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Neurogenic heterotopic ossification : a diagnostic and therapeutic challenge in neurorehabilitation.
Correspondence Address:
Heterotopic ossification (HO) is an important cause of restriction in range of movements and secondary motor disability following neurotrauma, orthopaedic interventions and burns. It has not received focussed attention in non-traumatic neurological disorders. In a prospective study of 377 patients, on medical problems in neurological rehabilitation setting, 15 subjects (3.97%) had neurogenic heterotopic ossification. Their clinical diagnosis was: transverse myelitis (7), neurotuberculosis (4), traumatic myelopathy (2) and stroke (2). Hip (10), knee (4) and elbow joints (1) were involved. The risk factors included urinary tract infection (15), spasticity (6), pressure sores (13) and deep venous thrombosis (DVT) (6). The initial diagnosis was often other than HO and included DVT (3), haematoma (2) and arthritis (2). ESR and serum alkaline phosphatase levels were elevated in all but one subject. The diagnosis of HO was established using X-rays, CT Scan and three-phase bone scan. Following treatment with non-steroidal anti-inflammatory drugs, the range of motion improved in only four patients. HO resulted in significant loss of therapy time during rehabilitation. High index of suspicion about this complication is necessary for early diagnosis and prompt intervention.
Formation of mature lamellar bone in soft tissue is known as heterotopic ossification (HO). There are four forms of HO viz neurogenic HO (NHO), myositis ossificans, hereditary HO and HO after burns.[1] The neurogenic HO is mostly reported after trauma to central nervous system and is an important cause of disability in neurological rehabilitation. Several factors, both hereditary and acquired, have been implicated in the pathogenesis of NHO. However, their exact role is far from clear. The primary neurological deficits may modify the clinical features of HO. Therefore, its diagnosis is often delayed and requires high index of suspicion. This report describes patients with NHO, seen at neurological rehabilitation unit, National Institute of Mental Health and Neurosciences, Bangalore, India.
Fifteen subjects from a prospective study[2] of medical problems in neurological rehabilitation unit, who had clinical and radiological evidence of NHO, form the basis of this report. Detailed history regarding trauma, surgery, onset and evolution of neurological symptoms and interval between the onset of neurological deficits and features suggesting NHO was recorded. Location, aetiology and severity of the neurological lesion was noted. American Spinal Injury Association (ASIA) impairment scale was used to describe the completeness of the spinal cord lesion.3 Risk factors for NHO like deep venous thrombosis (DVT), spasticity, pressure sores and urinary tract infection were documented. Clinical features of HO, namely decreased range of motion (ROM) at the affected joint, fever, erythema at the involved site, localised soft tissue swelling and warmth were looked for. Laboratory investigations, including erythrocyte sedimentation rate (ESR), serum alkaline phosphatase (SAP) levels, X-rays, computerised axial tomography scans, ultra-sonography and bone scans, were reviewed. Therapeutic response to drugs was also evaluated.
During this study, among 377 patients who were admitted to neurological rehabilitation unit, 15 patients (3.97%) had clinical and radiological evidence of NHO. Among 13 subjects with spinal cord disorders, the lesion was complete (ASIA grade - A) in nine patients and incomplete (ASIA grade - B) in four. Neurosurgical procedures of the spine were carried out in four patients. Two patients had Pott's spine, one had traumatic myelopathy and one had negative exploration for suspected tumour. In addition, one patient each had hemiplegia due to vasculitis and quadriparesis due to cerebral venous thrombosis. The initial symptoms of NHO were: pain (8), swelling (11) [Figure - 1] and restricted ROM (15). The concomitant risk factors were DVT (6), spasticity (6), pressure sores (13) and urinary tract infection (15). Erythrocyte sedimentation rate (ESR) was elevated in all and ranged between 30 mm and 115 mm during first hour. Serum alkaline phosphatase (SAP) levels were elevated in all except one subject. Initial plain X-rays of the involved joints were normal in eight subjects, however serial X-rays showed NHO in seven of them [Figure - 2] and [Figure - 3]. In one subject with normal X-rays, bone scan revealed NHO. Computerised tomographic (CT) scan, done in two subjects, revealed calcification around hip joints [Figure - 4]. Eleven patients were treated with indomethacin, two patients each received diclofenac sodium and ibuprofen. Range of motion exercises and active physiotherapy were stopped till all signs of inflammation subsided and ESR and alkaline phosphatase returned to normal levels. Range of motion improved in four subjects, three of whom had received indomethacin and one diclofenac sodium.
NHO is often regarded as a complication of traumatic brain and spinal cord injuries[1],[5],[6] and its incidence, among them, varies from 16% to 53%. However, its incidence in non-traumatic neurological disorders is not known. In the present series, 15 of the 377 patients (3.97%) admitted to neurological rehabilitation unit developed this complication. NHO is reported to be more common among patients with cervical cord injury, but in the current series only two patients had cervical myelopathy. Bravo-Payno et al also did not find any significant association between the level of SCI and NHO.[7] Hip, knee and elbow joints have predilection for HO.[6] The distal joints are usually spared except in burns.[1] In the current study, hip joints were the most frequently affected (n=10). Among four subjects with knee joint involvement, three had bilateral affection. Early manifestations of NHO may mimic DVT, arthritis, haematoma, infection and tumour. Only in eight instances NHO was considered as the first diagnosis. Awareness and high index of suspicion are essential for early diagnosis. Pain is the most common symptom of NHO,5 however, it may be absent, as in our cases, due to severe sensory deficits associated with the primary neurological disease. Limitation of range of motion, the most common sign of HO, was present in all and should arouse suspicion among care givers. Elevation of level of alkaline phosphatase is a hallmark of NHO8 and is considered a sensitive, convenient and inexpensive investigation for early detection. Some authors even recommend empirical treatment for NHO based on SAP levels.[5] However, these levels may be elevated in patients with hepatic dysfunction, fractures and bone tumours. Whenever possible, the diagnosis of HO should be confirmed by other investigations. ESR of more than 35 mm in first hour is reported to be an early indicator of NHO. However, it has low specificity as it may be raised due to concomitant conditions like pressure sore and urinary tract infection. Despite these limitations, both the tests are very frequently used for assessing the activity of NHO.[1] Plain X-rays are helpful in the diagnosis and monitoring the progression of NHO1 but may be negative during early stages. In the present study, Xrays were initially normal in eight patients and it was only on serial study that calcification was demonstrated. NHO may involve soft tissue structures like blood vessels and nerves near the joint.[4],[9] CT, being more sensitive, helps in early detection of NHO and delineation of bone from soft tissues. In two of our patients, CT clearly defined the extent of soft tissue involvement. The 'gold standard' for the diagnosis is three-phase bone scan.[1] This was done in two subjects and revealed NHO in one patient with negative X-rays. The limitations of this test are cost, radiation and lack of easy availability of this facility. Ultrasonography is believed to be useful in the early diagnosis of HO and differentiation of HO from primary bone tumours, haematomas and abscess.[6],[10] However, it was not carried out routinely in our patients. Risk factors for NHO include DVT, spasticity, severe trauma, pressure sores, complete spinal cord injury, urinary tract infection and vigorous physiotherapy. [1],[5],[7] Rapid and frequent stretching of spastic limbs can result in traumatic muscle tears. Cassar- Pullincino et al observed muscle necrosis, haemorrhage and cellular proliferation in the central hypoechogenic zone surrounded by an intermediate echogenic zone of osteoblast and immature bone. The outer zone consisted of mature bone with trabecular pattern.[11] Bodley et al also observed early bone formation and macrophages containing haemosiderin in NHO.[10] These studies suggest that microtrauma might be contributory to its pathogenesis.[10],[11] Deep venous thrombosis is considered a risk factor as well as a complication of NHO.[4],[7],[9] In the present series, six patients had DVT and in two of them DVT preceded heterotopic ossification. Management of NHO is difficult and includes disodium etidronate, indomethacin, physical therapy, radiation, surgery, verapamil and warfarin.[1],[4],[5],[12],[13],[14] Once the process of bone formation is complete, the response to treatment is poor. The aim of medical treatment, thus, is to prevent NHO in high risk patients and to avert recurrence after surgery. Diphosphonates interfere with the conversion of amorphous calcium phosphate to hydroxyapatite crystals,[1],[5] and is used in dosage 20 mg/kg/day for three to six months for prophylaxis of NHO. Their side effects include fracture of long bones, fever, myalgia, leucopaenia, bone pains and rebound ossification. Indomethacin inhibits prostaglandin synthetase and reduces inflammation. This decreases the mesenchymal cell proliferation and interferes with new bone formation. Among 11 patients, who received indomethacin, range of motion improved in three. Role of ROM exercises is controversial as it may increase the inflammation and accelerate bone formation.[5] Some authors recommend ROM to maintain the mobility of the joint and prevent ankylosis while others prefer to treat them with 'benign neglect'.[1] Radiation prevents the conversion of precursor cells to bone forming cells. Once NHO is established, radiation therapy is said to be ineffective but may have role in preventing recurrence after surgery.[1],[5] Surgical removal of the ectopic bone tissue is indicated only after six months of conservative therapy and is often a difficult procedure. It is contraindicated if there is any clinical or laboratory evidence (raised ESR and SAP level) of active NHO. In conclusion, this report highlights the occurrence of NHO in a variety of neurological and neurosurgical disorders in a rehabilitation setting. Unsupervised vigorous exercises may contribute to the formation of NHO. Lack of awareness and absence of pain due to primary neurological disorder account for delay in the diagnosis. Once, fully formed, there is no effective treatment. Thus, unexplained swelling or reduction in ROM of joints of paretic limbs, rapid ESR and elevated SAP levels should warrant a search for HO. Treatment includes rest to the affected limb in acute phase and indomethacin and diphosphonates till signs of inflammation subside and ESR and SAP levels return to normal. Early detection and prompt intervention are essential for disability limitation.
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