12.1.1 Etiology and Pathogenesis

Rett syndrome is a progressive neurodevelopmental disorder. It was first described by Dr. Andreas Rett ¹ in 1966 and given the eponym by Hagberg et al in 1983. ² This condition is thought to affect approximately 1 in 10,000 females and is often due to a sporadic mutation of the methyl-CpG-binding protein 2 gene (MECP2) on the X-chromosome. ^{3 ,​ 4 ,​ 5} This gene mutation has been shown to affect cells in the locus coeruleus, which is responsible for noradrenergic innervation to the cerebral cortex and hippocampus. ⁶ In fewer than 10% of cases, mutations in other genes including CDKL5 or FOXG1 have also been identified in these patients. ⁷ The predominance of females with Rett syndrome is due to the sex-linked mutation, and males with MECP2 gene mutations either do not survive to term or die before the age of 2 years due to a severe encephalopathy.

Children with Rett syndrome typically undergo normal development in the early stages of growth and then regress in motor and language function. Four stages of this syndrome have been described. ^{8 ,​ 9} During the antenatal period, the child develops normally for the first 6 to 10 months of life. Between 1.5 to 3 years of age, there is regression of volitional hand movements and speech, as well as social withdrawal. This is followed by a plateau phase during which the symptoms stabilize for several years, until eventually there is late regression of motor function resulting in progressive scoliosis, dystonia, and spasticity. Due to this characteristic progression of symptoms, the diagnosis of Rett syndrome is often based on clinical assessment and is then verified by genetic testing. ¹⁰

Females with Rett syndrome can often live up to 40 years or more. A recent publication from the Australian Rett Syndrome Database reported a likelihood of survival of 77.6% at 20 years and 59.8% at 37 years. ¹¹ In their cohort of 396 adult female patients with Rett syndrome, over 50% were ambulating (most with assistive devices), and two-thirds (64%) were taking antiepileptic medications. Scoliosis was the most common orthopaedic condition in these patients, affecting 86% of the cohort, with 40% of those having undergone corrective surgery. Bassett and Tolo reported on 258 patients from the International Rett Syndrome Association and identified a 46% incidence of scoliosis in that cohort. ¹² They reported that bracing was largely unsuccessful to control curve progression during adolescence, and surgical correction and fusion was required in the majority of patients.

12.1.2 Disease-Specific Deformity Characteristics and Comorbidities

Patients with Rett syndrome typically present with a long C-shaped thoracolumbar curve in the coronal plane and increased global sagittal kyphosis similar to the deformity observed in other neuromuscular conditions. Most patients also develop a pelvic obliquity with concomitant hip instability. The deformity can be rapidly progressive during adolescence due to vertebral growth as well as progressive neuromuscular imbalance and spasticity as described previously in the fourth stage of this disease. Some studies have reported deformity progression of 14 to 21 degrees per year, ^{13 ,​ 14} with continued progression after skeletal maturity. ¹⁵ While the spinal deformity remains flexible during childhood, the curve often becomes structural and rigid early in adolescence (Fig. 12‑1). Brace treatment can be used as a temporizing measure in patients with a flexible deformity or in patients with significant medical comorbidities and contraindications to surgical treatment.

Patients with Rett syndrome are especially medically labile and have numerous medical comorbidities that need to be managed by a multidisciplinary team. Epilepsy is present in up to 80% of affected individuals. ¹⁶ Although about 50% of seizures can be controlled by medications, intractable epilepsy is more common in girls with decelerated head growth and can be triggered in the perioperative period due to physiologic stresses of surgery. Irregular breathing and nonepileptic vacant spells can also occur in these patients due to their immature brainstems, leading to sudden death. ¹⁷ Additionally, a defective control mechanism of carbon dioxide exhalation leads to respiratory alkalosis or acidosis requiring prolonged ventilator support and intensive care management. ¹⁸ Some patients also experience sudden violent screaming that can last for hours or even days. This behavior may signal extreme pain, although on examination there does not seem to be any somatic abnormality. ¹⁹ This phenomenon has been described as “brain-pain-crying” and may lead to overmedication and sedation, further depressing the respiratory drive in these patients.

12.1.3 Disorder-Specific Techniques

In 2009, a modified Delphi technique was used to integrate available published evidence, parental input, and expert opinion to arrive at a general consensus for managing scoliosis in patients with Rett syndrome. ²⁰ This study concluded that surgery should be considered when the deformity magnitude was approximately 40 to 50 degrees. The primary indications for surgery were progressive deformity, pain, loss of sitting balance, deteriorating ambulatory status, and progressive restrictive lung disease. ^{20 ,​ 21} Surgery should also only be considered after all medical comorbidities are optimized and with close involvement of specialized anesthesia and intensive care teams to minimize perioperative complications. Despite these measures, the incidence of complications after scoliosis surgery in this patient population remains high, ranging from 50 to 100%. ^{22 ,​ 23 ,​ 24} The most common complications were due to pulmonary (ventilator-acquired pneumonia, pneumothorax, pulmonary effusion) or gastrointestinal compromise (pancreatitis, gastric ulceration, superior mesenteric artery syndrome, acute abdominal distension).

Surgical considerations specific to this patient population should aim to minimize blood loss, minimize infections, monitor neurologic changes, and optimize fixation in osteoporotic bone. Lessons learned from other neuromuscular conditions can be applied to this patient population. Tranexamic acid or other antifibrinolytic agents should be considered to decrease blood loss and transfusion requirements. ²⁵ Established operating room teams with consistent anesthesiologists, surgical technicians, and two experienced surgeons can be used to decrease surgical time. Preoperative skin preparation, prophylaxis with gram-positive and gram-negative coverage, and vancomycin powder in the surgical wound may decrease infection rates. ²⁶ Neuromonitoring with somatosensory and motor evoked potentials is often possible in this population and should be used to prevent spinal cord injury during surgical correction. ²⁷

The spinal deformity in Rett syndrome often requires instrumentation and fusion of the entire thoracolumbar spine. The majority of the patients will require extension to the pelvis if there is a substantial pelvic obliquity present. We recommend the pelvic obliquity be corrected with pelvic instrumentation (iliac bolts or sacroiliac screws) as in the cerebral palsy population (see Chapter 16). With the seizure activity, the most rigid spinal instrumentation should be used (Fig. 12‑2). Our preference is to use segmental fixation to the spine with pedicle screws and sublaminar wires/bands as needed to stabilize osteoporotic bone. Intraoperative traction may be used to facilitate deformity correction and instrumentation. Anterior spinal release/instrumentation and fusion may be rarely required in very immature patients or with rigid spinal deformities. However, the underlying cardiopulmonary compromise should alert the surgeon in exercising caution if considering anterior thoracic spine surgery.

12.1.4 Evidence-Based Outcomes

Outcome studies of scoliosis surgery in patients with Rett syndrome are primarily case series. They report approximately 50 to 60% correction of the main spinal deformity with a well-balanced sagittal profile and improved pelvic obliquity. Hammett et al ²⁸ published their results in 2014 on 11 patients with Rett syndrome and average 5-year postoperative follow-up (range: 2–8 years). The mean preoperative spinal deformity measured 71 degrees (range: 44–105 degrees) and was corrected to an average of 27 degrees (range: 10–46 degrees). Patients were treated with posterior segmental instrumentation and fusion to the pelvis with either hybrid (sublaminar wires, hook, and screws) instrumentation or an all–pedicle screw construct. Eight patients (73%) had significant complications, primarily respiratory and wound infections. Similarly, in 2012, Gabos et al ²² reported on 16 patients with mean 4.7-year follow-up. All patients were instrumented from T1 to the pelvis using unit rod instrumentation. The coronal deformity improved on average from 68 degrees (range: 38–100 degrees) preoperatively to 16 degrees (range: 5–40 degrees) at final follow-up. No patients in this series experienced deterioration in ambulatory status over the follow-up period despite fusion to the pelvis.

Larsson et al ²⁹ reported on postoperative function, seating position, and self-reported quality of care measures in 23 girls with Rett syndrome and neuromuscular scoliosis. All patients were treated with posterior segmental instrumentation and fusion with hybrid constructs (sublaminar wires, hooks, and screws), with a majority of patients (83%) being fused to the pelvis. Seven patients had concomitant anterior instrumentation and fusion with the Zielke apparatus (n = 3) or Aaro instrumentation (n = 4). Ten patients (44%) experienced postoperative complications in the short term, requiring pulmonary support and antibiotics for superficial wound infections, while three patients experienced deformity progression in the midterm with extension of the fusion into the cervical spine (n = 1) or to the pelvis (n = 2). Preoperative median deformity magnitude was 66 degrees (range q1–q3: 51–83 degrees) and at average 74-month follow-up (range: 49–99 months) was 17 degrees (range q1–q3: 8–33 degrees). The caregivers reported improvement in seating position, daily activities, time used for rest, and cosmetic appearance. The authors concluded that surgical intervention was successful in improving posture, which would decrease the risk for pressure sores, improve pulmonary function, and improve the general health of the child.

12.2.1 Etiology and Pathogenesis

Charcot–Marie–Tooth disease (CMT) is one of the most common hereditary motor and sensory neuropathies with an estimated prevalence of 0.5 to 1 per 2,500. ^{30 ,​ 31} This condition was described by French (Charcot and Marie) and British (Tooth) neurologists in 1886 as a peroneal muscle atrophy. ³² In 1968, Dyck and Lambert identified the electrophysiologic characteristics of these inherited neuropathies and used them to develop the first classification system. ^{33 ,​ 34} The type I neuropathies are associated with slow nerve conduction velocities with histologic findings of hypertrophic demyelination, while the type II neuropathies have normal or mildly reduced nerve conduction velocities with pathologic evidence of axonopathy. More recently, genetic testing has been used to classify these neuropathies and more than 80 genes have been identified. ³⁵ CMT type I represents about 70% of all inherited neuropathies. It has an autosomal dominant inheritance and is due to duplication of the peripheral myelin protein 22 gene (PMP22) on chromosome 17. ³⁶ Overexpression of PMP22 results in a toxic aggregation of this protein, resulting in demyelination of the nerves and prolonged conduction velocities.

CMT neuropathy is length dependent, affecting the longest nerves first and most significantly. Distal limb weakness and muscle atrophy are the first clinical features of this disease, and the lower extremities are often affected earlier than the upper extremities. This diagnosis should be included in the differential when examining toddlers with delayed motor development, toe walking, or frequent tripping and falling. Patients also often present with complaints of foot abnormalities including flat feet or high arches. CMT is less likely if these findings are unilateral, and the child should be evaluated for a mononeuropathy or another spinal cord disease. Sensory deficits in CMT are less severe than motor nerve dysfunction and typically result in decreased vibration or joint position sense instead of changes in pin-prick or temperature sensation. ³⁷

12.2.2 Disease-Specific Deformity Characteristics and Comorbidities

Previous studies have reported a 10 to 40% prevalence of scoliosis in patients with CMT ^{38 ,​ 39 ,​ 40} ; however, certain genetic subtypes have been associated with a higher prevalence. ^{41 ,​ 42} Unlike idiopathic scoliosis, there seems to be a predominance of male CMT patients with scoliosis. In the series by Karol and Elerson, ³⁹ 60% of the patients with scoliosis were male. The most common spinal deformity pattern is also different from the right thoracic hypokyphotic deformity observed in most patients with idiopathic scoliosis. In the series by Karol and Elerson, ³⁹ there was a 33% prevalence of left thoracic curves, and nearly 50% of the curves were hyperkyphotic. They also report that spinal deformity progression in patients with CMT may be dependent on the extent of neurologic disease and the magnitude of hyperkyphosis. Nonambulatory patients all had significant curve progression requiring surgical treatment.

Comorbidities in this patient population often involve the musculoskeletal system. Foot and ankle abnormalities are common, often resulting in pes cavus and claw feet; however, occasionally these patients can also present with pes plano valgus. ⁴³ Gait abnormalities are often due to foot and ankle weakness and contractures resulting in functional compensation as seen with excessive hip abduction or steppage gait pattern. Upper extremity involvement initially presents with hypothenar atrophy and can progress to finger flexion contractures and interosseous muscle wasting. Decreased vibration and altered proprioception may be more difficult to identify.