Lumbar Spinal Involvement in Calcium Pyrophosphate Dihydrate Disease: A Systematic Literature Review

Background

Calcium pyrophosphate dihydrate disease (CPPD) is a pathology defined by a deposit of crystals of calcium pyrophosphate dihydrate in the joints. Spinal CPPD is present in different clinical pictures depending on its location. The location of the cervical spine is best known as crowned dens syndrome, but the locations can affect all parts of the spine. Clinical presentation could be acute, subacute, or chronic spinal pain. It can even mimic infectious spondylodiscitis in its spinal form. But often, it is of radiological discovery, where the deposition of CPPD crystals occurs within the hyaline cartilage and especially within fibrocartilages.¹ Although CPPD has several radiographic features in common with primary osteoarthritis, the axial location of the calcifications is an important criterion of distinction.²

Thus, the clinical pictures can be diverse and mislead the clinician in his diagnosis. It is therefore important to know the different presentations of this pathology.

This study aimed to report the case of a lumbar spine CPPD location and to review clinical, imaging features of lumbar involvement in CPPD patients, and treatments that have been implemented.

Case Report

Written informed consent has been provided and signed by the patient to have the case details and any accompanying images published. A 73-year-old patient, with a history of multiple comorbidities, presented with chronic knee and shoulders pain. X-rays revealed calcifications of the cartilages and entheses in the knees, shoulders, and pelvis, as well as symphysitis. We made the diagnosis of CPPD and the patient was put on colchicine for 15 days with clinical improvement. Six months later, she complained of non-inflammatory L5 sciatica associated with neuropathic pain (DN4 score was 6/10), without signs of impingement. Plain radiography showed levoscoliosis and nonspecific degenerative findings (disc space narrowing, osteophyte formation). Lumbar CT scan disclosed calcifications of the interspinous ligaments, yellow ligament, anterior and posterior disc calcifications, and a focal median and left paramedian protrusion at the L5-S1 level, with cranial migration of 9mm (Figures 1–3). The patient was put on colchicine (1mg daily) and rehabilitation. Symptoms were decreasing and pain relief was reported. At 36 months of follow-up, she still complained of sciatica flare-ups.

Figure 1 A CT-scan sagittal image shows linear calcification into the L3-L4, L4-L5 and L5-S1 (Arrow) intervertebral discs.

Figure 2 Axial CT-scan image of the lumbar spine, exhibiting calcification of the interapophyseal joint cartilage (Red Arrow) in (A) and ligamentum flavum (Black Arrow) in (B).

Figure 3 AxialCT-scan image of the pelvis showing linear bilateral calcification of the sacroiliac joint (Head arrow).

Literature Review

Methods

Database and Search Strategy

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The search of articles was performed in PubMed, Google Scholar, Medline, Scopus, and Cochrane library databases. The following keywords were used: (“Chondrocalcinosis” OR “Calcium Pyrophosphate Dihydrate Disease”) AND (“Spine” OR “Osteoarthritis, Spine” OR “radiculopathy” OR “sciatica” OR “lumbar vertebrae”). Keywords referred to medical subject heading (MeSH). All references list of the retained papers were also screened manually for additional eligible studies. Titles, abstracts, and full reports of the identified articles were systematically screened.

Study Selection Criteria

Papers screened for eligibility were case reports, meta-analysis, systematic reviews, letters, cross-sectional, prospective and retrospective studies published in English or French that incorporate CPPD of the lumbar spine. Articles that treated other joints, cervical and thoracic spine were not included. Studies of more than 20 years were excluded.

Data Extraction and Quality Assessment

All selected articles were reviewed by two authors. Each article was analyzed through a critical reading platform: Fichas de LecturaCritica 3.0 to determine whether it fulfilled or not validity criteria. All data were extracted using a standardized template: title, author, type of the study, year of publication, and study population. For case reports, clinical presentation, imaging, biological findings, and treatment were mentioned. Only studies rated “High” or “Average” were selected. For cohort studies, we used the Newcastle Ottawa Scale (NOS). For case series and case reports, we used the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports.

Statistical Analysis

We used descriptive statistics to report data.

Results

Flow Chart of the Study

A total of 167 articles met the search criteria using electronic databases searches (PubMed, Google Scholar, Scopus, and Cochrane library databases manual research, references lists). We identified 110 studies after screening titles and abstracts and removing duplicates. After excluding the cervical and thoracic location and assessing the value quality of the studies, we retained 28 articles (20 case reports, 2 case series, 1 family survey, 4 retrospective studies, and 1 a prospective study) involving totally 62 patients. Among the studies selected, 4 screening studies with asymptomatic patients were performed on histological specimens (Figure 4).^3–6 Detailed characteristics of all studies included are summarized in Table 1.

Table 1 Overview of the Studies on Lumber CPPD

Figure 4 Flow chart of the study.

Characteristics of the Patients

The age ranged between 39 and 89 years old. Among patients with lumbar spine deposits of CPPD, 32 were women.^7–21 In the other studies, the epidemiological characteristics such as age and gender were not mentioned, as they concerned histological specimens of operated discs.^3–6 A history of CPPD was present in 40 patients.^17,20,22,23 Five patients had more than two comorbidities including diabetes, hypertension, coronary artery disease, hypothyroidism, gout, prostate cancer, stomach, and cervical tumor.^{8,11,14,18,24,25}

Clinical Features

Duration of Symptoms and Background Circumstances

- The duration of symptoms varied between one day (acute back pain)^{10,14,15,22,26–28} and 8 years.⁹ The affection has been discovered during back pain in 22 cases.^{7,11,12,15–19,21,29,30} Sciatica has been observed in 13 patients.^{12,15–19,21,26,29,30} Neurological signs revealed the disease in 9 cases^{15–19,26,29,31,32} and consisted in dorsiflexion weakness,^{15–17,19,26} stiffness,³¹ hypesthesia,³² paresthesia,^15,33 foot drop and numbness¹⁸ with residual urine sensation,²⁹ urinary retention,¹⁵ and abnormal tendon reflexes.¹⁵ Fever was present in 6 cases.^{7,10,14,25,27,33} In two cases, the symptomatology led to a misdiagnosis of a urinary tract infection.^10,27

- In 5 studies, the diagnosis was made on histological specimens of patients operated on for degenerative spine, canal stenosis, or disc disease.^3–6,20 Moshrif et al diagnosed 24.3% of lumbar CPPD among 152 patients with a history of peripheral CPPD (knees, wrists, shoulders, hip, and pubic symphysis).²⁰ Gruber et al found 14.69% lumbar CPPD among patients operated for herniated discs, degenerative disc disease, and recurrent disc herniation.²⁰ In the study conducted by Yayama et al, 62/206 (30.1%) of the discs taken from patients operated on for asymptomatic narrow lumbar spine, and 37/64 (57.8%) in patients operated on for spondylolisthesis showed deposits of calcium pyrophosphate.⁵ Ariyawatakul et al led a retrospective study on lumbar spinal stenosis patients who had undergone a decompressive laminectomy. Histological examination identified eighteen patients among 34 that had CPPD.⁴

Diagnostic Method

Imaging

- Among the 62 patients, plain radiographs (X-ray) have been required in 13 cases,^{8,10–14,17–20,24,26–28,30} and showed calcifications in 2 cases.^8,28 X-rays have mainly allowed diagnosing an underlying pathology such as degenerative spinal disease, spondylolisthesis, collapse fractures, or indirect signs of the narrow spinal canal.

- A CT scan has been prescribed in 15 cases,^{9,11–13,15–18,20,22,25–29} and has detected calcium deposit in 7 of them (61%).^{11–13,17,20,22,28} The lesions observed on CT scan were: calcium deposit in intervertebral joints,^13,22,28,29 calcified cystic lesion,^9,11 interspinous bursitis,¹³ calcification of the ligamentum flavum and the intervertebral disc,²⁰ or degenerative joint disease.¹⁶ The CT scan was useful for performing a CT-guided biopsy for the histological diagnosis of the lesion.^7,16,25 In two of the five cases where X-ray and CT scans were available, CT scan showed calcifications while plain radiographs were normal.^11,13

- MRI: The elementary lesions observed in the MRI images were: increased signal within the intervertebral disk on the T1 and T2-weighted sequences,²⁶ an increased signal of the lumbar facet joints compatible with inflammation,^{7,13,16,25,30} degenerative disc disease,^8,14,24 calcified or not cystic lesion at the side of the facet joints,^{9,11,19,26,27} intramedullary mass mimicking a schwannoma,^12,24 extradural heterogeneous mass-like lesion in the anterior epidural space.²⁹ Spondylodiscitis/osteomyelitis was observed in 7 cases;^{7,10,16,21,22,25,28} and was associated to an image of epidural phlegmon in one case,²⁶ Gadolinium-enhanced T1 hypersignal in two cases,^13,27 intradural calcified lesions with no post-contrast enhancement in one case.¹⁷ The image of an abscess was found in 2 cases.^22,25 A cord compression was reported in 6 cases.^{8,15,18,19,29,30} MRI showed calcifications or a chalky material in 4 cases.^9,11,17,18

Histological Examination

Biopsy and Needle Aspiration

A disco vertebral biopsy was performed to eliminate spondylodiscitis based on the MRI features in 3 patients.^7,16,25 A percutaneous soft tissue biopsy was performed in 3 cases.^22,26,27 An aspiration of the facet joint effusion and the cerebrospinal fluid for bacteriological examination in 2 cases.^14,15 Histological examination established the diagnosis of CPPD in 21 patients among all studies including the retrospective ones.^{8,9,11–19,21,22,24,25,27–30}

Treatment

Medical Treatment

NSAIDs were prescribed in 5 cases^{7,10,13,16,27} with clinical and biological improvement. Colchicine was used in 2 cases and the symptomatology disappeared under treatment.^16,22 Interleukin-1 receptor antagonist (Anakinra) was prescribed in one patient with clinical and biological improvement.²⁸ Antibiotics (Ceftriaxone) were attempted in one case even if no microorganism was found, and the patient improved significantly.²⁵ A low-dose steroid (Decadron) (6 mg every 6 hours, stopped at day 7) has been used in one case.¹⁶

Surgical Treatment

Surgery was attempted in 13 patients.^{8,9,11,12,17–19,21,24,26,29,30} In all cases, surgery was performed for an etiology other than CPPD: either for decompression, tumor resection, or laminectomy. Histological examination was performed on surgery specimens in patients who underwent surgical interventions for different pathologies. CPPD was found after tumor resection of a schwannoma-like mass,^12,24 surgical decompression of a herniated disc⁸ or a compressing mass^9,11,19,29 or radiographic bony destruction with sterile culture on biopsy,²⁶ neurological symptoms requiring a laminectomy,^17,18 spinal stenosis caused by a posterior bony protrusion from a collapsed vertebral body¹⁸ or a worsening discitis despite well-conducted medical treatment.²¹ Improvement after surgery was observed in 8 patients^{8,11,12,17–19,26,29} and not mentioned in one patient.²⁴ A therapeutic failure was observed in two cases.^21,30 In one case, after the failure of surgical decompression, a second surgery was performed (distal L4 and proximal L5 laminotomies followed by flavectomy and medial facetectomy to expose the cyst.).²²

Discussion

This review aimed to evaluate the involvement of the lumbar spine in CPPD. Most of the studies included were case reports (n = 20), suggesting that this pathological feature is still uncommon. However, through this review, we were able to show that the axial CPPD is not only rare, but also underdiagnosed, regarding the non-specificity of clinical signs, and the variable performance of imaging techniques.

In our review, spinal deposition of calcium pyrophosphate crystals was reported in 62 patients. The diagnosis of axial CPPD was made in the majority of cases postoperatively, on histopathological specimens in patients who initially consulted for chronic lower back pain. In those studies, the prevalence of spinal CPPD varied between 14.7% and 57.8%. Most of the patients were women, aged between 39 and 89.

A cross-sectional study involving 2157 cases of CPPD in US veterans reported a point prevalence of 5.2 per 1000, all joints included, with an average age of 68 years and 95% of male prevalence.³⁴ However, to our knowledge, the prevalence of lumbar spine CPPD has not been reported.

Among the case reports, most authors reported that a chronic symptom of CPPD in the lumbar spine which was lower back pain and radiculopathy due to compression of spinal nerves. CPPD of the lumbar spine was usually asymptomatic. Many of the patients with CPPD were elderly and have unrelated degenerative disease of the spine. However, CPPD can produce severe degenerative disk disease, often involving multiple levels.³⁵ The thoracic and lumbar regions are often affected, especially at the L2-L3 disc level.³⁶

As the clinical features are not specific, imaging is required for diagnosis. The radiographic presentation of spinal CPPD can vary from simple calcium deposit to spinal masses, tophi, and hematomas causing compressive phenomena. Its diagnosis can be challenging because of this radiographical ambiguity and its relationship to osteoarthritis.²¹ In this review, conventional radiographs showed disc calcifications in only 2 out of 13 patients. Studies have shown that arthropathy can precede radiographically detectable cartilage calcification, and the calcification may not always be dense enough to be visualized on conventional radiographs, or it may be difficult to identify if the joint is severely damaged.³⁷ In one study of 3228 patients undergoing knee arthroscopy, a radiographic diagnosis ofkneeCPPDwasmade in only 4% of patients with pathologically proved CPPD crystal deposition.³⁸

A systematic literature review and meta-analysis supported the high specificity and low sensitivity of conventional radiography in the diagnosis of CPPD and showed that ultrasound was more sensitive and less specific than plain radiographs in detecting CPPD.³⁹

When the conventional radiography is non-effective, a CT scan may help to detect calcifications. In this review, CT scan showed calcifications while plain radiographs were normal in only two cases, but this can be explained by the fact that X-ray was not performed or not mentioned in 13 cases. In the study led by Moshrif et al, CT scan was more sensitive than conventional radiography in detecting intervertebral disc and vertebral ligament calcification.²⁰

MRI showed calcifications or a chalky material in 4 cases.^9,11,17,18 It has been reported that MRI was poorly sensitive to detect calcium deposits because CPP-containing tissues seem isointense to neural tissue on T1 weighted images and iso to hyperintense on T2 weighted sequences but were able to reveal endplate and disc inflammation.²⁰ Our review showed that MRI misled the diagnosis in several situations. Indeed, the hyper signal related to the edema and the juxta-articular collections related to calcified cysts were confused with an infection and epidural abscesses. For example, in the case described by Petit et al, MRI showed short-tau inversion recovery (STIR) hyper signal on the lumbar facet joints.⁷ Grobost et al reported the appearance of L4-L5 spondylodiscitis, with epidural abscesses, Gadolinium-enhanced signal in L4-L5 zygapophysial joints, and intervertebral lumbar disks.²² In the case reported by Mikhael et al, MRI showed an increased signal within the L5-S1 intervertebral disk and the endplates of the L5 and S1 vertebrae on the T1 and T2-weighted sequences.²⁶ Pazkad et al showed an increased signal consistent with inflammation.²⁵ In this study, CPPD was complicated by authentic osteomyelitis and the patient improved under antibiotics.²⁵ Another misleading image on MRI was compressive mass, which corresponds to a calcified cyst. MRI detected a cystic lesion at the side of the facet joints in 5 cases,^{9,11,19,26,27} an intramedullary mass mimicking a schwannoma in 2 cases,^12,24 and an extradural heterogeneous mass-like lesion in the anterior epidural space in one case.²⁹

It has been demonstrated that subchondral cysts are among the hallmarks of this arthropathy. The cysts usually are larger, more numerous, and more widespread than those in osteoarthritis. Cysts may form before cartilage loss is evident.³⁵ This proves the diagnostic difficulty in front of a compressive mass on MRI when calcifications are not visible. In this case, the CT scan may be an alternative before proceeding with the biopsy.

The discovertebral biopsy, despite its invasive character,allowed to make the diagnosis in almost 21 patients.^{3,5–9,11,12,14,16–19,21,22,24–26,29,31} It often showed a fibrous tissue with positive birefringent crystal deposits.

CPPD crystals may be deposited in the ligamentum flavum and posterior longitudinal ligament, leading to myelopathy, cord compression, and spinal stenosis.^40,41

In our review, surgery was attempted in all cases where there was a compressive mass, a degenerative spine with a surgery indication, or in the event of failure of medical treatment, and was always efficient.^{8,9,11,12,17–19,29,31–33,42} It consisted of a decompressive surgery in the majority of cases. As for pharmacological treatment, it consisted of NSAIDs, Colchicine, and Interleukin-1 inhibitor (Anakinra). Studies that have looked at the treatment of axial CPPD have compared it to that of gout. As both crystal diseases are mediated by IL-1-driven processes, the therapeutic intervention first targets acute inflammation consisting of Colchicine, NSAIDs, and glucocorticoids.⁴³

In a systematic review of the literature summarizing the management of CPPD, intravenous Colchicine demonstrated efficacy in pain and seizure reduction. Methotrexate was effective over an average duration of 7.4 weeks of treatment. Hydroxychloroquine was efficient in 85% of patients, with 50% responding within a month. Significant improvement in pain and objective assessment was observed with Magnesium Carbonate supplementation, with a pronounced placebo effect. Anakinra efficiency was also reported. ACTH analogues led to the resolution of pseudogout attacks within 4.2 days. Tocilizumab improved disease activity in all patients after 3 months-treatment but had some adverse effects.⁴³

Clinical experience supports the effectiveness of NSAIDs in CPPDarthritis. However, to our knowledge, there are no clinical trials of NSAIDs in this condition. Despite this, they are recommended as one of the first-line treatments for acute CPP crystal arthritis.⁴⁴ NSAIDs should be prescribed with caution, given the risk of toxicity and since patients with CPPD are usually elderly with multiple comorbidities. Low-dose steroids have been used in one case.¹⁶ This is particularly relevant in elderly individuals with comorbidities. No recent data has added to our knowledge of the use of Glucocorticoids in CPPD.⁴⁴

The major advance in the management of CPP crystal arthritis over the last decade has been the use of biological agents. Martinon et al demonstrated that CPP crystals are capable of activating the inflammasome NLR-P3- caspase1-interleukin-1beta (IL-1b) pathway present in innate immune cells such as neutrophils.⁴⁵ Three IL-1b blocking agents are currently authorized for humans by the FDA: a monoclonal antibody against IL-1b (canakinumab); a recombinant IL-1 receptor antagonist (anakinra); and a dimeric fusion protein of IL-1 receptor and IL-1 receptor accessory protein (rilonacept).

Anakinra use was described in cervical and thoracic spine CPPD, in association with Colchicine is a 3-days course and the patient improved.³³ In peripheral arthritis, Anakinra showed efficiency in decreasing pain and was well-tolerated.^46–49

In our review, it was used in only one study, with a clinical and biological improvement.²⁸

Conclusion

CPPD of the lumbar spine is an underdiagnosed pathology due to its nonspecific clinical features and its radiographic ambiguity, often associated with degenerative changes.

Through this review, we tried to identify the most frequent clinical and imaging features, but also the misleading clinical signs and diagnostic pitfalls of this disease (Table 2). In case of inflammatory back pain in elderly subjects, without an infectious gateway, the diagnosis of CPPD should be systematically considered, especially if the patient has a history of spinal surgery or degenerative changes on standard radiography. The absence of calcifications on conventional radiographs does not rule out CPPD. The CT scan is more sensitive than conventional radiographs to visualize calcifications and should be requested in case of doubt.

Table 2 Summary of the Most Common and Misleading Clinical and Imaging Features in CPPD

When MRI is indicated, because of neurological or infectious signs, the diagnosis of CPPD is still appropriate, even if the images are in favor of spondylodiscitis or osteomyelitis, since it can masquerade calcifications. Lumbar spine CPPD can even mimic a compressive cystic mass. In these two cases, the discovertebral biopsy is the Gold Standard and should be performed whenever the diagnosis is uncertain. It shows, in most cases, deposits of birefringent crystals in polarized light. The treatment is not well-established and includes a medical and a surgical component. As for the pharmacological treatment, NSAIDs (to be used with caution), or low-dose glucocorticoids could be efficient. Interleukin 1 inhibitors are an innovative alternative given their mechanism of action. Finally, surgery is useful when CPPD is associated with degenerative phenomena, compressive cysts or if it is responsible for spine stenosis.