Heterotopic Ossification: A Rare Complication in Guillain-Barré Syndrome
Elia Coppens* MD, Ammar Kassouha MD, Armin Schnider PhD, Béatrice Leemann MD
Department of Clinical Neurosciences, Geneva University Hospital, Switzerland
Neurogenic Heterotopic Ossification (HO) as a complication of central nervous system lesions, traumatic brain injury (TBI) or spinal cord injury (SCI) has been well documented. Only rarely has it been described in disorders of the peripheral nervous system, such as Guillain-Barré Syndrome (GBS). This case report presents a 63-year-old man who’s delayed diagnosis showed intermediate phase HO, 4 months after onset of GBS. The patient’s participation in therapy and activities of daily life were severely altered by pain and associated decreased range of motion of both hips. In the absence of a positive response to NSAID, physiotherapy and opïoids, a single-dose radiotherapy of 7 Gy for antalgic purposes was applied with favorable effects on pain, followed by functional improvement. Following our observations and a literature review, causative factors, physiopathology, clinical presentation and treatment options will be discussed.
Keywords: Heterotopic Ossification; Guillain-Barré Syndrome; Pain Treatment; Rehabilitation
HO: Heterotopic Ossification;
GBS: Guillain-Barré syndrome;
SCI: Spinal Cord Injury;
TBI:Traumatic Brain Injury;
THA: Total Hip Arthroplasty;
MRC: Medical Research Council Scale;
VAS: Visual Analogue Scale;
PROM: Passive Range of Motion;
FIM: Functional Independence Measure Scale;
ADL: Activities of Daily Living ;
BMP-4: Bone Morphogenetic Protein 4;
NSAID: Non-Steroidal Anti-Inflammatory Drug;
PgE: Prostaglandin E;
MRI: Magnetic Resonance Imaging;
SPECT: Single-Photon Emission Computed Tomography;
CT: X-ray Computed Tomography
A 63-year-old man, diagnosed with severe axonal and myelinic Guillain-Barré Syndrome (GBS), was initially hospitalized 45 days in the intensive care unit where a tracheotomy was performed for respiratory assistance. Antiganglioside antibodies test returned positive. The patient was treated with intravenous immunoglobulin during a period of 5 days, followed by 5 cures of plasmapheresis, before being transferred to the general medicine department. An anticoagulant treatment was also introduced to treat a pulmonary embolism, a secondary complication. Four months after the onset of the disease, respiratory independence and swallowing function were restored, but limb paresis persisted (Medical Research Council scale (MRC) M2 in the lower limbs and M4 in the upper limbs) and the patient was referred to our inpatient neurorehabilitation unit. At admission, the patient presented significant mechanical and inflammatory pain in both hips, distinct from existing neurogenic pain. The pain was reported to vary from 4 to 7 on the Visual Analogue Scale (VAS). Passive range of motion (PROM) of both his hip joints was severely diminished by pain and the sitting position was limited to a few minutes daily in an inclined comfort wheel-chair. The Functional Independence Measure scale (FIM®) revealed a score of 56 out of 126 points, compatible with a level of moderate to total assistance. The pain was moderately responsive to antalgic treatments such as fentanyl transdermal patch in combination with hydromorphone. Plain radiographs of the pelvis showed bilateral heterotopicossifications of the hip joints, compatible with Brooker’s class III on the left hip and class IV on the right hip. Serum alkaline phosphatase levels were dosed at 269 U/l (N: 30- 125), calcium levels were normal. A SPECT-CT scan fused with Tc99m-MDP bone scintigraphy (Figure 1) showed abnormal activity predominantly at the right hip, extending from the acetabulum to the trochanter, compatible with active heterotopic ossification. A daily treatment with 75 mg of Indomethacine was introduced but had to be interrupted because of adverse effects. A local para-articular infiltration of the right hip with 10cc of lidocain 1% did not bring any relief. Looking for alternative pain treatment options, we performed a MEDLINE literature search and found one case report  in which pain due to intermediate HO was treated with radiotherapy in a Spinal cord injury (SCI) patient, using a total of 20 Gy. In order to limit potential radiation-induced complications, we chose to apply a dose of 7 Gy, as used in total hip arthroplasty (THA) prophylaxis protocols [2,3], 2 months after diagnosis of intermediate phase HO. No adverse effects were observed. Clinical response was favorable, with VAS – scores, ranging from 0 to 4, one week after therapy. We noted an improvement in the PROM of both hip joints making it possible for the patient to maintain a sitting position for several hours daily. At two weeks post radiotherapy, gait rehabilitation permitted mobilization with a two-wheel walker for a distance of 35 meters. Overall improvements of ADL’s were reflected in FIM®-scores evaluated at 86 out of 126 points revealing a level of moderate assistance. Serum alkaline phosphatase levels after radiotherapy were at 96 U/l.
Figure 1.Anterio-posterior 3D reconstruction of SPECT/CT fused with bone scintigraphy showing metabolic active hetereotopic ossification (red) para-articularly to the hip joint, touching muscles and ligaments in a patient with GBS.
Heterotopic Ossification (HO) is the process of mature osseous growth in the soft tissue, usually para-articularly. It often occurs as a complication of neurological disorders such as spinal cord injury and traumatic brain injury, but is rarely described in acute peripheral nerve diseases, like Guillain-Barré Syndrome [4-6]. The pathophysiology of HO remains unclear. In GBS patients, like in this case, associated factors such as prolonged immobilization, respiratory assistance, prolonged intensive care and severe axonal lesions are documented [4-6]. However, development of HO appears to require other factor(s) such as genetic, metabolic, trophic or neurohumoral factors [6,7]. Inflammation appears to play a role as prostaglandin is thought to be involved in the upregulation of osteogenic growth factors, such as bone morphogenetic protein 4 (BMP-4), which in turn regulates differentiation of mesenchymal cells into osteoblasts .
HO’s evolution resembles closely to normotopic osteogenesis, and follows predictable stages of maturation . Mainstay prophylactic and treatment options are NSAIDS, physiotherapy, bisposphates and radiotherapy, but their efficiency depends largely on the time of administration: NSAIDs administered in the early stage, have been shown to prevent HO by blocking PgE synthesis . Bisphosphonates are believed to inhibit the mineralization of organic osteoid and so can halt HO progression only when bone lesions are immature, and thus invisible on conventional radiographs. Therefore, early identification is mandatory when clinical suspicion arises. Sonography and Nuclear bone scans have been assessed for early diagnosis prior to radiographic evidence of HO[7,8]. MRI appears to be the most sensitive technique for identifying small early lesions, but may be nonspecific.
In this patient, the poor clinical response to NSAIDS could be explained by an advanced state of HO and early interruption of treatment due to adverse effects. Gentle physical therapy, known to preserve movement and prevent ankylosis , was in this case limited due to refractory pain. Surgery was not desirable in this patient with active intermediate HO, in the absence of neurovascular complications like thrombophlebitis, nerve entrapment, or severe mechanical limitations of the hip joints. We were surprised by the fast impact of radiotherapy on pain control and the associated significant functional improvements. Radiotherapy is generally believed to inhibit mesenchymal cell differentiation, hence halting the ossification process. On the other hand, radiotherapy is well known to decrease pain associated with the inflammatory reaction, as found in active HO . Further research should be performed to differentiate these positive findings from a placebo effect. Interestingly, serum alkaline phosphatase levels after radiotherapy were diminished in this patient, but a nuclear bone scan performed 1 month after radiotherapy showed persistent abnormal activity in both hip joints, confirming that normalization of serum alkaline phosphatase levels does not correlate with maturation of HO .
This case is atypical, as HO remains a rare complication in GBS patients. When facing limited treatment options such as in this case, we found it important to share our findings for documentation and future reference. However, early diagnosis remains mandatory, allowing access to conventional treatment options with optimal effects, hence limiting possible long-lasting functional disabilities. Therefore, physicians should keep the diagnosis of HO in mind when severe GBS patients complain of decreased ROM and joint pain.
We thank Gaël AMZALAG of the Department of Nuclear Medicine, HUG, for 3D reconstruction of SPECT/CT fused with bone scintigraphy (Figure 1).
Cite this article: Coppens E, Kassouha A, Schnider A, Leemann B. Heterotopic Ossification: A Rare Complication in Guillain-Barré Syndrome. J J Physical Rehab Med. 2015, 1(4): 018.