BRAIN INJURY, 2003, VOL. 17, NO. 6, 535–544 Case study Acquired heterotopic ossification in the settings of cerebral anoxia and alternative therapy: two cases Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. KAREN S. G. CHUA and K. H. KONG Department of Rehabilitation Medicine, Tan Tock Seng Hospital, Republic of Singapore (Received 25 February 2002; accepted 7 June 2002 ) Acquired Heterotopic Ossification (HO) has been well described in the literature as a recognized complication following spinal cord injury, traumatic brain injury and joint arthroplasty. Commonly, large proximal limb joints are affected. The underlying mechanisms for ectopic bone formation remain poorly elucidated. Post-stroke hemiplegia as a cause of neurogenic HO is rare, and no published reports of HO occurring after anoxic brain injury in adults have been documented. This study reports two unusual cases of acquired HO: (1) Polyarticular HO involving the ankle joint in a 24-year-old Chinese female who suffered severe anoxic encephalopathy following near drowning which resulted in persistent vegetative state; and (2) Elbow HO in chronic post-stroke hemiplegia occurring as a complication of alternative therapy following repeated forceful manipulation by a traditional practitioner in a 46 year-old male. Introduction Acquired Heterotopic Ossification (HO) is a recognized complication of various traumatic aetiologies such as spinal cord injury (SCI), traumatic brain injury (TBI), burns, surgical resection and joint arthroplasty. The incidence, sites and clinical presentation of HO in SCI and TBI have been extensively documented in the literature [1, 2]. Commonly, proximal limb regions and major joints such as the hips, shoulders, pelvis, elbows and knees are involved, typically below the level of lesion in those with SCI. Reported incidences range from 16–53% after SCI and 11–70% after TBI depending on diagnostic methods used [1–3]. Three-to-10% of patients with HO may develop severe functional limitations and joint ankylosis [1–4]. There remains no uniform agreement on the aetiology or pathogenesis of HO. The transformation of primitive mesenchymal cells in connective tissue into osteoblastic tissue and osteoid involve diverse and poorly elucidated triggers, ranging from bone morphogenic proteins, human skeletal growth factors to genetic, neurological and traumatic factors. The presence of limb spasticity, fracture, infection and pressure sores are generally believed to increase the likelihood of development of HO [1, 2]. Correspondence to: Dr Karen S. G. Chua, Department of Rehabilitation Medicine, Tan Tock Seng Hospital, Singapore, 17, Ang Mo Kio Ave 9, Singapore 569766, Republic of Singapore. e-mail: karen_chua@ttsh.com.sg Brain Injury ISSN 0269–9052 print/ISSN 1362–301X online # 2003 Taylor & Francis Ltd http://www.tandf.co.uk/journals DOI: 10.1080/0269905021000010104 K. S. G. Chua and K. H. Kong Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. 536 Non-traumatic HO occurring after stroke, cerebral anoxia or myelopathy is uncommon [5]. HO occurring after stroke is rare, with only three published cases in the literature over the past 20 years [5–7]. It is likely that post-stroke HO may be an under-diagnosed entity because of the challenges of diagnosis in stroke due to other causes of pain and the presence of multiple impairments, which may confound diagnosis of this condition. HO occurring after cerebral anoxia in adults has so far not been reported, although a higher incidence of HO in adolescent hypoxic brain-injured patients compared to the paediatric TBI population has been documented [8]. Distal joints are also uncommonly affected in HO from any cause [1]. This study reports two unusual presentations of HO: (1) polyarticular HO including the ankle joint in a 24 year-old Chinese female with severe anoxic encephalopathy resulting in persistent vegetative state (PVS) following near-drowning at 5 months post-injury and, (2) a 60-year-old Indian male who developed florid HO at 18 months post-stroke in the hemiplegic elbow following alternative therapy. It is believed these represent the first reports of HO in the settings of cerebral anoxia and alternative therapy. Case report (1) CSC, a 24 year-old Chinese female suffered severe anoxic encephalopathy following near drowning in Taiwan, Republic of China. She was asystolic on admission, with a Glasgow Coma Scale (GCS) score of 3/15. She was immediately intubated and ventilated. Her acute course was complicated by acute respiratory distress syndrome and recurrent pneumonia. Tracheostomy was performed on day 14 post-injury. She suffered late post-traumatic seizures and intractable cortical epileptiform myoclonus which were treated with Phenytoin and Sodium Valproate. She was weaned off ventilator at day 54 and transferred at 3 months post-injury to Singapore for continued management. Clinically, she remained vegetative, with tracheostomy and continuous nasogastric tube feeding. She had persistent low-grade fever (37.78C) with no known septic focus despite extensive investigations and transamintis secondary to Sodium Valproate and Phenytoin. CT scans of the brain, hepatobiliary ultrasound scans and lower limb Doppler ultrasound scans were all normal. Sodium Valproate was eventually discontinued with improvement in her transamintis and her myoclonic jerks resolved with administration of Clonazepam and high-dose Piracetam 4.8 g/day via nasogastric tube. A percutaneous endoscopic gastrostomy tube (PEG) was inserted on week 18, as she remained severely dysphagic. Her tracheostomy and urinary catheter were removed 1 week later. At 5 months post-injury, she was transferred to inpatient brain injury rehabilitation. She was Ranchos Los Amigos Scale (RLAS) level II consistent with PVS [9]. She had low-grade pyrexia of 388C and left optic atrophy. No visual fixation, tracking or visual threat response was present. Ophthalmologic assessment confirmed left ischaemic optic neuropathy and bilateral cortical blindness. She had mass startle responses and brief orienting responses to non-specific auditory stimuli. She was unable to obey commands or verbalize. She was tetraplegic with decerebrate posturing, totally dependent and incontinent of bladder and bowel. Spasticity of bilateral upper limb pronators, wrist and finger flexors (modified Ashworth scale Unusual presentations in neurogenic HO 537 Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. (MAS) grade 2) and MAS grade 3 in both hamstrings were present [10]. Bilateral heel cord plantar flexion contractures were present with extension lag of 158. At day 6 of rehabilitation (week 21 post-injury), spontaneous right ankle joint and forefoot redness, warmth and swelling were observed without restriction in range of motion (ROM). There was no decubitus ulceration. No other joints were clinically involved. Plain X-rays of the involved ankle joint were normal and a skeletal survey of the shoulders, elbows, pelvis, hips and knees revealed HO in both infero-medial aspects of the shoulders and left elbow (figure 1). Her leucocyte counts were normal, sedimentation rate was mildly elevated at 33 mm/hour and serum alkaline phosphatase level (SAP) was elevated at 229 IU/L (bone Figure 1. Radiographic evidence of HO involving the shoulder at 5 months post-anoxic PVS. 538 K. S. G. Chua and K. H. Kong Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. predominance), serum uric acid and rheumatoid factor were normal. Needle aspiration of the right ankle joint yielded a dry tap and blood and urine cultures were negative after 2 and 7 days. Triple phase bone scans confirmed scintigraphic evidence of HO in multiple joints—bilateral shoulders, left elbow, right hip, right knee, right ankle joint and right calcaneum. In particular, intense tracer uptake was present in the right ankle and both shoulder joints, with mild-to-moderate activity in the remaining involved joints (figure 2). Indomethacin 25 mg TID via PEG was instituted on day 6 of rehabilitation. Forty-eight hours later, her fever, ankle joint redness and swelling resolved completely. Etidronate Sodium at 20 mg/kg/body weight was started on day 10 of rehabilitation. She remained afebrile, and no clinical Figure 2. Triple-phase bone scan case showing increased uptake in multiple joints, especially right ankle joint after cerebral anoxia. Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. Unusual presentations in neurogenic HO 539 recurrence was noted over the next 5 weeks. SAP level at day 21 of rehabilitation decreased to 172 IU/L. She received bilateral lower limb serial casts for her heel cord contractures and intramuscular Dysport 500U (Botulinum toxin A) injections to bilateral distal upper extremities with good results. SAP level prior to discharge showed a decreasing trend to 145 IU/L. Etidronate was reduced to 10 mg/kg/body weight and Indomethacin was continued post-discharge. She was prescribed a custom-fitted wheelchair seating system with head support and pressure-relief cushion. She was discharged home in PVS at 28 weeks post-injury after 6 weeks of inpatient rehabilitation. At 8 months post-injury, there was minimal change in her functional and cognitive status and there was no clinical recurrence of HO in the right lower limb, SAP level was normal. Indomethacin was stopped and Etidronate continued for a further 3 months. Subsequent review at 1 year post-injury showed no clinical recurrence and SAP level was normal. Case report (2) KBM, a 60-year-old right-handed Indian male suffered acute hypertensive rightsided basal ganglia haemorrhage. Investigations revealed no secondary cause for his hypertension and young stroke. His GCS score was 7/15 on admission with dense left hemiplegia. Emergency sterotactic aspiration of the 60 cc intracerebral haematoma was performed on day 2 and he was transferred to inpatient stroke rehabilitation at day 25 post-stroke. On admission, he had reduced level of arousal, short attention span and severe cognitive impairment (abbreviated mental test score 2/10). Dense left flaccid hemiplegia (motor power 0/5 in the entire left side), left hemi-sensory loss, significant left hemi-spatial neglect and urinary incontinence were present. He was also dysarthric and dysphagic requiring feeding via a nasogastric tube. There was no language impairment. His rehabilitation course was complicated by aspiration pneumonia. After 4 weeks of rehabilitation, there was minimal motor recovery (upper limb motor power 0/5, lower limb motor power 1/5) and mild spasticity was present in the left wrist flexors and gastrocnemius (MAS 1). There was improvement in attention span and orientation, but severe hemispatial neglect persisted. Fibreoptic endoscopic evaluation of swallowing did not reveal silent aspiration, hence oral feeding was commenced without complications. His nasogastric tube was removed on day 55 post-stroke. Functionally, he required moderate-maximal assistance for transfers and activities of daily living and remained chair-bound. Modified Barthel scale scores (0–100) were 5 and 18 on admission and discharge, respectively [11]. He was discharged home on day 85 post-stroke after 8 weeks of inpatient rehabilitation. Community-based therapies were continued twice weekly for a further 3 months and cranioplasty was performed successfully at 5 months post-stroke. At 18 months post-stroke, he presented with left elbow swelling, tissue firmness, warmth, severe pain and fixed ankylosis at 908 of elbow flexion. There was no documented fever or other joint swelling. The patient revealed that, with the help of his wife, he had sought alternative treatment from a traditional practitioner over the past 8 months, as he was dissatisfied with the lack of functional recovery in his left upper limb. This consisted of forceful manipulation of the left upper limb, particularly the left elbow joint by the K. S. G. Chua and K. H. Kong 540 Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. practitioner for 60 minutes each time and repeated weekly. The hemiplegic lower limb was not manipulated. He reported severe pain and left elbow swelling after the second treatment session. Radiographs revealed HO in the left elbow joint with some degree of ankylosis. No fracture was observed (figure 3). Radiographs of the shoulder and wrist joints showed no ectopic bone formation. White cell counts were normal, ESR 15 mm/hour, SAP levels were elevated at 409 IU/L. Three-phase bone scan showed intense tracer uptake in the left elbow joint and to a lesser extent over the hemiplegic left shoulder, wrist and hip (figure 4). Oral Indomethacin was started at 50 mg PO TID, together with gentle passive range of motion exercises by a community-based physiotherapist; however, this was Figure 3. Radiograph of left elbow showing florid HO. Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. Unusual presentations in neurogenic HO Figure 4. 541 Scintigraphic evidence of intense HO activity in left elbow joint at 18 months post-stroke. poorly tolerated. The patient and family subsequently agreed to discontinue treatment with his traditional practitioner. Two weeks later, there was minimal reduction in pain and inflammation, but his range of motion had improved and 208 of passive elbow extension was permitted. Downward trend in SAP levels to 375 IU/L were noted. Oral Sodium Etidronate 1000 mg/day PO was added. Three months later (22 months post-stroke), the left elbow was cool and non-tender without swelling. Passive ROM from 90 to 708 flexion was permitted without pain. There was a further decrease in SAP levels to 248 IU/L and ESR was 10 mm/h. Indomethacin was reduced to 25 mg TDS and Sodium Etidronate was reduced to 600 mg/day for a further 3 months. Limited surgical resection of HO was planned when SAP levels normalized. K. S. G. Chua and K. H. Kong 542 Discussion Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. HO after cerebral anoxia HO occurring after cerebral anoxia in adults has not been reported in the published literature. The causal relationship between neurogenic HO and cerebral anoxia is unknown. In addition, involvement of a distal joint such as the ankle or foot in HO is also rare. Traumatic and inflammatory aetiologies were unlikely in this patient in view of absent history of trauma, normal serology and negative bacteriology. As her initial ankle radiographs showed no evidence of ectopic bone formation, the diagnosis of RSD was also considered prior to scintigraphic confirmation of HO. RSD involving the lower limb has been reported previously but not following stroke or anoxia [12, 13]. Her profound cognitive disability made an objective assessment of the presence of neuropathic pain impossible, although this may have aided the diagnosis of RSD. Elevated SAP levels with bone predominance favoured the diagnosis of HO rather than RSD. Her rapid clinical response, resolution of pyrexia which was thought to be related to HO, and normalization of SAP levels with Indomethacin and Etidronate were consistent with HO. It is likely that HO may be misdiagnosed or missed in anoxic PVS patients due to profound cognitive impairment, perceived poor overall functional prognosis beyond 3 months and frequent post-acute discharge placement in nursing homes where medical screening and vigilance may be sub-optimal. Post-stroke HO Taly et al. [5], in a prospective study of 377 patients with various neurological insults, found an incidence of 4% of HO in non-traumatic neurological disorders in a rehabilitation setting. Of these, 13.3% (2/15) were due to stroke, with diagnoses made using radiography, CT scans and three-phase bone scans. Hajek [6] and Baron et al. [7] reported single case reports of post-stroke HO occurring in the acute (less than 3 months) phase of stroke. It is likely that HO following stroke remains an under-diagnosed entity and may not be as rare as thought due to several factors. First, the presence of other causes of pain such as co-morbid degenerative arthritis, soft-tissue pain, deep venous thrombosis, focal spasticity, dysesthesia, neuropathic pain and RSD frequently coexist in stroke, and may confound the clinical picture and diagnosis of HO. Secondly, impairments such as severe aphasia, cognitive impairment, hemi-spatial neglect and sensory loss may add to the difficulties in making a correct diagnosis. Hence, a high index of clinical suspicion is needed to diagnose and differentiate HO from other painful limb conditions in stroke. The second case of HO was atypical in its late presentation at more than 1 year post-stroke and underlying aetiology. The onset of HO, regardless of aetiology, generally ranges from 4–12 weeks, with a peak occurrence at 2 months [1]. Alternative therapy as a precipitating cause of HO has never been described in the literature, and this was the main contributing factor in this patient, through athrogenic pathways secondary to forceful manipulation. Subsequent microtrauma to the joint and/or peri-articular tissues or stress fractures could pre-dispose the development of Myositis Ossificans (MO) and HO. Brain Inj Downloaded from informahealthcare.com by Nyu Medical Center on 06/23/15 For personal use only. Unusual presentations in neurogenic HO 543 The scintigraphic activity observed in the hemiplegic shoulder, hip and contralateral knee were most likely caused by degenerative changes rather than neurogenic HO foci, as there was no new neurological event and KBM was already 18 months post-stroke. Ectopic bone was not demonstrated in the shoulder radiographs. The causal relationship between forceful manipulation and the development of HO in humans remains controversial. While histological studies in rabbits have shown that HO and MO occurred within 2–5 weeks following forcible passive exercise of immobilized limbs, this model represents traumatic HO rather than modification of neurogenic HO pathways through manipulation [1, 14]. However, similar pathologic findings have not been reported in humans. Forceful joint manipulations have also been reported as successful treatment modalities in TBI patients with HO causing severe functional limitations and bony ankylosis [15]. Garland’s series of 28 HO joints in 16 TBI adults reported postoperative sustained gains in joint ROM in 64% of joints and no exacerbation of the HO process despite multiple manipulations [15]. Conclusion HO after anoxia and stroke are rare and may pose diagnostic difficulties in those with profound cognitive and physical disabilities. The exact pathophysiologic mechanisms for HO in these settings remain poorly elucidated. A high index of clinical suspicion, and investigations such as radiographs, scintigraphy and metabolic tests may aid diagnosis. Early treatment may minimize further functional disability caused by HO-related joint pain and ankylosis. The role of forceful manipulation in the causation and development of HO warrants further research. It is recommended that HO be considered as a differential diagnosis in those with stroke or cerebral anoxia presenting with spontaneous joint pain or swelling. In the authors’ local population, where patients concurrently use both conventional and traditional treatments after stroke; often without the knowledge of their primary care physicians, complications relating to the use of complementary therapies should routinely be looked for. References 1. G ARLAND, D. E.: A clinical perspective on common forms of acquired heterotopic ossification. Clinical Orthopedics, 263: 13–29, 1991. 2. S TOVER, S. L.: Heterotopic ossification after spinal cord injury. In: R. 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