bone mineral density [64] though the intensity of the dis- ease itself is independent of age [21]. Non-operative Management Early treatment improves the clinical course It has been demonstrated that early treatment can improve the clinical course and general treatment outcome [13, 15]. The mainstay of treatment remains drug therapy in conjunction with structured exercise programs. However, debate continues on the effect of structured exercise programs [19]. The current best available evidence suggests that physiotherapy is beneficial for people with AS. However, it is still not clear which treatment protocol should be recommended in the management of AS [32]. Pharmacological Therapy There is a rank order for drug therapy The medication armamentarium includes [19, 110]: non-selective and selective cyclooxygenase (COX) inhibitors (NSAIDs) analgesics disease modifying antirheumatic drugs (e.g., sulfasalazine) corticosteroids TNF- inhibitors In a “rank order,” NSAIDs represent the first choice of medication and are given continuously or during the onset of disease. However, the individual response depends on the agent and often several different medications have to be tested. NSAIDs are the first choice for treatment When continuously applied, patients with NSAIDs show reduced pain and increased activity in daily life [13, 15, 71]. Also one study with NSAIDs as a ther- apy for AS led to the inhibition of radiographic progression [102]. Typical side effects of non-selective NSAIDs are gastrointestinal ulcera and bleeding, whereas COX-2 selective inhibitors show cardiovascular complications. When NSAIDs fail, disease-modifying antirheumatic drugs (DMARDs), i.e., sulfasalazine or methotrexate, can be used as an alternative. Sulfasalazine is used against periph- eral joint pain. There is no objective evidence that treatment with DMARDs is effective for AS [13]. When inflammation cannot be controlled by the aforemen- tioned drug therapy, inhibitors of TNF-␣ are indicated (e.g., infliximab, adalimu- mab and etanercept). These monoclonal antibodies show a significant improve- ment in function, spinal mobility and quality of life in comparison to placebo [13, 15, 71]. In addition, a significant regression of spinal inflammation can be dem- onstrated [16]. The hope is that with suppression of spinal inflammation struc- TNF- inhibitors are potent and effective pharmacologi- cal agents but are not without serious side effects tural damage of bony structure can be delayed. The clinical outcome is slightly worsewhenthesemedicinaldrugsareusedforthetreatmentofchronicAScom- pared to acute AS [15, 71]. Therefore, an early diagnosis is essential. However, severe side effects have been reported with the use of TNF- inhibitors, e.g., leu- kopenia, allergic pulmonal reactions and reactivation of tuberculosis disease [13]. 1068 Section Tumors and Inflammation Physiotherapy Physiotherapy is an essential part of treatment Besides medical treatment physiotherapy plays an important role [31, 32, 101]. Main goals are pain reduction, prevention of hypomobility of the affected seg- ments and improvement of activity of daily life [32]. Continuous physiotherapy should take place and the patient should perform a daily home exercise program. A high level of motivation and compliance by the patient could substantially improve outcome. The primary goal of the physiotherapy is postural exercises which should preserve the natural spinal alignment during the process of ankylo- sis. Study results showed that supervised group physiotherapy programs were better than individualized home exercise regimes and individualized home exer- ciseswerebetterthannophysiotherapy[31]. Patient Education Patient education is a very important treatment component Patient education is a very important component with the ability to support all the therapeutic measures applied to patients suffering from ankylosing spondyli- tis. In most developed countries efficient self-help organizations have been established aiming for a better information policy, awareness of ankylosing spondylitis in the public as well as supporting the affected individual. Self-help organizations are key to an integrated therapeutic approach by medical doctors, physiotherapists, patients and their families. Through the excellent cooperation of medical doctors, physiotherapists, patients and their relatives, the incidence of neglected, untreated and therefore upsetting chronic cases is very low in Switzer- land. Treatment Recommendations A combined ASsessment in Ankylosing Spondylitis (ASAS) working group and European League Against Rheumatism (EULAR) task force has postulated a flowchart and ten main recommendations for the management of AS ( Fig. 2, Table 5). Figure 2. Treatment recommendations ASAS/EULAR flowchart summary (modified) of the recommended management of AS based on clinical expertise and research evidence [110]. Ankylosing Spondylitis Chapter 38 1069 Table 5. Expert propositions on treatment Treatment of AS should be tailored according to: current manifestations of the disease (axial, peripheral, entheseal, extra-articular symptoms and signs) level of current symptoms, clinical findings, and prognostic indicators disease activity/inflammation pain function, disability, handicap structural damage, hip involvement, spinal deformities general clinical status (age, sex, comorbidity, concomitant drugs) wishes and expectations of the patient Disease monitoring of patients with AS should include: patient history (for example, questionnaires), clinical parame- ters, laboratory tests, and imaging, all according to the clinical presentation, as well as the ASAS core set. The fre- quency of monitoring should be decided on an individual basis depending on symptoms, severity, and drug treatment Optimal management of AS requires a combination of non-pharmacological and pharmacological treatments Non-pharmacological treatment of AS should include patient education and regular exercise. Individual and group physical therapy should be considered. Patient associations and self-help groups may be useful NSAIDs are recommended as first line drug treatment for patients with AS with pain and stiffness. In those with increased GI risk, non-selective NSAIDs plus a gastroprotective agent, or a selective COX-2 inhibitor, could be used Analgesics, such as paracetamol and opioids, might be considered for pain control in patients in whom NSAIDs are insufficient, contraindicated, and/or poorly tolerated Corticosteroid injections directed to the local site of musculoskeletal inflammation may be considered. The use of sys- temic corticosteroids for axial disease is not supported by evidence There is no evidence for the efficacy of DMARDs, including sulfasalazine and methotrexate, for the treatment of axial disease. Sulfasalazine may be considered in patients with peripheral arthritis Anti-TNF treatment should be given to patients with persistently high disease activity despite conventional treatments according to the ASAS recommendations. There is no evidence to support the obligatory use of DMARDs before, or concomitant with, anti-TNF treatment in patients with axial disease Total hip arthroplasty should be considered in patients with refractory pain or disability and radiographic evidence of structural damage, independent of age. Spinal surgery – for example, corrective osteotomy and stabilization proce- dures – may be of value in selected patients ASAS/EULAR expert propositions on the management of AS developed through three Delphi rounds [110] Operative Treatment General Principles Indications for surgery arerareinpatientsunder rheumatologists’ surveillance Surgical intervention is rarely necessary in cases with AS when the patient is under medical surveillance with a baseline therapy and physical exercises. However, in some cases the inflammatory process cannot be controlled very well and spinal deformities develop [21, 22]. Indications for surgery are strong limitations in daily life due to progressive kyphotic deformity and unacceptably severe chronic pain non-responsive to conservative management. The usual age at surgery is in the late 30s and 40s [28, 29, 108]. Patients with AS are prone to developing spinal fractures [34, 40, 77] and discitis [61]. In these cases, surgery is indicated ( Table 6 ): Table 6. Indications for surgery Absolute Relative unstable spinal fractures painful sagittal imbalance kyphosis-related progressive myelopathy loss of horizontal gaze progressive spondylodiscitis chin-chest impingement stable spinal fractures with delayed fracture healing segmental instability Conservative treatment of spinal fractures is often unsuccessful In cases of spinal fractures, conservative treatment is often hampered by the con- comitant sagittal imbalance leading to a high non-union rate and progressive deformity. Although there is a general trend for good bone healing in patients 1070 Section Tumors and Inflammation with AS, there are individuals with very active disease in whom this is not the Cauda equina syndrome is a rare complication case. A rare side effect of a massive kyphotic deformation of the whole spinal col- umn is cauda equina syndrome. This syndrome develops only after a long his- tory of ankylosing spondylitis. Clinical symptoms are slowly progressive with sphincter disturbance and impotence. The pathogenesis is unclear. However, it is hypothesized that arachnoiditis can affect adherence of individual nerve roots to the arachnoidal surface. MRI showed florid, multilocular dural ectasia, marked irregularity and thickening of nerves, and adherence to the dural diverticula [30, 85]. Therapy consisted of a lumboperitoneal shunt, which is effective [51]. Planning of Osteotomies Meticulous preoperative planning is mandatory to avoid over- or undercor- rections which cannot be compensated The ultimate goal of surgery is to rebalance the spine and correct the chin-brow to vertical angle (CBVA) [92] to an extent that the patient is again able to look straight ahead, or to resolve a chin-chest impingement (in case of severe cervico- thoracic kyphosis. It is very important to plan precisely the level and extent of the osteotomies because the spine usually cannot compensate for any resulting over- or undercorrections. It is also important to assess the mobility of the hip and knee joint and to consider the mobility of these joints in the planning for surgery. The planning can be done using: lateral standing whole spine radiographs lateral photography [72] Using the whole spine lateral radiograph, the vertebral bodies are traced out on transparent paper. The paper is cut with scissors at the level of the target osteo- ab c Figure 3. Planning of lumbar osteotomy Graphic planning: a Transparent paper is placed over the whole spine standing lateral radiograph. The spine is traced out and the gravity line from C2 is added. The target level of the osteotomy is identified (red area). The paper is cut along the superior border of the osteotomy. b The upper part of the paper is rotated until the gravity line falls in front of the sacrum (or through the hip joints if depicted on the radiograph). The resulting angle κ is the target correction angle. The dens should be vertically oriented at the end of the planning. Photographic planning: c A horizontal line is drawn at the level of the umbilicus and graphically separated into three parts. A vertical line is drawn intersecting the horizontal line between the posterior and middle thirds. The intersection point of the two lines is connected to the meatus externus of the ear and the lateral femur condyle, respectively. The sum of the resulting angles and responds to the whole body kyphosis angle (WBKA) and is the target angle for correction. The chin-brow to vertical angle (CBVA) should be assessed and taken into account to avoid overcorrection. Ankylosing Spondylitis Chapter 38 1071 tomy,whichusuallyliesatL2orL3forlumbarsubtractionosteotomies.The rotating hinge lies in the anterior vertebral cortex. The upper part of the drawing is then adjusted until sagittal balance is achieved. The required correction angle can then be measured as a result of the resulting overlap on the sketch ( Fig. 3a, b). Themaximumanglewhichcanbeachievedatonelevelisabout40degrees[63, 72, 100]. Spinal corrections demanding more than 40 degrees of correction should rather be treated with a second osteotomy, which may be performed at the thoracic or lumbar level. In cases of severe sagittal imbalance, radiographs cannot depict the whole spine on one film. In these cases, planning using lateral photography can be done as described by Min et al. [72] ( Fig. 3c). Potential problems related to patient positioning and intubation/ventilation must be considered Another important aspect is the perioperative anesthesia. Patient positioning and intubation often are very difficult due to kyphotic deformation. The surgeon must take these issues into account prior to surgery. Furthermore, the vital capacity can be reduced because of a kyphosis-related restricted pulmonary dis- ease. A preoperative lung f unc t ion test is recommended. With the advent of intraoperative neuromonitoring, surgery using local anesthesia and sedation is outdated. Neuromonitoring is nowadays regarded as indispensable for a safe deformity correction (see Chapter 12 ). Surgical Techniques The first corrective osteotomy of AS was described by Smith-Peterson in 1945 [90]. This surgical procedure in the thoracolumbar spine consisted of a mono- segmental V-shaped opening wedge osteotomy during local anesthesia. Only later was this operation technique combined with internal stabilization, which was not available in the 1940s. Due to the relatively high rate of postoperative complications, new operation techniques such as the polysegmental posterior wedge osteotomy or the closing wedge (pedicle subtraction) osteotomy were introduced [11, 47, 74, 100]. Today, the monosegmental [28, 33, 63, 74] or poly- segmental closing-wedge technique [45, 98] is preferred for the thoracolumbar region. Thoracolumba r Closing Wedge Osteotomy The most common technique is a closing wedge osteotomy The most common technique is the closing wedge osteotomy [50, 63]. In 1963, Scudese introduced this new technique with the aim of reducing perioperative and postoperative complications seen with the opening wedge osteotomy [86]. The underlying concept is to achieve a monosegmental extension while keeping the anterior longitudinal ligament intact. The procedure is usually carried out at the L3 or L2 level depending on the sagittal alignment. Corrections of more than 40 degrees at one level should be avoided The closing wedge technique consists of removal of the posterior elements including the pedicles (pedicle subtraction osteotomy)( Fig. 4, Case Introduc- tion ). This technique is often combined with a so-called eggshell procedure (i.e., decancellation of the vertebral body) [11, 33, 74]. A posterior wedge excision of the vertebral body is then performed under protection of the spinal cord. The closingwedgeosteotomycanbeappliedtooneortwolumbarvertebraedepend- ing on the desired amount of correction. However, corrections of more than 40 degrees at one level should be avoided. In general, the outcome of closing wedge osteotomies ( Table 7) is satisfactory [14, 45, 88]. However, function can only moderately be enhanced [45]. 1072 Section Tumors and Inflammation ab cd Figure 4. Lumbar pedicle subtraction osteomy (closing wedge) a The osteotomy starts by instrumenting the spine with pedicle screws three levels above and below the osteotomy to allow for a rigid stabilization of the osteotomized spine. b The posterior elements (i.e., spinous, transverse laminae, and articular processes) are removed until only the pedicle stumps at the transition to the posterior wall of the vertebral body are left. The cancellous part of the vertebral body is then resected with curettes in the form of an “eggshell” procedure. c The remaining posterior bridge between the two wholes of the pedicle stumps is then resected by a large Kerrison ron- geur. d The created wedge is then closed using a motorized operation table lordosing the whole patient. Posterior rods are applied further compressing the wedge resulting in a tension band osteosynthesis. A posterolateral fusion is added across the osteotomized level. Multisegmental Posterior Wedge Osteotomy MPWO predominately addresses segmental thoracic kyphosis Main goal of the multisegmental V-shaped posterior wedge osteotomy (MPWO) is to address a thoracic kyphosis where extensive closing wedge osteotomies would jeopardize the spinal cord. This type of osteotomy results in a more har- Ankylosing Spondylitis Chapter 38 1073 . of bone fractures easier and thus helps inelucidating “occult” fractures [46]. CT scan is helpful in the detection and localization of spinal fractures The domain of the CT is the diagnosis of. Criteria The diagnosis is difficult at an early stage The diagnosis of AS is difficult at an early stage because of non-specific clinical symptoms and a lack of radiological signs. Therefore, AS often. disease progression and ankylosis. The general objectives of treatment are ( Table 4): Table 4. General objectives of treatment control of inflammatory processes pain relief prevention of disease progression