A novel treatment strategy with hyperbaric oxygen of chronic osteomyelitis and pseudoarthrosis in a child with congenital hereditary sensory and autonomic neuropathy type 4 congenital insensitivity to pain with anhidrosis syndrome: a case report

Initial presentation and deformity

A 7-year-old girl of Kurdish ethnicity, with no previous family history of genetic disorders, was diagnosed with HSAN IV CIPA at the age of 5 years. The diagnosis was originally suspected as the child did not notice multiple minor injuries. She was born and raised in Sweden within a well-functioning family, developed intellectually normally until the age of 6 years, and investigation revealed no other medical or dental history related to any other illness. She presented in March 2016 to the orthopedic emergency department (ED) with a left proximal tibial Salter-Harris II fracture with minimal displacement. She had previously been treated for soft tissue infections and metatarsal fractures, and had continuous clindamycin 150 mg three times daily (TID) per oral prophylaxis. On admission, her general appearance was normal, she was afebrile with normal pulse, blood pressure, and respiratory rate. The knee and lower leg were swollen. She showed some discomfort on palpation but was unable to stand. The parents were not aware of any specific trauma as the cause for the fracture. Blood tests, including C-reactive protein (CRP) and white blood cell (WBC) count, were normal.

Initial cast treatment of the left tibia fracture resulted in a 20° varus deformity of the tibia after 1 week, likely owing to the patient’s inability to restrict weight bearing.

To avoid further displacement, closed reduction and percutaneous pin fixation were attempted. However, 3 weeks after surgery the patient was hospitalized again owing to septic osteomyelitis of the fracture and septic arthritis in the left knee. The pins were subsequently removed, the arthritis drained, and intravenous antibiotics treatment was commenced (Fig. 1A). Along with renewed cast immobilization (and subsequent orthosis) the fracture eventually healed after 1 year. However, the healed fracture did result in a medial slope in the tibial physis, a varus deformity of 30°, and leg length discrepancy (Fig. 1B). Owing to this deformity, the patient had difficulty walking and was mostly confined to a wheelchair.

Reconstructive ambitions

Despite the well-known risk of complications, a multidisciplinary decision was made to attempt surgical correction of the deformity in the hope of allowing the patient to remain ambulatory. In April 2019, the patient underwent a reconstruction of the left medial femur condyle with a chevron osteotomy and a temporary lateral physiodesis. The combined surgery slowed the progression of varus deformity, but it did not sufficiently improve the patient’s persistent deformity and ability to walk. In August 2022, a second surgical correction with a high tibial osteotomy was performed. The osteotomy was stabilized with a total of four percutaneous pins (Fig. 2A). A wound swab on 1 September showed mixed Gram-negative flora susceptible to clindamycin. A follow-up in October 2022 revealed no signs of healing despite the osteotomy remaining in place. In November 2022 a superficial pin infection was noted, and there were still no signs of healing on the radiographs.

Residual pseudoarthrosis and osteomyelitis

In January 2023, the pins were removed in the operating room, but the osteotomy remained unstable and was stabilized with an intramedullary titanium elastic nail (Fig. 2B), and 2 weeks later the patient presented again at the ED with a suspected osteomyelitis and wound infection around the nail entry point. A wound swab on 31 January showed Gram-negative mix, susceptible to clindamycin. Cefotaxime 2 g three times a day intravenously, clindamycin 600 mg three times a day intravenously, and vancomycin 1.24 g three times a day intravenously was initiated for 7 days followed by continued clindamycin prophylaxis orally. In February 2023, radiographs confirmed a chronic pseudoarthrosis and no signs of healing of the osteomyelitis.

In an attempt to promote healing, the patient underwent an extraction of the nail, open debridement, and implantation of CERAMENT^® V with vancomycin (Bonesupport AB, Lund, Sweden) in March 2023 (Fig. 3). Tissue samples from the debridement on 27 March revealed growth of Corynebacterium species susceptible to linezolid, therefore, linezolid 600 mg twice daily intravenously was added to the treatment regimen and continued for 4 weeks. A wound swab on 6 April was negative.

HBOT

Despite the previous surgical and antibacterial treatment, a follow-up computed tomography (CT) scan in July 2023 showed limited signs of bony healing, and the tibia was not stable to manual manipulation. A multidisciplinary decision was made to attempt HBOT. The treatment was commenced in July 2023. HBOT treatment was undertaken in July–August 2023 with 40 treatments, 5 days a week, 100% oxygen at 2.4 bar, 113 minutes with two air breaks in a multiplace chamber.

SPECT/CT and MRI

Single-photon emission computed tomography (SPECT)/CT and magnetic resonance imaging (MRI) of the lower limbs were performed before and after the HBOT, approximately 5 months apart.

Outcome

In October 2023, imaging with SPECT/CT and MRI confirmed a completely healed osteotomy and no signs of osteomyelitis. The SPECT/CT revealed slightly decreased perfusion in the affected tibia after HBOT, which can be expected with a healed infection (Fig. 4). The patient was allowed to weight-bear with support. At 1-year follow-up, in January 2024, the patient showed no clinical signs of infection and was able to walk short distances indoors with support. The alignment obtained by the corrective osteotomy had been maintained.

Interpretation of treatment and results

In this case, with a persistent pseudoarthrosis that was recurrently infected, multiple treatment modalities were used in conjunction. It can thus not be known whether the HBOT treatment was the main factor for healing. The surgery, the CERAMENT^®V, and the antibiotic regimen could be equally or more important. The HBOT treatment did, however, correlate in time with healing (Fig. 5). The HBOT treatment was well tolerated by the child and no adverse effects were noted.

Physiological and pharmacological aspects of HBOT for patients with CIPA

The decision to attempt HBOT was based on the established benefits for osteomyelitis in general, and the theoretical benefits for CIPA specifically. HBOT has a number of theoretical positive effects on patients with CIPA. HBOT is an established adjuvant treatment in both acute and chronic infections, with distinct effects on the innate immune system [24, 25]. Dysfunction and apoptosis in nerve cells can explain some of the features involved in the syndrome but the complex interplay between the nervous system, stem cell-activation, and immune response is far from understood [26]. However, it has been shown that communication between sensory nerves and osteoblasts through NGFβ–TrkA signaling is essential for load-induced bone formation in mice [27], and inhibition of NGFβ-TrkA signaling negatively regulates aberrant stem cell differentiation, and causes a delay in cartilage and bone formation [28]. HBOT has been shown to be effective for bone healing in a small randomized controlled trial (RCT) with patients suffering from femoral head necrosis (FHN) [29]. A suggested mechanism, derived from the RCT, is the activation of osteoclasts through osteoprotegerin (OPG), the receptor activator of NF-kB ligand (RANKL), and the receptor activator of NF-kB (RANK) systems [30]. NGFβ–TrkA signaling is crucial for macrophage signaling and neutrophil migration, which may explain the increased susceptibility to S. aureus infections in patients with CIPA [31, 32]. HBOT has also been shown to affect various parts of the integrated stress response (ISR), including the unfolded protein response (UPR) and the DNA damage response (DDR) [33, 34]. Since TrkA has such a wide array of intracellular functions in various cells, we speculate that an unspecific modulator of ISR may serve as a bypass mechanism of NGFβ that has a positive effect on the innate immune function and bone formation. NGF and HBOT have also been shown to improve learning, memory ability, and sensory motor function in neonatal rats after hypoxic ischemic brain damage [35]. HBOT has also been shown to reduce neuroinflammation and protect mitochondrial function, consequently preventing neuronal apoptosis in a murine model [36]. It would therefore be highly interesting to test HBOT in an animal model with a TrkA mutation to explore whether there is also a possible effect on neuronal function that could prevent or delay the inevitable complications of this extremely rare but devastating hereditary disease.

Imaging with SPECT/CT and MRI in patients with CIPA

(^99mTc)-tetrofosmin is a radiopharmaceutical, commonly used for mapping myocardial perfusion, but the method can also be used to image osteomyelitis in extremities [37]. SPECT/CT increases the accuracy in the diagnose of osteomyelitis compared with planar SPECT [38]. MRI is useful in the diagnosis and follow-up of osteomyelitis because of its high sensitivity and availability. To increase the specificity for osteomyelitis, fluid-sensitive sequences including short-tau inversion recovery (STIR) sequences are particularly useful. In STIR sequences, the signal from fat is decreased, increasing the visibility of inflammatory changes and fluid collections [39].

Ethics approval and consent to participate

The Sahlgrenska University Hospital Ethical Board reviewed and approved the project, given written informed consent by the parents and child.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. The child was also orally informed with separate information, adjusted for the age of the child. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no potential competing interests and no financial support for the research, authorship, and/or publication of this article.