The vertebral syndrome in various types of mucopolysaccharidosis: clinical features and treatment

The paper presents recommendations on the assessment and treatment of vertebral pathology in patients with various types of mucopolysaccharidosis. The recommendations are based on literature data and the authors’ own experience. The purpose of the publication is an invitation to the discussion in the format of an expert consensus.

The opportunities of targeted therapy have attracted attention not only to mucopolysaccharidosis (MPS) but also to growing trends in improving the quality of life, in particular due to timely neurosurgical and orthopedic interventions.
More than a year and a half has passed since the establishment of an inter-rater group for treating MPS patients within the Association of Traumatologists and Orthopedists of Russia. Now, it is time to review the preliminary results.
We briefly describe the main tasks faced by the group's experts: 1) recruitment of a multidisciplinary team of experts (geneticists, pediatricians, general practitioners, orthopedists, neurosurgeons, anesthesiologists, neurologists, rehabilitation physicians) to assess the syndromic status of the entire nosologic group and a particular patient; substantiation of rehabilitation approaches, including the surgical one; 2) preparation of a federal clinical guidelines draft; 3) coordination of interdisciplinary patient logistics; 4) planning of multicenter and survey studies based on intra-and interrater assessment.
At the 11th All-Russian Congress of Traumatologists and Orthopedists of Russia held in Saint-Petersburg, April 11-13, 2018, there was a second round table discussion on syndromic assessment of the status of MPS patients and aspects of early diagnosis and approaches in treatment of the orthopedic pathology. The presented paper is the first product of the expert group. The authors will gratefully welcome all comments and suggestions.

General methodology of guidelines
The clinical guidelines on the diagnosis and treatment of spinal pathology in different MPS types were developed by a group of experts based on the evidence-based medicine principles. Information was searched in the Medline (Pubmed version), Embase (Dialog version), and Cochrane Library electronic databases, based on a systematic review of the literature, using, in particular, a consensus of study's author opinions.
MPS belongs to the group of orphan diseases, which excludes large cohort and randomized studies; therefore, only expert opinions published within the last two decades can be used to develop protocols for the diagnosis and treatment of spinal disease.

Design
An analysis of publications devoted to this problem demonstrated that almost all of the publications were based on series of clinical cases. No studies that might be attributed to an ASMOK (Association of Medical Societies for Quality of Medical Care and Education) level exceeding 2+ and to I or II evidence level were found. Accordingly, all guidelines in this document are of evidence level C or less.
The purpose of this study is to develop the algorithm for treatment of vertebral syndrome in patients with different types of MPS.
The paper is presented mainly in the form of tables for the most vivid presentation of the material. We have already used this form, and, in our opinion, it is very convenient for perception and practical application. The features of selection and analysis of the material are deliberately not considered in the presented guidelines.
Methods used to assess the quality and strength of evidence are as follows: -consensus of experts; -assessment of the evidence level in accordance with a rating scheme (Table 1).

Definitions and classification
MPS is a group of complex heterogeneous progressive diseases caused by deficiency of lysosomal enzymes involved in the glycosaminoglycan degradation pathway [1]. Depending on the deficiency in one of the 11 lysosomal enzymes (chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and/ or hyaluronate), seven main MPS types are distinguished ( Table 2). The manifestations are associated with impaired utilization and accumulation of glycosaminoglycans in lysosomes of cells in all organs [2]. According to the international classification of hereditary skeletal diseases [3], all MPS types belong to the group of lysosomal storage diseases involving the skeleton (multiple dysostosis).
Multisystem phenotypic symptoms. Products of abnormal metabolism cause physical development delay, coarsening of facial features, mental retardation, skeletal dysplasia, hepatosplenomegaly, frequent respiratory infections leading to respiratory failure, cardiovascular disorders, eye diseases, hard hair growth, and changes in the skin [4,5]. All MPS types, except for, probably, MPS III, are associated with these somatic symptoms.
Neurocognitive disorders (including mental deficiency, adaptive behavior and motor skill learning, impaired attention and memory, delayed speech development), which are usually associated with sleep disorders and epileptic seizures that often occur in MPS III, can also be observed in patients with MPS I, II, and VII [6].
Secondary neurological symptoms, often in the form of motor deficit, develop in the following cases [7][8][9][10]: 1) in stenosis at the foramen magnum level with spinal cord compression, hydrocephalus, and Chiari I malformation; 2) in kyphotic (kyphoscoliotic) deformity of the thoracolumbar spine, often resulting in vertebromedullary conflict; 3) in peripheral nerve lesions associated with tunnel syndromes (the most common manifestation is carpal tunnel syndrome).
A review of spinal changes in MPS, which are able to cause secondary neurological manifestations, is presented in Table 3.
The objectives and basic principles of conservative treatment of children with different MPS types are presented in Table 4.
The follow-up protocol for patients with MPS is provided in Table 5.
The basic principles and surgical treatment approach for spinal pathology in MPS are presented in Tables 7 and 8. Fig. 1 shows the surgical treatment approach for spinal pathology in patients with different types of MPS. Surgical correction of spinal pathology in MPS is performed with allowance for the features of vertebral syndrome (Table 9).

Limitations to the use of guidelines for surgical treatment of spinal pathology in MPS
The main purpose of the described approaches is to preserve the patient's motor activity, quality of life, and social adaptation. Therefore, the main contraindications to complexity of positioning with head fixation application of the guidelines include: -decompensated concomitant pathology, including that caused by the underlying disease, which is life-threatening or having significant limitations for the expected survival period; -communication gap with parents regarding the goal of an oriented treatment strategy; -infectious processes in the exacerbation period.

Conclusion
Spinal pathology is one of the leading syndromic manifestations of MPS. The spinal dysmorphism syndrome complex includes three typical syndromes: stenosis of the craniocervical junction, most typical of MPS type I, II, and VI; craniocervical instability (which is often combined with stenosis) in MPS type IV; and kyphosis/kyphoscoliosis in MPS type I, IV, and VI.
A key component of early screening for vertebral syndrome is assessment of the patient's neurological and motor status. The most accepted tools are the modified scale of the Japanese Orthopedic Association (mJOA), Nurick scale, 6-minute walk test, and 3-minute stair climb test.
Deterioration of the neurological status and quality of life in the setting of confirmed stenosis and instability as well as progression of spinal deformity underlie prognostically vital indications for surgical correction. Decompression and occipital-cervical fusion are indicated in patients with instability and stenosis at the craniovertebral junction level.
Stable segment-by-segment fixation of the spine is indicated for local kyphotic/kyphoscoliotic curves, within five spinal motion segments.
Spinal fixation by dynamic systems is preferable for extended spinal deformities.
The guidelines do not concern the possibility of age and interdisciplinary continuity, detailed planning of the treatment approach with assessment of a perioperative risk, and desire to solve orthopedic and neurosurgical tasks within one session. These circumstances underlie the need for multidisciplinary and multicenter studies.
The study was conducted without financial support.

Table 4
Objectives and basic principles of conservative treatment of children with different types of mucopolysaccharidosis [31][32][33][34] Improvement of neurological condition* Anticholinesterase drugs, anticonvulsants, dehydration. Currently, there is no effective treatment of neurological complications Improvement of orthopedic status Corset therapy, massage, exercise therapy, orthotics, orthopedic correction of pathological arrangements, contractures, etc.
Social adaptation** Physical and functional rehabilitation, training to use assistive devices -verticalizers, braces, devices * The most valid tools for assessing the neurological status of patients with different types of mucopolysaccharidosis are the modified scale of the Japanese Orthopedic Association (mJOA), Nurick scale, 6-minute walk test, and 3-minute stair climb test.
** Scored integrative assessment of disabilities and role limitations is often performed using the Functional Independence Measure (FIM) scale.

Table 5
The recommended protocol to follow-up patients with different types of mucopolysaccharidosis [8,17,[36][37][38][39] Examination Before surgery Table 6 The system for assessment of spinal cord compression at the craniovertebral junction level to decide the need for surgical treatment [35] Score Test results Clinical neurological examination     Appearance and radiological findings of a 3-year-old child with kyphosis associated with mucopolysaccharidosis type IH: a -before surgery; b -structural changes in the apical vertebral bodies; c -signs of spinal cord compression; d -after correction and instrumented fixation of deformity at the T9-L4 level; e -after surgery

Fig. 4
Appearance and radiological findings of a 6-year-old child with scoliotic deformity associated with mucopolysaccharidosis type IVA: a -before surgery; b -after correction and posterior instrumented dynamic fixation of deformity at the T5-L2 level

Таблица 9
Variants of surgical correction for spinal pathology with allowance for vertebral syndrome features Spinal pathology Features of orthopedic correction Instability, stenosis, and combination of instability and stenosis at the craniovertebral junction level; foci of myelopathy (Fig. 2) Decompression and posterior instrumented fixation (occipital-cervical fusion) Local (no more than five spinal motion segments) spinal deformities, local kyphosis of more than 20°, and scoliosis of more than 40° (Fig. 3) Stable segmental fixation of the spine Extensive (more than five spinal motion segments) spinal deformities, kyphosis of more than 20°, and scoliosis of more than 40° (Fig. 4) Dynamic spine fixation