Neurogenic heterotopic ossification : a diagnostic and therapeutic challenge in neurorehabilitation.

AB Taly, KP Nair, PN Jayakumar, D Ravishankar, PL Kalaivani, B Indiradevi, T Murali 
 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560029, India., India

Correspondence Address:
A B Taly
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560029, India.
India

Full Text

::   Introduction

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.

::   Material and methods

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.

::   Results

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.

::   Discussion

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.

References