CLINICAL CASE OF SURGICAL TREATMENT OF ACQUIRED HETEROTOPIC OSSIFICATION IN A PATIENT WITH SEVERE COMBINED TRAUMA

Heterotopic ossification (extraskeletal ossification) is a pathological process that involves the formation of bone within soft tissues, i.e. where bone shouldn't exist. This process can be observed in structures such as skin, subcutaneous tissue and skeletal muscle. In more rare cases, ossifications can form in the walls of blood vessels and the intestinal mesentery. Although ossification can occur anywhere, it is most common near large joints (knee, hip, elbow, and shoulder).

Heterotopic ossification was first described by Patin in 1692 while working with children diagnosed with myositis ossificans progressiva. In 1918, Dejerine and Ceillier described in detail the histological, anatomical and clinical features of the formation of ossifications in soldiers who suffered spinal injuries during the First World War. Following the work of Dejerine and Ceillier, Marshall Urist described the osteoinductive properties of bone morphogenic protein in ectopic structures such as muscle. This was and is still considered a "landmark discovery" in all orthopedic research.

Etiology/Causes

The exact pathophysiology of heterotopic ossification is unknown. The transformation of primitive mesenchymal connective tissue cells into osteoblastic tissue and osteoid involves diverse and poorly understood triggers. These triggers are thought to include genetic, post-traumatic, neurogenic, post-surgical and reactive lesions of the arms and legs. Genetic forms include two types: fibrodysplasia and progressive osseous heteroplasia. These types are described as massive deposits of heterotopic bone around multiple joints in the absence of an inciting event (ie, trauma). This is the most severe type of ossification, progressively developing throughout life and seriously affecting health, duration and quality of life.

Post-traumatic ossification begins with the proliferation of spindle cells during the first week after a traumatic event. Within 1-2 weeks, a primitive osteoid develops. After the second week, primitive cartilage and bone can be seen. Trabecular bone forms 2-5 weeks after injury. As mineralization progresses, amorphous calcium phosphate is gradually replaced by hydroxyapatite crystals. After about 6 months, real bone appears in the connective tissue.

Neurogenic heterotopic ossification occurs after sickle cell anemia, hemophilia, tetanus, poliomyelitis, multiple sclerosis, and toxic epidermal necrolysis. Also, neurogenic ossification develops only in places distal (located below) the level of spinal cord injury. The areas where ossification forms are almost always on the affected side of the body (in the case of brain injury or stroke). Postoperative ossification most often occurs after procedures requiring open reduction, internal fixation, or joint replacement surgery.

Reactive lesions of the hands and feet are usually associated with periosteum or periarticular fibrous tissue, which distinguishes this category from myositis ossificans. These lesions occur in three clinical and radiological conditions: periosteal osteochondromatosis, reactive periostitis, subungual exostosis.

Rehabilitation period

The most important step on the path to full recovery is the tactics of gradual restoration of the body. The basic rule is to take care of the injured area of the body; smooth movements are important. Do not overwork the body with excessive loads. Physical therapy should be selected exclusively by a specialist.

In case of severe pain, the doctor will prescribe the necessary set of medications and painkillers. At the end of the treatment and rehabilitation period, the duration of which is individual for each patient, it is necessary to conduct a verification ultrasound examination.

Prevalence

After amputation of the lower extremities (7%).
After TBI (10-20%). The hip joint is most often affected, followed by the elbow.
After spinal cord injury (20-40%).
After hip replacement (55%).
After an elbow fracture and/or dislocation (90%); after a forearm fracture (20%).

In a recent study, Foruria et al. The prevalence of ossification in all elbow pathologies with which people were admitted to the emergency department over a 5-year period was studied. He found that the highest prevalence of heterotopic ossification was observed in displaced olecranon fractures and associated humeral fractures. The site of ossification was most often located on the posterior side of the ulna. Risk factors for ossification include luxation or subluxation at the time of injury, open trauma, and severe chest trauma. During surgical treatment of the pathology, ossifications formed in 37% of participants.

Ossification of joints

If the joints were seriously injured, and the patient did not consider it necessary to visit a specialist, then the risk of pathological ossification of the joints increases significantly. With this formation, the movement of the joint is sometimes completely blocked, which seriously complicates a person’s daily life.

The most well-known type of ossification is ossification of the hip joints. It develops in childhood or early infancy. There is a high probability of developing ossifiers in utero. Regardless of the moment when the first signs of the disease appear, at the age of twenty it becomes chronic. In addition to the stiffness of joint movement, their fusion cannot be ruled out. In this case, the joints are completely immobilized, and ankylosis begins to develop. Another factor in this disease is the formation of blood clots in the nerve trunks, and the patient experiences severe pain.

It is necessary to take into account certain norms in the development of the hip joints. So, around the eighth month of pregnancy, the fetus develops a joint structure. In each child, ossification of the hip area occurs at its own time, that is, the development of this process occurs completely individually. However, approximate statistics are still available:

At the initial stage, only the structure of the hip joint appears in the child. This process lasts until the first three months after the baby is born. Ossification of the femoral heads has not yet begun.
The second period covers up to six months. Ossification is occurring, but not completely yet. The female sex develops much faster than the male in this process.
The third stage includes development up to the age of five. During this period, bone tissue increases significantly.
The final period covers the age from 12 to 20 years, when the bone tissue is fully formed.

If any deviations were observed during these periods, then after the final stage they will be permanent, and treatment of the disease can be very difficult.

Classification

Brooker's classification of heterotopic ossification

Class 1: Island of bone in the soft tissue around the hip joint.
Class 2: Bone spurs arising from the pelvic bone and the proximal end of the femur (distance between them is at least 1 cm).
Class 3: Bone spurs arising from the pelvic bone and the proximal end of the femur (distance between them <1 cm).
Class 4: ankylosis of the hip joint.

Brooker did not describe class 0, but subsequent studies using Brooker's classification defined class 0 as the absence of radiographic evidence of ossification.

Classification according to Schmidt and Hackenbrock

Region 1: heterotopic ossification just below the tip of the greater trochanter of the femur.
Region 2: Ossification below and above the tip of the greater trochanter.
Region 3: ossification strictly above the apex of the greater trochanter.

Grade A: Single or multiple ossifications <10 mm without contact with the pelvic or femoral bone.
Grade B: ossification >10 mm without contact with the pelvic bone, but with possible contact with the femur; lack of transition from the femur to the proximal part of the greater trochanter; no signs of ankylosis.
Grade C: ankylosis due to a strong bridge between the femur and pelvic bone.

McAfee classification (after total intervertebral disc arthroplasty)

0: no ossification.
1: Ossifications are not within the boundaries of the disc and do not interfere with movement.
2: Ossification within the boundaries of the disc, but does not block movement.
3: ossification within the edges of the disc and interfering with the movement of the prosthesis.
4: ankylosis.

Symptomatic manifestations

The clinical picture includes several obvious symptoms unique to this disease:

Pain in the injured area.
Swelling in the area where the growth develops.
Hardening and redness.
With heterotopic ossification, there is difficulty in joint movements or their complete absence due to pain accompanying movement.
Disturbances in the structure of nerve fibers such as the formation of blood clots or bedsores.
Bruising.

An equally important factor in such a disease is that the nerve endings are pinched, which is naturally accompanied by pain. This occurs due to the fact that bone growths form in areas where their presence was not initially intended in the body.

If such symptoms are detected, you must immediately contact a specialist before the disease becomes chronic and causes serious damage not only to health, but also to the person’s life as a whole.

Stages of development

Chronology of the development of heterotopic ossifications

0 days: + / - erythema, swelling, pain.
7 days: palpable mass.
7-14 days: poorly defined shadow on the radiograph.
14-21 days: osteoid deposition, radiographic shadows.
21-35 days: “dot veil” effect.
24 days: certain radiographic findings.
30 days: mineralization shows a zonal pattern (best seen on CT scan).
45 days: a histological “zonal” pattern is evident, reflecting well-formed mineralization at the periphery.
180-365 days: mature bone development.

Clinical picture

Clinical signs and symptoms of heterotopic ossification may appear as early as 3 weeks (or up to 12 weeks) after spinal cord injury, musculoskeletal injury, or other associated events. The first sign of ossification formation is usually loss of joint mobility and impairment of joint function. Other signs include swelling, redness, warmth at the site of the lesion, pain, and a palpable mass. In some cases, an increase in body temperature may occur.

Diagnosis

The pathological condition is diagnosed based on the symptomatic picture and the results of a blood test; an increase in alkaline phosphatase levels is observed. On an x-ray, the first manifestations of the pathological condition will be visualized only 7-10 days after the onset of the disease. For the purpose of early diagnosis, modern medicine uses a three-phase scanning method in the area of bone particles; in phase I of the examination, a local increase in blood supply and accumulation of isotope tracers in the tissue is noticeable.

Diagnostics

Ultrasonography

Detection of ossifications 2 weeks earlier than with x-ray examination.
Ultrasonography is more accurate than any laboratory tests.
Essential for practitioners advocating rapid/active physical therapy.
Eliminates the high rate of false positive physical examination results.

Triphasic scintigraphy

Diagnostic and therapeutic purposes of observation.
Phases 1 and 2 indicate hyperemia and blood accumulation (pre-ossification processes).
Usually a positive result takes 2-4 weeks.
Serial bone scans used to monitor metabolic activity within the ossificate to determine optimal timing of surgical resection and predict postoperative complications.

Radiography

A soft tissue mass is the earliest radiographic sign.
Heterotopic ossification is observed on radiographs 4-6 weeks after injury, and has a typical appearance of rounded ossification with a luminous center.
Radiography does not detect mineralization of ossificate during the first weeks after injury/onset of disease.
Often used to classify ossification after hip replacement.
Differential diagnosis: avulsions, osteochondral fragments, soft tissue calcification, and osteosarcoma.

MRI/CT

MRI is not routinely used to evaluate ossification.
CT can detect soft tissue ossification at earlier stages than standard radiography.

Use of technetium-99 and methylene diphosphonate

The most sensitive imaging modality for early detection and assessment of ossification maturity.
Can be used to monitor metabolic activity within ossifications and determine the appropriate time for surgery and predict postoperative relapses.
Usually positive result >2 weeks (before radiographic confirmation).

Prostaglandin E2 (PGE2)

Monitor PGE2 excretion with 24-hour urinalysis.
PGE2 is considered a reliable bone marker for early detection and treatment response.
A sudden increase is an indication for bone scintigraphy.

Alkaline phosphatase

Often used in the early detection of ossification. Alkaline phosphatase levels increase significantly at the very beginning of ossification formation and remain at a plateau for 4 weeks.
Cannot be used to obtain clinical conclusions about ossification maturity or recurrence.
Acute fractures often have similar alkaline phosphatase values, which limits the use of this indicator in the diagnosis of ossification.

Elevated creatine kinase levels

Correlates with histological muscle damage and disease severity.
Not specific for heterotopic ossification.
Allows to predict a higher risk of development and severity of ossification.
May be useful in planning and assessing response to treatment.

Matrix metalloproteinase-9

Marine animal models suggest that this may be an early biomarker indicating the formation of ossifications.

Note: The lack of simple objective measures to identify ossification leads to early misdiagnosis and inadequate treatment.

What is the danger

Without treatment, ossification can be complicated by the following pathologies and processes:

joint fusion;
thrombosis and compression of nerve endings;
development of malignant neoplasm;
ossification of ligaments and articular apparatus.

All these processes lead to disability of the patient, so treatment of pathology is a prerequisite for a full life in the future.

Differential diagnosis

The initial inflammatory phase of ossification formation can mimic other pathologies, such as cellulitis, thrombophlebitis, osteomyelitis or a tumor process. Other differential diagnoses include deep vein thrombosis, septic arthritis, hematoma, or fracture. In addition, it is believed that deep vein thrombosis and ossification are related. This is thought to be due to mass effect and local inflammation stimulating clot formation. Thrombus formation is caused by venous compression and phlebitis.

Accompanying illnesses

The most common diseases found in combination with heterotopic ossification are:

Ankylosing spondylitis.
Rheumatoid arthritis.
Hypertrophic osteoarthritis.
Diffuse idiopathic skeletal hyperostosis.
Paget's disease.
Quadriplegia and paraplegia.

Treatment

Treatment of ossification largely depends on the number of ectopic bone formations, their location, and the patient's associated functional limitations.

The first goal of treatment is to identify patients at risk of developing ossification and their preventive treatment. Research supports the effectiveness of two other approaches to treating ossification: 1) surgical excision and 2) radiation therapy.

Preventative treatment

Further research is needed in this area, but experimental options currently exist. These include:

Local radiotherapy

A decrease in frequency in all classes according to the Brooker classification, but the greatest effect is observed in classes 3 and 4 (compared to NSAIDs).
Treatment is better carried out in the postoperative period than in the preoperative period.
The use of radiotherapy as a preventive treatment mainly concerns patients after hip replacement.
Pluripotent mesenchymal cells can prevent the development of heterotopic ossification.
A dose of 700-800 cGy for local irradiation in the first four postoperative days prevents the development of ossification in high-risk patients.

Oral Indomethacin

Drug therapy

Medications are prescribed to patients at risk of developing ossification. There are two types of drugs that have been shown to have both preventive and treatment benefits. These include nonsteroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates.

NSAID (indomethacin)

Inhibition of differentiation of mesenchymal cells into osteogenic cells (direct effect).
Inhibition of post-traumatic bone remodeling by suppressing prostaglandin-mediated (indirect action) and anti-inflammatory responses.

Bisphosphonates

Inhibition of calcium phosphate precipitation.
Slowing down the aggregation of hydroxyapatite crystals.
Inhibition of the conversion of calcium phosphate to hydroxyapatite.

Note: Physicians should be aware of the potential complications (mostly gastric related) in patients taking NSAIDs on a regular basis.

Surgical intervention

Surgical treatment has two goals: to change the position of the affected joint and/or improve its mobility. In his work, Garland suggests the following timing of surgical interventions.

6 months after traumatic development of ossification.
1st year after development of ossification due to spinal cord injury
18 months after the development of ossification due to traumatic brain injury.

The above deadlines were established to determine the most optimal timing of surgical intervention. Clinicians must determine whether the ossification is ripe for surgical removal to reduce the risk of intraoperative complications such as bleeding and subsequent recurrence. The use of bone scans to determine the metabolic activity of the lesion and serum alkaline phosphatase levels often aids in decision making. Shehab describes the criteria by which surgical removal of heterotopic ossification is recommended. These criteria are:

A significantly reduced range of motion of the affected joint (eg, less than 50 degrees for the hip) is the most serious complication of heterotopic ossification.
Absence of local temperature, swelling, redness or other clinical manifestations of an acute process.
Normal serum alkaline phosphatase level.
Return of bone scans to normal (or nearly normal); If serial quantitative bone images are obtained, there should be a sharply decreasing trend followed by a steady state for 2-3 months.

Rehabilitation in the postoperative period

It is recommended to begin a rehabilitation program within the first 24 hours after surgery. The program should last for 3 weeks to prevent adhesion (tissue sticking together).

Physical therapy

Physical therapy has been repeatedly shown to benefit patients suffering from heterotopic ossification. Preoperative physical therapy may be used to preserve structures around the lesion. Range of motion exercises (passive exercises, active assistive exercises, and active exercises) and exercises to strengthen surrounding muscles help prevent muscle atrophy and joint stiffness.

Note: Caution must be exercised when working with patients with ossification. Too active therapy can aggravate their condition and lead to inflammation, swelling, hemorrhage and increased pain.

Postoperative rehabilitation has also been shown to be effective in patients undergoing surgery for heterotopic ossification. Postoperative treatment of ossifications is similar to preoperative treatment, but much more emphasis is placed on controlling swelling, treating scarring, and preventing infectious complications.

Calandruccio outlined a rehabilitation treatment protocol for patients undergoing surgical excision of heterotopic ossification of the elbow joint.

The rehabilitation stages and goals for each stage are as follows:

Stage I (1 week)

Goals:

Prevention of infectious complications.
Reducing tissue stress at the surgical site.
Reducing pain.
Reducing swelling.
Increase in range of motion up to 80%.
Maintain range of motion of the wrist and shoulder joints.

Stage II (2-8 weeks)

Goals:

Reducing pain.
Reducing swelling.
Limitation of activities of daily living.
Measures to increase scar mobility and proper tissue remodeling.
Exercises to engage surrounding muscles.

Stage III (9-24 weeks)

Goals:

Self-management of pain.
Preventing a surge in functional activity.
Strengthening muscles.
Increasing range of motion (if restrictions remain).
Return to previous activity levels.

Note: Both of the above studies were mainly aimed at the rehabilitation of the elbow joint affected by heterotopic ossification. However, the goals and steps of the rehabilitation process can be used to guide the treatment of ossification in other locations.

Radical measures

If previous measures are ineffective, they resort to surgical techniques aimed at excision of ossifications. However, some complications are possible: bleeding, sepsis and recurrence of the pathology. Relapses of the disease are extremely rare when surgery is performed after the final maturation of bone formations. Thus, it is carried out after a year and a half after injury. To reduce the likelihood of recurrence after surgical excision, certain patients are prescribed radiotherapy with minimal doses, and long-term courses of drugs based on etidronic acid are indicated.