Heterotopic ossification following acute illness: a case report Researcher (reporters): Dr Litelu TI: MB., ChB. Registrar, Department of Internal Medicine, Universitas Hospital and University of the Free State School of Medicine, Bloemfontein, South Africa. Supervisor: Dr Jansen Van Rensburg BJ, MB., ChB. MMed (Internal medicine), FCP(SA), Cert. Rheumatology AbAsbtrsatrcat:c t: BaBcakcgkrgoruonudn: dH: eHteerteortooptoipc iocs osisfsiicfaictiaotnio ins ias raa rraer ceo cnodnitdiiotnio tny ptyipfiiefdie bdy b fyo fromrmatiaotnio onf o bfo bnoen ien i n exetxratraar taicrutilcaurl asor fsto tfits stuises.u Teh. Te hceo ncodnitdioitnio hna sh abse ebne elnin lkinedk etdo tsoe vseervaelr rails rki sfka cftaocrtso grsiv geinv irnigse r tiose to itsi tcsl acslasisfsiicfaictiaotnio. n. WWe ree rpeoprot rotn o an caa csaes oef o af 4a ..4 y4e ayre aorl do lmd amlea lpea ptiaetniet nwt hwoh wo aws adsi adgiangonseodse wd iwthi tthh ihs ectoenrodtiotipoinc foollsoswifiincagt iaodnm fioslslioowni nfogr apdumlmisosinoanr yfo TrB p. uTlhmeo pnaatrieyn Tt Bd.o Tehs en poat thieanvte dthoees t ynpoitc hala vries kth fea ctytoprisc al dersicsrki bfaecdt oinrs r deceescnrti bEnedg liinsh r elacnengut aEgneg lliisther laatnugrue.a Hgeis lcitaesrea tius rael.s oH uisn ccaosme mis oanls od uuen tcoo mthme on due ditfofu tshee i ndvifofulvseem inevnot lovfe mhies njot ionft sh. is joints. Case history: reported having been confused for part of the admission. Unfortunately no cerebrospinal fluid A 44 year old male was referred to us from a investigations were done during the admission in neighbouring country (Lesotho) due to stiffness of Lesotho and on presentation to us, the patient was his elbows, knees and hips after recovering from completely lucid and in control of his faculties. pulmonary TB in hospital. He was admitted to a hospital in Lesotho in May 2013 and was He experienced no pain in the ossified joints, discharged 3 months later. It was noticed that he except when movement was forced. There was no was unable to move his hips, knees and elbows at history of trauma to the joints nor to any part of discharge. X-rays revealed fusion of the involved his body leading up to the initial admission. He joints due to periarticular soft tissue ossification. denied morning stiffness in the uninvolved joints. He was also diagnosed with HIV-1 infection He also denied fever since discharge from the during admission in Lesotho. The patient had no hospital in Lesotho. other known medical conditions. The patient The patient is employed as a supervisor in the primary regime of anti-retroviral therapy military. He does not use alcohol and does not prescribed in Lesotho. Consisting of a once a day smoke tobacco. There is no family history of combination of Tenofovir, Lamivudine and skeletal disease and his parents and siblings were Efavirenz. He was diagnosed with vitamin D all healthy. deficiency and a secondary hyperparathyroidism, which may contribute to an abnormal calcium to Clinical examination revealed a stable patient, phosphate ratio. wheelchair bound with restricted joint movement in multiple joints. The range of movement was He was discharged from our unit on his anti- restricted in multiple joints, as follows: retroviral therapy, vitamin D and calcium supplementation. Hips: Right- 0 cm and left- 5 cm in all planes The patient was handed over to our centre’s Knees: Right, flexion and extension- 5 cm and left- orthopaedic department to continue with surgical 5 cm therapy. He had his first surgery in August 2017. Elbows: Right, flexion and extension- 0 cm and The right proximal femur was operated on with left- 5 cm good results. He has done well in rehabilitation of this joint. The surgical team chose total hip Ankle (subtalar): Both minimal terminal restriction replacement rather than resection of the All the other joints had normal ranges of motion heterotopic bone due to extensive osteoarthritis of including the spine. the joint. He is scheduled to undergo further surgery as planned by the orthopaedic X-rays done at his initial consultation are shown department. (figures 1 to 4). No ossification of his wrists was noted on X-ray. He did not have limited movement in these joints. Literature review A skeletal scintigram done during surgical planning revealed increased uptake in multiple Introduction: areas, including but not exclusive to the clinically Heterotopic ossification (HO) is a condition and radiologically involved joints. It also revealed characterised by formation of mature lamellar decreased uptake in both knees, which had bone outside of the periosteal borders of the ossification on X-rays. These findings were noted skeleton.1,2,3 Other calcium deposition bodies, in 2016 and a repeat scan in 2017 showed a outside of the skeleton, are differentiated from it similar pattern, despite the patient’s condition by not being lamellar nor mature bone. These being present for over five years in 2017. other extra-skeletal conditions include processes A CT scan of the right hip reported osteoarthritis such as malignant calcification, calcinosis cutis of the right hip apart from the ectopic bone mass. and dysmorphic calcifications. The pathogenesis and radiologic images of these other conditions Some of his blood results are shown in table 1. differ in comparison to HO. Heterotopic His HIV infection was well controlled on a ossification is the umbrella term for three groups Congenital myositis ossificans of conditions. These are classified as follows: Post traumatic/ non congenital myositis Figure1 ossificans Neurogenic heterotopic ossification.3,4 Some authors use different subtype classifications with all or two of these conditions grouped into a class.2 However in some literature this condition is seen classed under the larger umbrella syndrome of Ectopic calcification as a general term to also include the other conditions already mentioned Figure 2 above. 5 This discussion will focus on the third group of conditions. This group is often referred to as heterotopic ossification in the literature. FiFigure 5 Figure 3 Figure 6 Figure 4 Figures 5 and 6: X-rays of the patient’s pelvis showing total hip replacement of the right hip Figures 1 to 4: Pictures of presenting X-rays showing the ossification (orange arrows) of the patient’s elbow, knee and hip joints September 2015 2016 2017 Sodium- mmol/l 141 145 139 Potassium- mmol/l 4,7 3,9 5,0 Urea- mmol/l 3,6 4,0 4,4 Creatinine- µmol/l 76 92 64 Calcium- mmol/l 2,38 2,31 2,39 Phosphate- mmol/l 1,02 0,85 Parathyroid hormone- pmol/l 13,6 11,9 Vitamin D nmol/l 42,08 32 12,4 HIV viral load Less than 150RNA copies Table 1: The patient’s laboratory results over time Figure 7 Figure 7 : Skeletal scintigram showing high activity in the involved joints (orange arrows) while others show little uptake (blue arrows). The left wrist shows high activity (green arrow), a result of extravasation of tracer around the access point. Some joints show high activity even though they clinically showed no limitation of movement (black arrows) From henceforth, the term HO will be used to seed in the wound, the incidence of HO following describe the patient’s condition and not the whole hip arthroplasty is also reduced.12 This suggests group. direct seeding as a trigger for HO during hip reaming. This is further supported by the fact that Aetiopathology: the incidence of HO was reduced by using a No direct cause of HO has been described. Recent plastic draping on the wound during hip evidence suggests a complex event, involving the arthroplasty.16 However, the data is conflicting interaction of bone morphorgenic protein (BMP), when hip resurfacing, which avoids reaming, is the endothelium and the interstitial stem cell compared to total hip arthroplasty.14,16 The theory differentiation.6,7,8 There is also evidence to of seeding is limited to patients with local trauma suggest that hypoxia may drive the condition as a possible cause for the development of HO.17-22 through oxidative stress and chymase expressing There are also reports of cases of HO following mast cells.9 The endothelium has been shown to various other episodes of ill health. These include play a critical role in the formation of this bone protracted ICU stay, mechanical ventilation, burns mass, but other factors are also likely involved as and central nervous system (CNS) injury; be it the suppression of endothelial growth does not traumatic, infective/inflammatory, a brain tumour completely stop the occurrence of HO, albeit with or stroke.17,23-30 evidence from a mouse model.10,11 The inciting Lane et. al. reported on a patient who developed factor however remains elusive. One can only HO following prolonged immobilisation in ICU.31 hypothesise from certain common characteristics This raises the possibility of immobility as a more in the groups of patients who develop the important cause of HO, rather than the CNS injury condition. itself. This may be more so in those with neurologic injury, confounding the efforts to try Risk factors: and delineate a causal relationship. This theory is The early cases of HO were noted in children and supported by the fact that most patients with then later a similar condition was noted in soldiers neurologic injury causing reduced power in a who had injury to their spinal cords.4 It has also limb tend to develop HO in the limb with paresis. been noted in patients after total hip Pek and colleagues however reported on a patient arthroplasty.4,16-18 This has given rise to multiple with stroke who developed HO in the limbs not 30 theories as to the development of this condition. affected by the paresis that resulted. From recent Most theories are directed at the occurrence of HO English language literature it seems likely that the following local iatrogenic trauma at surgery. disease is of multi factorial aetiology possibly Which led to the assessment of different surgical inciting the proposed pathologic events to result in approaches in relation to HO development.12-15 the bone formation. It may also be speculated that Studies show that different surgical approaches the post traumatic and the non-traumatic HO are show different incidences of HO as a two separate conditions with the same outcome. complication.1,15 It has also been shown that by This may explain the difference in the inciting reducing the amount of bone fragments which can factor in the two groups. Clinical presentation: rather than an orthopaedic selection. Plain X-rays are also used to grade the disease. The Brooker HO can present as a subacute or chronic system is most commonly used. This system grades condition. 11 In the acute phase it may be the disease on severity or proximity of the misdiagnosed as a localised infective process such ossification across a joint. With grade 1 being as an abscess or acute myositis.32 This is because small islands of bone noted and grade 4 being a these patients will often present with features of completely ankylosed joint.4,42 acute inflammation such as fever, pain, and swelling. Often at this stage the plain X-ray will A high index of suspicion is therefore needed to show no abnormal bone formation.11,27 A make the diagnosis outside incidental findings on correlation has been demonstrated between the imaging. In a patient who loses range of motion in level of the inflammatory response to an injury a joint area following any of the stated risk factors, and the risk of developing HO post-op.33 The role HO has to form part of the differential diagnoses. of inflammation is further strengthened by the A normal X-ray should then not be sufficient to effectiveness of NSAIDs as prophylactic agents.34- exclude HO, should no other diagnosis be 39 Whether the inflammatory reaction is an early established. It has been proven that MRI is a better sign of HO or a risk factor is not clear. Some imaging modality.26,30 This is especially true when patients do not have this early disease investigating early disease.27 The adage of symptomatology, presenting instead with the more investigating a hypothesis rather than ‘investigate common chronic phase of the disease. This is and see’ approach, remains important as Choi et usually hallmarked by a reduction of the affected al, reported on two cases where MRI was used and joint’s range of motion.9,25,40 There is often no pain a wrong diagnosis of myositis and osteomyelitis at this stage. When present, the pain may range were made, only to be refuted later when HO between minimal and tolerable to complete and became obvious.32 To summarise, X-rays remain incapacitating, depending on the grade of disease the most commonly used method of investigation. diagnosed.4,11,31 There may be localised tenderness X-rays may however miss early disease, which due to a fracture after forceful movement of an MRI may elucidate.27 Bone scintigraphic scanning ankylosed joint. In a proportion of patients, HO is is reserved mainly for assessing maturity of the completely asymptomatic.4,11 The condition may ectopic bone in planning for surgery.18 present as an incidental finding on radiographs. Suggesting underreporting of the true prevalence of HO. Even though some series described the prevalence in X-rayed populations, the participants all had conditions necessitating the imaging and thus making this a non-inclusive population.41 Study of random X-rays might give a better inclusive population to study, more so if these would be a general hospital X-ray cache Treatment Surgery remains the definitive therapy. Many gastrointestinal side effects of the nonselective patients will not require surgery as the degree of COX inhibitors.36 symptoms will be minimal, if at all.17,18 The aim of Radiation therapy is used as both primary surgery is to restore adequate movement of the prophylaxis and secondary prophylaxis.47 A study affected joints, thus obviating the need to operate found the combination of radiation and NSAID should there be minimal limitation of joint 25 therapy to have some synergy. 19 Radiation was movement. A better goal will be to improve shown to have fewer side effects and to be more movement rather than restoring it to normal effective when compared to NSAID therapy.47 ranges. This in light of the fact that range of Though there remains a risk for oncogenesis with motion in the operated joints is often less than the radiation therapy. The clinician still carries the unaffected joints even after extensive and 40 responsibility of explaining this to his/her patient successful surgery. The bone mass may rarely when one of these is to be chosen. cause impingement of structures, especially neurovascular bundles. Surgery may have to be Bisphosphonates are effective therapy once HO undertaken to alleviate this.26,43 has developed, while NSAIDs are better as prophylaxis.38,39 As noted above, surgery remains Medical therapy has mainly been used as the mainstay of therapy. It however also carries prophylaxis in high risk groups and post some risk of complications. Wound sepsis and excision.11,19,35-38,44-47 The NSAID, Indomethacin is recurrence of HO are the most prominent of the most widely used medication in this regard. It surgical complications.4,30,40 The recurrence of HO has been shown to be the best primary can be treated with surgery and prophylactic prophylaxis. It has also been shown to reduce the measures.48 incidence of HO when compared to placebo and to reduce the bone mass in those who develop the There are some novel therapies still being disease on the medication. NSAID therapy showed investigated. Imatinib, a potent PDGF (an no protection in children with severe cerebral important inducer of endothelial growth) inhibitor palsy and hip abnormalities requiring surgical has been shown to reduce the incidence of HO in intervention.34 One study showed success in mice.11 Remote ATP hydrolysis has also been resorption of some of the bone mass on shown to prevent heterotopic bone formation.38 indomethacin therapy.21 There is a paucity of literature on this approach. COX 2 inhibitors are as effective as nonselective COX inhibitors for prophylaxis. They can thus be used to reduce the Discussion: HO is a rare condition and our patient’s case is Reports of HO following encephalitis may also be unique. The patient had no typical risk factors evidence of the link between injury to the CNS and commonly found to be related to the development developing HO. We postulate that our patient’s of HO. Though we do not have a full record of his CNS may have been involved in his initial illness, admission in Lesotho for his index episode of thus making this the tenuous link to the other illness, the history does not suggest anything that reported cases. has been reported to be linked to the occurrence of HO is now more commonly seen as a HO. A possible tenuous link is that of a possible complication of hip replacement surgery. Some meningitis/encephalitis during the admission. This studies demonstrated a link to the amount of bone is postulated due to the patient reporting to have fillings that are allowed into the joint space during no memory of most of his time in hospital and his the procedure as a clear risk factor. A direct link to relatives relaying that he had been confused. The our patient's case and the other reported cases is referring doctor reported that he was admitted for not possible. The cases of post-CNS injury and pulmonary TB and was treated for this post-operative HO development may be linked by successfully. As can be seen in the patient's reduced mobility. laboratory workup, he had no major biochemical abnormalities at the time of his admission to our Our patient has a dark complexion and we took facility. This may be because it had already been this as a likely contributor to his vitamin D two years since the onset of joint stiffness and the deficiency. This together with being house bound initial admission. with little exposure to UV radiation. We also postulate that the vitamin D deficiency is a Though we were not involved in his initial possible explanation for the delay in the ectopic admission we postulate that it is unlikely that the bone maturation. patient was immobilised in all the involved joints. Immobility may be an inciting factor in the Conclusion: development of HO in patients with paralysis. This may explain the cases of HO developing in This case presents in a very unusual manner and patients following stroke and trauma with leaves many questions to be answered. We thus subsequent paralysis. The reported cases of HO pose questions that we can only postulate answers following prolonged ICU stay may suggest to at this stage and hope further research can reduced mobility as a risk factor. A case report of elucidate the answers. The questions which we the non-paretic limb being affected by HO may be feel need further probing are: evidence against this type of theory. The reported 1. Is there a possible immunologic link to patient had injury to the CNS, causing paralysis. heterotopic ossification? This being that HO occurred in limbs not affected by paralysis in our patient was diagnosed with HIV this case. The report may lead to theorising that infection during the initial admission injury to the central nervous system is the main when he developed HO. precipitant rather than the resultant paralysis. 2. In comparison to excision, how does joint 4. How would treating the vitamin D replacement fare? This being due to the deficiency affect the course of the ectopic therapeutic option taken by our bone formation, maturation and risk of orthopaedic team as well as it being an recurrence post surgery? established risk factor for this disease Our patient has a long journey of surgeries process. and rehabilitation in front of him and we 3. Does the vitamin D axis affect the ectopic hope to learn from his condition. bone mass the same way it affects normal skeletal tissue? References: 1. Shehab D, Elgazzar AH, Collier BD. Heterotopic ossification. Journal of nuclear medicine 2002; 43(3): 346-363 2. Caglayan G, Kutsal YG. Heterotopic ossification-an update. J PMR Sci 2014; 17: 181-188 3. 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