|Year : 2011 | Volume
| Issue : 3 | Page : 101-108
Surgical management of Pott's disease of the spine in pediatric patients: A single surgeon's experience of 8 years in a tertiary care center
R Kumar, AK Srivastava, RK Tiwari
Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||10-Oct-2011|
Head of the Department, Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Study Design: A retrospective, case study of 64 pediatric patients who underwent spinal surgery for Pott's spine and have minimum 6 months follow-up. Objective: The aim of this study was to evaluate the surgical management and outcome of 64 pediatric Pott's spine cases operated by single surgeon over last 8 years, with a minimum follow-up of 6 months. The prognostic significance and the outcome of the demographic factors, location of the disease, and its surgical approach were also evaluated in these patients. Materials and Methods: The data collected retrospectively from the institute's record case sheets of the 64 pediatric patients with Pott's disease of the spine, operated between 2002 and 2010 in the Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, were analyzed. The study population consisted of 40 male and 24 female pediatric patients. Clinical findings included back pain, paraparesis, kyphosis, fever, sensory disturbance, and bowel and bladder dysfunction. Results: The most common region of Pott's disease was the thoracic region [21/64 (33%)] followed by craniovertebral junction (CVJ) [17/64 (27%)]. At presentation, all of the patients had neurological features of spinal cord compression. All patients were treated with antituberculous chemotherapy which was continued after the surgical intervention also. Transthoracic surgical approach [18/64 (28%)] was the most frequently required surgery followed by transoral decompression with posterior fusion [12/64 (19%)] depending on the site of disease and compression of neuraxis. Initially, more than two-third of the patients were in poor grade of Kumar and Kalra scoring as well as modified Kumar and Kalra scoring, which were reduced to about one fifth after the surgical intervention, and the outcome was good as the condition of 46 patients (72%) improved significantly. Conclusion: Currently, treatment of spinal tubercular infections requires a multidisciplinary team that includes infectious diseases experts, neuroradiologists, and spine surgeons. The key to successful management is early detection and timely and judicious surgical intervention, the decision of which needs to be taken in view of clinicoradiological compression of the spinal cord and nerve roots, age of the patient and responsiveness of ATT.
Keywords: Pediatric Pott′s spine, Pott′s spine, surgical intervention in pediatric Pott′s spine
|How to cite this article:|
Kumar R, Srivastava A K, Tiwari R K. Surgical management of Pott's disease of the spine in pediatric patients: A single surgeon's experience of 8 years in a tertiary care center. J Pediatr Neurosci 2011;6, Suppl S1:101-8
|How to cite this URL:|
Kumar R, Srivastava A K, Tiwari R K. Surgical management of Pott's disease of the spine in pediatric patients: A single surgeon's experience of 8 years in a tertiary care center. J Pediatr Neurosci [serial online] 2011 [cited 2023 Feb 7];6, Suppl S1:101-8. Available from: https://www.pediatricneurosciences.com/text.asp?2011/6/3/101/85726
| Introduction|| |
Pott's disease is the most common form of skeletal tuberculosis (TB) in developing world and constitutes 1-3% of all cases of TB. ,, It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis and that each year, about 9 million people develop any form of TB, of which about 2 million die. About 1 million (11%) of this 9 million annual tubercular cases are children under 15 years of age. Three-fourth of these childhood cases occurs annually in 22 high burden countries that together account for 80% of the world's estimated incident cases.  One-fifth to one-fourth of these TB cases reside in India.
The Pott's disease of spine is usually secondary to pulmonary or abdominal TB as 10% of the extra pulmonary TB patients report skeletal involvement and about half of these patients develop infection within the spinal column. But sometimes Pott's disease itself may be the first manifestation of the TB.  Despite this huge disease burden, children's access to anti-tuberculosis treatment in most endemic areas remains poor, as our national TB control programs focus mainly on the treatment of sputum smear-positive adults. 
Pott's disease of spine is the most dangerous form of skeletal TB as it may lead to bone destruction, deformity, and paraplegia.  It usually develops when the local immune responses of the host are compromised or overwhelmed by the tubercular bacilli. The different anatomical locations where this process can occur include vertebrae, intervertebral disc space, along the spinal axis, epidural or intradural space within the spinal canal, and adjacent soft tissues. The most frequent site of spinal TB is the thoracolumbar junction. The incidence decreases above and below this level. Back pain, fever, weakness, weight loss, fatigue, and malaise in addition to the varying neurological manifestations and paraparesis of varying severity depending upon the location are the usual symptoms of the disease. The role of surgery in Pott's disease of the spine is still debatable. The surgical intervention is usually considered when there is severe spinal instability or progressive neurological symptoms accompanied with evidence of cord compression or deformation. , The advent of magnetic resonance imaging (MRI) has helped a lot in the early detection and more precise localization of lesion,  but the things are still not clear as to when conservative management alone is the choice of treatment for Pott's disease and when the surgical intervention is needed for better outcome.
The aim of most of the surgeries was directed toward post-tubercular deformity, but recently, aggressive management by different approaches has been taken to alleviate compression even in active disease. ,, The first attempt at surgical management was laminectomy;  however, because of its failure to address the anterior component of the disease process and the frequent complication of postoperative spinal instability, it is superseded by other approaches. Posterior fusion technique that drastically reduces the kyphotic deformity was a good choice, but associated extensive preoperative infection and pronounced kyphosis often catapulted in fusion failure.
Hodgson and Stock later used an anterior approach with great success.  This surgical approach is gaining ground in many cases. Surgery done during the active course of the disease is safer and the response is faster and better than when it is performed after the disease has been cured.  Moreover, the importance of early diagnosis, start of appropriate treatment and its continuation for adequate duration along with the proper counseling of the patient and family members with the timely surgical intervention is the key for the success in achieving a good outcome. ,
| Aims and Objectives|| |
The aim of this study was to evaluate the surgical management of pediatric patients with Pott's disease operated by single surgeon over last 8 years with at least 6 months of follow-up of each case. The prognostic significance and the outcome of the demographic factors, location of the disease, and the choice of the surgical intervention in these patients were also evaluated.
| Materials and Methods|| |
A retrospective review of 74 pediatric patients of Pott's disease of spine, who underwent surgical intervention by single surgeon due to various reasons between 2002 and 2010, was done in the Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, a tertiary care center. Data of 64 patients were included in the study, who had been followed at least for 6 months as 10 patients who either lost to follow-up or had inadequate record/follow-up were excluded. Demographic details like age and sex of the patients to correlate with their prognostic outcome were obtained. Their general condition with neurological signs and symptoms were noted. The onsets of cord involvement and neurological compromise, duration of symptoms, the degree of cord compression were also obtained. All the patients had received anti-tubercular therapy preoperatively or postoperatively as per the protocol, following or along with surgery. Four-drug regimen (RHEZ) for at least 4-6 weeks to gauge the response was given (10-20 mg/kg/day rifampicin, 10-20 mg/kg/day isoniazid, and 15 mg/kg/day ethambutol in a single daily dose; and pyrazinamide 20-35 mg/kg/day in two divided doses). If the patient showed improvement, the drug therapy was continued for 18-24 months. In cases of no improvements or hepatotoxicity, the patients were switched to modified antitubercular treatment (ATT) with the addition of ofloxacin and streptomycin and modification of doses of isoniazid and rifampicin or discontinuation of them.
The location and the site of the lesion as well as the surgical approach toward the lesion were also obtained. Pre- and postoperative Kumar and Kalra clinical scoring system  was applied to analyze the outcome of the patient of craniovertebral junction (CVJ) and modified Kumar and Kalra clinical scoring system (unpublished data) was applied for rest of the spine as breathing is spared in rest of spine. This was excluded while evaluating myelopathy other than high cervical myelopathy caused by CVJ Pott's spine.
Kumar and Kalra scoring system
Kumar and Kalra clinical scoring system was applied to analyze the outcome of the patient while evaluating high cervical myelopathy of CVJ involvement.
Grading as the maximum score is 30 in CVJ involvement:
Grade 1: 25-30
Grade 2: 19-24
Grade 3: 13-18
Grade 4: <13
Modified Kumar and Kalra scoring system
As breathing is spared in the spinal involvement other than CVJ Pott's spine, this was excluded while evaluating myelopathy.
Grading as the maximum score is 25 in view of sparing of respiration:
Grade 1: 21-25
Grade 2: 16-20
Grade 3: 11-15
Grade 4: <11
| Results|| |
The majority of the patients were males [n = 40 (~63%)] in their second decade of their life and the distribution was nearly 3:1 between males and females, with male preponderance [Table 1] [Chart 1].
Most of the pediatric Pott's spine cases (35) were seen in their first decade of life [n = 64 (~55%)] while 29 cases were more than 10 years of age (~45%) [Table 2].
Most of the signs and symptoms were attributed to the localization of the lesion in addition to the constitutional symptoms, if any. Distribution and frequency of the pain in the concerned region, motor and sensory loss as per the disease site and status and autonomic involvements were as given in [Table 3].
Location of the lesion
Twenty-one out of 64 patients had the involvement of thoracic spines (~28%) while 17 patients had the involvement of CVJ (~27%). Ten patients had the lesion in their thoracolumbar region (~16%) while 6 patients each had the lesion in their cervical and lumbosacral regions (~9% each). Four patients had cervicothoracic involvements (~6%) [Table 4] [Chart 2].
There were 17 (~27%) cases of CVJ lesion, out of which transoral approach with posterior fusion was done in 12 patients (~19%) while the remaining 5 cases (~8%) were treated with posterior fusion only. All the 6 cases (~9%) of cervical lesion were treated by cervical laminectomy. All the 4 cases (~6%) of cervicothoracic lesion were treated with transmanubrial approach. There were 21 cases (~33%) of thoracic lesion out of which 18 cases (~28%) were operated by transthoracic approach while the remaining 3 cases were managed with posterolateral approach. There were 10 cases (~16%) of thoracolumbar lesion out of which 7 cases were treated with posterolateral approach, 2 cases were operated by the retroperitoneal approach while 1 case was managed with laminectomy. We had six cases (~9%) of lumbosacral region out of which four were managed by laminectomy and two cases by retroperitoneal approach. All the approaches were decided depending upon
[Table 5] shows the individual treatment approach to the patients [Chart 3].
- site of maximum compression;
- involvement of bony element and soft tissue inflammation/abscess;
- maximum clinical involvement of tracts (anterior, posterior or lateral) and
- stability of spine.
Most of the patients included were of poor grade; with 32 (14%) and 12 (36%) patients in preoperative grade 3 and grade 4, respectively. There were only 8 and 12 patients who presented in grade 1 and grade 2, respectively. Forty-six of the included patients had improvement or stabilization of their disease process and only two patients showed deterioration in their grades. The improvement was chiefly seen in CVJ and cervicothoracic patients.
At the last follow-up visit (mean follow-up: 9.2, range 6-12 months), the majority of patients (n = 51) were in grades 1 or 2 and only 13 patients were in grades 3 or 4 [Table 6]a.
As far as the outcome of the patient is concerned, after the surgical intervention, 46 subjects (~72%) improved to better grades while 18 subjects (~28%) remained either stationary or even worse [Table 6]b [Chart 4].
| Discussion|| |
As we are one of the developing countries and the disease is associated with poor socioeconomic strata due to variety of reasons, the burden of the disease is really high in our country. As we are concerned about the pediatric population, the stakes are also really high because of morbidity associated with it.
While reviewing this important issue, we searched PUBMED for the Indian context where the text regarding the surgical intervention in Indian pediatric population was very limited.
Sharing our experience, most of the cases in our setup were seen in the first decade of the life [n = 35 (55%), age range = 5-15 years] and only 25% were seen after 20 years of age, quite paradoxical to the western figures which show higher involvement in adults. , This can be explained on the basis of high prevalence and close contact with inmates owing to the social structure prevailing in our country. The male preponderance was seen in line with the western literature. ,,
Pain was the most common clinical presentation in our pediatric cases. As Pott's spine is mainly an extradural pathology, it causes pain by various mechanisms like dural irritation, free nerve ending irritation in muscles as well as end plate changes and bony destruction. Motor symptoms were the next most common symptom mainly because most of the patients had upper cervical lesions. These patients had UMN type of weakness with spasticity and hyperreflexia due to involvement of corticospinal tract. Different kinds of sensory symptoms were encountered in the patients with overlapping of few symptoms depending upon the vertical and horizontal location of the lesion. Autonomic symptoms were caused by UMN type of bladder involvement due to high cervical myelopathy.
As far as location of the lesion is concerned, we encountered 17 cases of CVJ of Pott's spines second only to dorsal region of Pott's spine, quite paradoxical to the western literature.  For such a high number of CVJ involvement, we hypothesize that primary Ghon's complex, which is very prevalent in our country, might have resulted into CVJ Pott's spine in pediatric population similar to Grisel's syndrome. We are also the leading center in this part of the country for the management of CVJ lesions. Involvement of other parts of pediatric spine was in accordance with the western literature. 
As there are no established guidelines for the management of Pott's spine cases, we followed the following major indications for surgical intervention in our setup:
The approach toward the surgical intervention was based upon the site of the main involvement. The surgical approach was chosen as per the involvement of vertebral body or posterior elements, the signs and symptoms of the patient and soft tissue compressive mass.
- No improvement in neurological complications/morbidity even after 4-6 weeks of ATT excluding the drug defaulters.
- New neurological deficits developing during the course of treatment.
- Worsening of already present neurological complications during the treatment.
- Recurrence of neurological complications.
- Prevertebral cervical abscess with difficulty in respiration and deglutition, seemingly difficult resolution on chemotherapy during conservative treatment.
- Advanced cases of neurological involvement such as marked sensory or sphincter disturbances, flaccid paralysis or severe flexor spasms.
The results of the surgical intervention at CVJ lesions were very enthusiastic where we have dealt with either the transoral approach [Figure 1] with posterior fusion or posterior fusion alone, depending upon the condition and treatment protocol. There have been minimal changes in the way we use to do transoral decompression in due course of time, but for the posterior fusion we have walked over miles and have done either of these techniques described below.
- Occipito-C2 fusion with the removal of C1 using contour rod (usually in cases prior to 2004).
- Using Jain's technique by excavating C1 arch by drilling burr holes in the occiput bone. 
- Midline single titanium wirings (after 2007) (occiput-C2 or C1-C2 fusion) [Figure 2].
|Figure 1: a) Oral cavity exposed after application of boyle's retractor, b) Midline pharyngeal incision, c) Exposed odontoid after the removal of C1 arch, d) Drilling of odontoid along with lateral pillar ensuring a good size gutter|
Click here to view
Posterior fusion was done in the cases of mobile atlantoaxial dislocation after ensuring the adequate canal diameter with the help of an extensor view of the skiagram or CT scan. In almost all the cases, bone graft has been taken from the posterior rib. The outcome in these cases following successful surgical intervention was good.
|Figure 2: a) Atlanto-axial dislocation-Extensor view (MRI Scan), b and c) Posterior fusion done by titanium wiring (Skiagram), d) Posterior fusion done by multiple titanium wiring (Intraoperative)|
Click here to view
Transmanubrial approach in our setup has been done in the cervicothoracic region. Out of four transmanubrial approaches, we have done decompression followed by caging and plate fixation in three cases (75%) whose ages were between 15 and 17 years and only decompression without any instrumentation in the remaining one case (25%) where the patient was of 9 years of age. In this approach, the help from cardiothoracic vascular surgeon (CTVS) was taken to cut the medial part of the clavicular head and for the splitting of upper sternum and cutting half of manubrium to gain access of cervicothoracic, i.e. C7, D1 and D2 vertebrae. The closure was also done by the CTVS surgeon after decompression and instrumentation. External stabilization was also given in the form of corset. No deformity was seen after the follow-up though data from a long-term follow-up are needed to overrule long-term spinal deformity.
Transthoracic transpleural approach in our setup was quite frequent [n = 18 (28.1%)]. In this approach, the preferred side for intervention was left side, thus avoiding the liver to be in operative field [n = 14 (77.8%)], particularly when approaching lower dorsal spine. Initially, the CVTS surgeon helped us out with the initial part of surgery exposure, but nowadays the complete procedure is done by us only. Lately, single lung ventilation has also eased out the surgical procedure. Decompression was done in all the subjects while instrumentation was done in seven patients, where the age was ranging between 14 and 18 years.
Retroperitoneal approach was considered in four patients, out of whom two patients had lower dorsal region lesion with anterior compression while the other two had lumbosacral region lesion with anterior compression. The instrumentation was done in only one patient who was of 17 years of age where the caging and rod and screw fixation was done.
Laminectomy was mainly done for the posterior compression, where our emphasis was upon removal of less than one-third of medial facet to prevent the instability. Here, the instrumentation was not done in any of the cases.
As we have dealt with pediatric patients, our main concern was to prevent progressive deformity through the years as the anterior growth plates are more prone for destruction over time. , Our decision was based upon the compression and nonresponsiveness to the ATT, hypothesizing that anyhow the patient will deteriorate further and will definitively have progressive deformity. So, we opted for decompression and surgical instrumentation in relatively older age group of 15-18 years.
| Conclusion|| |
The management of Pott's disease with compromise of neuraxis and spine should be specific to each patient. Effective chemotherapy for Pott's disease is the gold standard and must be started at the early stages of the disease. Timely and judicious surgical intervention not just to curtail the spinal deformities or progressive neurological symptoms but also to alleviate compression even in active disease is the better management. A significant improvement is possible even in the patients belonging to the poor grade with judicious use of the surgical approach and ATT. Good prognosis is associated with 1) partial cord compression, 2) short duration of neural complications, 3) early onset cord involvement with delayed neural complications, 4) young age and 5) good general condition.
However, further long-term follow-up is needed to comment upon the spinal deformity after the surgical intervention and the data should be compared with the non-surgical group.
| References|| |
|1.||Behari S, Nayak SR, Bhargava V, Banerji D, Chhabra DK,Jain VK. Craniocervical tuberculosis: Protocol of surgical management. Neurosurgery 2003;52:72-81. |
|2.||Janssens JP, de Haller R. Pott's disease in a developed country. A review of 26 cases with special emphasis on abscesses and neurologic complications. Clin Orthop Relat Res 1990;257:67-75. |
|3.||Tuli SM. Results of treatment of spinal tuberculosis by "middle-path" regime. J Bone Joint Surg Br 1975;57:13-23. |
|4.||Guidance for national tuberculosis programme on the management of tuberculosis in children WHO/HTM/TB/2006.371. |
|5.||Kumar R. Spinal tuberculosis: With reference to the children of northern India. Childs Nerv Syst 2005;21:19-26. |
|6.||Starke JR. Childhood tuberculosis: Ending the neglect. Int J Tuberc Lung Dis 2002;6:373-4. |
|7.||Turgut M. Spinal tuberculosis (Pott's disease): Its clinical presentation, surgical management, and outcome. A survey study on 694 patients. Neurosurg Rev 2001;24:8-13. |
|8.||Rezai AR, Lee M, Cooper PR, Errico TJ, Koslow M. Modern management of Pott's disease. Neurosurgery 1995;36:87-98. |
|9.||Shridhar K. Tuberculosis of the spine. In: Ramamurthi B, Tandon PN, editors. Textbook of Neurosurgery. 2nd ed. New Delhi: Churchill Livingstone; 1996. p. 496-513. |
|10.||Kumar R, Das RK, Mahapatra AK. Role of interferon gamma release assay in the diagnosis of Pott disease. J Neurosurg Spine 2010;12:462-6. |
|11.||Alfredo QH, Peter J, Richard J, William SR, Philip RW. General principles in the medical and surgical management of spinal infections: A multidisciplinary approach. Neurosurg Focus 2004;17:E1. |
|12.||Moon MS, Woo YK, Lee KS, Ha KY, Kim SS, Sun DH. Posterior instrumentation and anterior interbody fusion for tuberculous kyphosis of dorsal and lumbar spines. Spine (Phila Pa 1976) 1995;20:1910-6. |
|13.||18. 18. Rajasekaran S. The problem of deformity in spinal tuberculosis. Clin Orthop Relat Res 2002;398:85-92. |
|14.||Albee FH. Transplantation of a portion of the tibia into the spine for Pott's disease. A preliminary report. JAMA 1911;57:885. |
|15.||Hodgson AR, Stock FE. Anterior fusion for the treatment of tuberculosis of the spine: The operative findings and results of treatment in the first one hundred cases. J Bone Joint Surg Am 1960;42:295-310. |
|16.||Hsu LC, Cheng CL, Leong JC. Pott's paraplegia of late onset: The cause of compression and results after anterior therapy. J Bone Joint Surg Br 1988;70:534-8. |
|17.||Grossfeld S, Winter RB, Lonstein JE, Denis F, Leonard A, Johnson L. Spine-complications of anterior spinal surgery in children. J Pediatr Orthop 1997;17:89-95. |
|18.||Jain AK. Treatment of tuberculosis of the spine with neurologic complications. Clin Orthop Relat Res 2002;398:75-84. |
|19.||Kumar R, Kalra S, Mahapatra AK. A clinical scoring system for neurological assessment of high cervical myelopathy: Measurements in pediatric patients with congenital atlantoaxial dislocations. Neurosurgery 2007;61:987-94. |
|20.||Leonard A, Johnson L. Spine-complications of anterior spinal surgery in children. J Pediatr Orthop 1997;17:89-95. |
|21.||Nussbaum ES, Rockswold GL, Bergman TA, Erickson DL, Seljeskog EL. Spinal tuberculosis: A diagnostic and management challenge. J Neurosurg 1995;83:243-7. |
|22.||Vidyasagar C, Murthy HK. Management of tuberculosis of the spine with neurological complications. Ann R Coll Surg Engl 1994;76:80-4 |
|23.||Ho E, Leong J. The pediatric spine: Principles and practice. In: Weinstein SL, editor. Tuberculosis of the Spine. 3rd ed. New York: Raven; 1994. p. 837-49. |
|24.||Jain VK, Takayasu M, Singh S, Chharbra DK, Sugita K. Occipital-axis posterior wiring and fusion for atlantoaxial dislocation associated with occipitalization of the atlas. Technical note. J Neurosurg 1993;79:142-4. |
|25.||Rajasekaran S, Shanmugasundaram TK, Prabhakar R, Dheenadhayalan J, Shetty AP, Shetty DK. Tuberculous lesions of the lumbosacral region: A 15-year follow-up of patients treated by ambulant chemotherapy. Spine (Phila Pa 1976) 1998;23:1163-7. |
|26.||Upadhyay SS, Saji MJ, Sell P, Sell B, Hsu LC. Spinal deformity after childhood surgery for tuberculosis of the spine. A comparison of radical surgery and debridement. J Bone Joint Surg Br 1994;76:91-8. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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