We have reviewed 1858 patients who had undergone a cervical laminoplasty and identified 43 (2.3%) who had developed a C5 palsy with a MMT (MRC) grade of 0 to 2 in the deltoid, with or without involvement of the biceps, but with no loss of muscular strength in any other muscles. The clinical features and radiological findings of patients with (group P; 43 patients) and without (group C; 100 patients) C5 palsy were compared. CT scanning of group P revealed a significant narrowing of the intervertebral foramen of C5 (p < 0.005) and a larger superior articular process (p < 0.05). On MRI, the posterior shift of the spinal cord at C4–5 was significantly greater in group P, than in group C (p < 0.01). This study is the first to correlate impairment of the C5 nerve root with a C5 palsy. It may be that early foraminotomy in susceptible individuals and the avoidance of tethering of the cord by excessive laminoplasty may prevent a post-operative palsy of the C5 nerve root

C5 nerve root palsy is a rare and potentially debilitating complication of cervical spine surgery. Currently, however, there are no guidelines to help surgeons to prevent or treat this complication. We carried out a systematic review of the literature to identify the causes of this complication and options for its prevention and treatment. Searches of PubMed, Embase and Medline yielded 60 articles for inclusion, most of which addressed C5 palsy as a complication of surgery. Although many possible causes were given, most authors supported posterior migration of the spinal cord with tethering of the nerve root as being the most likely. Early detection and prevention of a C5 nerve root palsy using neurophysiological monitoring and variations in surgical technique show promise by allowing surgeons to minimise or prevent the incidence of C5 palsy. Conservative treatment is the current treatment of choice; most patients make a full recovery within two years. Cite this article: Bone Joint J 2014;96-B:950–5

Aims. The aim of this study was to determine whether chilled irrigation saline decreases the incidence of clinical upper limb palsy (ULP; a reduction of one grade or more on manual muscle testing; MMT), based on the idea that ULP results from thermal damage to the nerve roots by heat generated by friction during bone drilling. Methods. Irrigation saline for drilling was used at room temperature (RT, 25.6°C) in open-door laminoplasty in 400 patients (RT group) and chilled to a mean temperature of 12.1°C during operations for 400 patients (low-temperature (LT) group). We assessed deltoid, biceps, and triceps brachii muscle strength by MMT. ULP occurring within two days post-operatively was categorised as early-onset palsy. Results. The incidence of ULP (4.0% vs 9.5%, p = 0.003), especially early-onset palsy (1.0% vs 5.5%, p < 0.001), was significantly lower for the LT group than for the RT group. Multivariate analysis indicated that RT irrigation saline use, concomitant foraminotomy, and opened side were significant predictors for ULP. Discussion. Using chilled irrigation saline during bone drilling significantly decreased the ULP incidence, particularly the early-onset type, and shortened the recovery period for ULP. Chilled irrigation saline can thus be recommended as a simple method for preventing ULP. Take home message: Chilled irrigation during laminoplasty reduces C5 palsy. Cite this article: Bone Joint J 2016;98-B:117–24

Purpose of the study. To investigate the efficacy of pedicle screw instrumentation in correcting spinal deformity in patients with quadriplegic cerebral palsy. Also to assess quality of life and functional improvement after deformity correction as perceived by the parents of our patients. Summary of Background Data. All pedicle screw constructs have been commonly used to correct adolescent idiopathic scoliosis. There is limited information on their effectiveness in treating patients with cerebral palsy and neuromuscular scoliosis. Methods. We reviewed the medical records and serial radiographs of 45 consecutive patients with quadriplegia who underwent spinal arthrodesis using pedicle screw/rod instrumentation and a standardised surgical technique (prospectively collected single surgeon's series). All patients were wheelchair bound with collapsing thoracolumbar scoliosis and pelvic obliquity. Twenty-eight patients had associated sagittal deformities. A telephone survey was performed by an independent investigator to assess parents' perception on surgical outcome. Results. Thirty-eight patients underwent posterior-only and 7 staged anteroposterior spinal arthrodesis. Mean age at surgery was 13.4 years (range 9-18.3) and mean postoperative follow-up 3.5 years (range 2.8-5). Pedicle screw instrumentation extended from T2/T3 to L5 with bilateral pelvic fixation using iliac bolts. Scoliosis was corrected from mean 82.5° to 21.4° (74.1%). Pelvic obliquity was corrected from mean 24° to 4° (83.3%). In posterior-only procedures, average blood loss was 0.8 blood volumes, ICU stay 3.5 days, and hospital stay 17.6 days. In anteroposterior procedures, average blood loss was 0.9 blood volumes, ICU stay 8.9 days, and hospital stay 27.4 days. Major complications included one deep infection and one re-operation to remove prominent implants but no deaths, no neurological deficit and no detected pseudarthrosis. Parents' survey demonstrated 100% satisfaction rate. Conclusion. Pedicle screw instrumentation can achieve excellent correction of spinopelvic deformity in quadriplegic cerebral palsy with low complication and re-operation rates and high parent satisfaction. Our study has demonstrated that spinal correction using segmental pedicle screw/rod constructs can be performed safely and with lesser major complications and reoperations compared to the traditionally used Unit rod or hybrid instrumentation. The greater degree of deformity correction and lesser rate of complications and reoperations due to non-union, prominent instrumentation or failed pelvic fixation using a pedicle screw compared to the Unit rod technique should be balanced against the increased implant cost

We describe 13 patients with cerebral palsy and lordoscoliosis/hyperlordosis of the lumbar spine who underwent a posterior spinal fusion at a mean age of 14.5 years (10.8 to 17.4) to improve sitting posture and relieve pain. The mean follow-up was 3.3 years (2.2 to 6.2). The mean pre-operative lumbar lordosis was 108. °. (80 to 150. °. ) and was corrected to 62. °. (43. °.  to 85. °. ); the mean thoracic kyphosis from 17. °. (-23. °. to 35. °. ) to 47. °. (25. °. to 65. °. ); the mean scoliosis from 82. °. (0. °. to 125. °. ) to 22. °. (0. °. to 40. °. ); the mean pelvic obliquity from 21. °. (0. °. to 38. °. ) to 3. °. (0. °. to 15. °. ); the mean sacral slope from 79. °. (54. °. to 90. °. ) to 50. °. (31. °. to 66. °. ). The mean pre-operative coronal imbalance was 5 cm (0 cm to 8.9 cm) and was corrected to 0.6 cm (0 to 3.2). The mean sagittal imbalance of -8 cm (-16 cm to 7.8 cm) was corrected to -1.6 cm (-4 cm to 2.5 cm). The mean operating time was 250 minutes (180 to 360 minutes) and intra-operative blood loss 0.8 of estimated blood volume (0.3 to 2 estimated blood volume). The mean intensive care and hospital stay were 3.5 days (2 to 8) and 14.5 days (10 to 27), respectively. Three patients lost a significant amount of blood intra-operatively and subsequently developed chest or urinary infections and superior mesenteric artery syndrome. An increased pre-operative lumbar lordosis and sacral slope were associated with increased peri-operative morbidity: scoliosis and pelvic obliquity were not. A reduced lumbar lordosis and increased thoracic kyphosis correlated with better global sagittal balance at follow-up. All patients and their parents reported excellent surgical outcomes. Lordoscoliosis and hyperlordosis are associated with significant morbidity in quadriplegic patients. They are rare deformities and their treatment is challenging. Sagittal imbalance is the major component: it can be corrected by posterior fusion of the spine with excellent functional results. Cite this article: Bone Joint J 2014;96-B:800–6

Introduction. Horizontal gaze palsy (HGP) in association with scoliosis has been reported in both orthopaedic and ophthalmological published work. Juvenile progressive scoliosis in combination with HGP is caused by a malfunction of the normal control mechanism for equilibrium related to the lower brain stem, mostly associated with ROBO3 gene mutation. The aim of this study is to establish the association of scoliosis and HGP. Methods. 13 cases (four families and three sporadic cases) with HGP and scoliosis were documented; other systemic and ocular associated findings were identified and genetic counselling was done. All patients had radiograph of the spine, cranial and spinal cord MRI, chromosome analysis, gene analysis, and full ophthalmological examination. Blood samples were tested for ROBO3 gene mutation at Engle Laboratory, USA. Results. Mean age at evaluation was 14·8 years (range 1–56). Scoliosis was of varying degree (Cobb angle range 10–65°, mean 38·4°), and horizontal pendularnystagmus of low amplitude and loss of conjugate horizontal eye movements were common in all patients. Scoliosis was early onset and progressive in all patients. Six of 11 patients underwent surgery (Cobb angle range 45–70°, mean 5·3°). There were four right thoracic, two left thoracic, three right thoracolumbar, and two left thoracolumbar curves. Two patients of the third family (cases 10 and 11) had mirror image thoracolumbar curves. Cranial and spinal MRI revealed cleft in medulla oblongata in all nine patients who underwent MRI. Two adult patients refused MRI and two infant MRI scans were suboptimal. Neurological examination was otherwise normal. Notably, the female patients of family 1 also had genital dysgenesis. This is the first report of this finding in association with HGPPS, and its significance is not yet known. Homozygous ROBO3 mutations were identified in affected members of all four families, despite no recognised consanguinity in two of the families. Two were homozygous nonsense mutations (G456X and W635X) and two families shared the same missense mutation (S1107R). Two of the three sporadic cases underwent mutation testing; one harboured a homozygous missense C901R mutation, whereas a mutation was not detected in the second (patient 4). There were no distinguishing features of patient 4, suggesting that she has a non-coding mutation or that there is a second HGPPS gene. Conclusions. Every child with HGP should be evaluated for a possibly associated scoliosis, which is a progressive condition. Our cases and other published work clearly indicate that even if scoliosis is not present at first evaluation, longitudinal follow-up will show the evolution and progression of scoliosis. ROBO3 mutation testing should be done

We have reviewed the cervical spine radiographs of 180 patients with athetoid cerebral palsy and compared them with those of 417 control subjects. Disc degeneration occurred earlier and progressed more rapidly in the patients, with advanced disc degeneration in 51%, eight times the frequency in normal subjects. At the C3/4 and C4/5 levels, there was listhetic instability in 17% and 27% of the patients, respectively, again six and eight times more frequently than in the control subjects. Angular instability was seen, particularly at the C3/4, C4/5 and C5/6 levels. We found a significantly higher incidence of narrowing of the cervical canal in the patients, notably at the C4 and C5 levels, where the average was 14.4 mm in the patients and 16.4 mm in normal subjects. The combination of disc degeneration and listhetic instability with a narrow canal predisposes these patients to relatively rapid progression to a devastating neurological deficit

Aim:

To present 11 patients with quadriplegia who developed severe lordoscoliosis or hyperlordosis. This is a rare deformity in children with CP, treatment is challenging and there are less than 20 patients ever reported.

Aims. To report the mid-term results of a modified self-growing rod (SGR) technique for the treatment of idiopathic and neuromuscular early-onset scoliosis (EOS). Methods. We carried out a retrospective analysis of 16 consecutive patients with EOS treated with an SGR construct at a single hospital between September 2008 and December 2014. General demographics and deformity variables (i.e. major Cobb angle, T1 to T12 length, T1 to S1 length, pelvic obliquity, shoulder obliquity, and C7 plumb line) were recorded preoperatively, and postoperatively at yearly follow-up. Complications and revision procedures were also recorded. Only patients with a minimum follow-up of five years after surgery were included. Results. A total of 16 patients were included. Six patients had an idiopathic EOS while ten patients had a neuromuscular or syndromic EOS (seven spinal muscular atrophy (SMA) and three with cerebral palsy or a syndrome). Their mean ages at surgery were 7.1 years (SD 2.2) and 13.3 years (SD 2.6) respectively at final follow-up. The mean preoperative Cobb angle of the major curve was 66.1° (SD 8.5°) and had improved to 25.5° (SD 9.9°) at final follow-up. The T1 to S1 length increased from 289.7 mm (SD 24.9) before surgery to 330.6 mm (SD 30.4) immediately after surgery. The mean T1 to S1 and T1 to T12 growth after surgery were 64.1 mm (SD 19.9) and 47.4 mm (SD 18.8), respectively, thus accounting for a mean T1 to S1 and T1 to T12 spinal growth after surgery of 10.5 mm/year (SD 3.7) and 7.8 mm/year (SD 3.3), respectively. A total of six patients (five idiopathic EOS, one cerebral palsy EOS) had broken rods during their growth spurt but were uneventfully revised with a fusion procedure. No other complications were noted. Conclusion. Our data show that SGR is a safe and effective technique for the treatment of EOS in nonambulatory hypotonic patients with a neuromuscular condition. Significant spinal growth can be expected after surgery and is comparable to other published techniques for EOS. While satisfactory correction of the deformity can be achieved and maintained with this technique, a high rate of rod breakage was seen in patients with an idiopathic or cerebral palsy EOS. Cite this article: Bone Joint J 2020;102-B(11):1560–1566

Aims. This study, using a surgeon-maintained database, aimed to explore the risk factors for surgery-related complications in patients undergoing primary cervical spine surgery for degenerative diseases. Methods. We studied 5,015 patients with degenerative cervical diseases who underwent primary cervical spine surgery from 2012 to 2018. We investigated the effects of diseases, surgical procedures, and patient demographics on surgery-related complications. As subcategories, the presence of cervical kyphosis ≥ 10°, the presence of ossification of the posterior longitudinal ligament (OPLL) with a canal-occupying ratio ≥ 50%, and foraminotomy were selected. The surgery-related complications examined were postoperative upper limb palsy (ULP) with a manual muscle test (MMT) grade of 0 to 2 or a reduction of two grade or more in the MMT, neurological deficit except ULP, dural tear, dural leakage, surgical-site infection (SSI), and postoperative haematoma. Multivariate logistic regression analysis was performed. Results. The significant risk factors (p < 0.050) for ULP were OPLL (odds ratio (OR) 1.88, 95% confidence interval (CI) 1.29 to 2.75), foraminotomy (OR 5.38, 95% CI 3.28 to 8.82), old age (per ten years, OR 1.18, 95% CI 1.03 to 1.36), anterior spinal fusion (OR 2.85, 95% CI 1.53 to 5.34), and the number of operated levels (OR 1.25, 95% CI 1.11 to 1.40). OPLL was also a risk factor for neurological deficit except ULP (OR 5.84, 95% CI 2.80 to 12.8), dural tear (OR 1.94, 95% CI 1.11 to 3.39), and dural leakage (OR 3.15, 95% CI 1.48 to 6.68). Among OPLL patients, dural tear and dural leakage were frequently observed in those with a canal-occupying ratio ≥ 50%. Cervical rheumatoid arthritis (RA) was a risk factor for SSI (OR 10.1, 95% CI 2.66 to 38.4). Conclusion. The high risk of ULP, neurological deficit except ULP, dural tear, and dural leak should be acknowledged by clinicians and OPLL patients, especially in those patients with a canal-occupying ratio ≥ 50%. Foraminotomy and RA were dominant risk factors for ULP and SSI, respectively. An awareness of these risks may help surgeons to avoid surgery-related complications in these conditions. Cite this article: Bone Joint J 2021;103-B(1):157–163

Aims

Surgical approaches to cervical ossification of the posterior longitudinal ligament (OPLL) remain controversial. The purpose of the present study was to analyze and compare the long-term neurological recovery following anterior decompression with fusion (ADF) and posterior laminectomy and fusion with bone graft and internal fixation (PLF) based on > ten-year follow-up outcomes in a single centre.

Aims

The optimal procedure for the treatment of ossification of the posterior longitudinal ligament (OPLL) remains controversial. The aim of this study was to compare the outcome of anterior cervical ossified posterior longitudinal ligament en bloc resection (ACOE) with posterior laminectomy and fusion with bone graft and internal fixation (PTLF) for the surgical management of patients with this condition.

Aims

Historically, patients undergoing surgery for adolescent idiopathic scoliosis (AIS) have been nursed postoperatively in a critical care (CC) setting because of the challenges posed by prone positioning, extensive exposures, prolonged operating times, significant blood loss, major intraoperative fluid shifts, cardiopulmonary complications, and difficulty in postoperative pain management. The primary aim of this paper was to determine whether a scoring system, which uses Cobb angle, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and number of levels to be fused, is a valid method of predicting the need for postoperative critical care in AIS patients who are to undergo scoliosis correction with posterior spinal fusion (PSF).

We report the incidence of and risk factors for complications after scoliosis surgery in patients with Duchenne muscular dystrophy (DMD) and compare them with those of other neuromuscular conditions. We identified 110 (64 males, 46 females) consecutive patients with a neuromuscular disorder who underwent correction of the scoliosis at a mean age of 14 years (7 to 19) and had a minimum two-year follow-up. We recorded demographic and peri-operative data, including complications and re-operations. There were 60 patients with cerebral palsy (54.5%) and 26 with DMD (23.6%). The overall complication rate was 22% (24 patients), the most common of which were deep wound infection (9, 8.1%), gastrointestinal complications (5, 4.5%) and hepatotoxicity (4, 3.6%). The complication rate was higher in patients with DMD (10/26, 38.5%) than in those with other neuromuscular conditions (14/84, 16.7% (p = 0.019). All hepatotoxicity occurred in patients with DMD (p = 0.003), who also had an increased rate of deep wound infection (19% vs 5%) (p = 0.033). In the DMD group, no peri-operative factors were significantly associated with the rate of overall complications or deep wound infection. Increased intra-operative blood loss was associated with hepatotoxicity (p = 0.036). In our series, correction of a neuromuscular scoliosis had an acceptable rate of complications: patients with DMD had an increased overall rate compared with those with other neuromuscular conditions. These included deep wound infection and hepatotoxicity. Hepatotoxicity was unique to DMD patients, and we recommend peri-operative vigilance after correction of a scoliosis in this group. Cite this article: Bone Joint J 2014; 96-B:943–9

Aim:. Our aim was to report the rate and risk factors for post-operative complications in Duchenne Muscular Dystrophy (DMD) patients undergoing spinal arthrodesis for scoliosis, with a comparison to neuromuscular scoliosis of other aetiology. Methods:. From a prospective single surgeon spinal deformity database, we identified all patients with neuromuscular disorders who underwent surgical correction for progressive scoliosis. We recorded demographic and peri-operative data, including complications and subsequent procedures. The rate and risk factors for complications was determined, with a sub-analysis of the DMD group to determine any peri-operative factors predictive of overall complication rates. Results:. There were 98 patients, 59 (60%) were male with mean age at surgery 14 yrs (7–19 yrs). Forty-eight patients had cerebral palsy (n=48, 49%) and 26 DMD (27%). The overall complication rate was 18.4% (n=18), with deep wound infection (DWI; n=9, 9.2%) and acute liver injury (ALI; n=4, 4.0%) most frequent. The complication rate was significantly higher in DMD patients (35%) compared to other neuromuscular disorders (13%; p=0.013). All ALIs occurred in DMD patients (p=0.004), with an increased DWI rate (19% vs 6%; p=0.053). On subanalysis, no peri-operative factors correlated with overall complication rate or DWI rate. Increased intraoperative blood loss was the only factor associated with ALI (p=0.036). Discussion:. Scoliosis correction has an acceptable complication rate in patients with neuromuscular diagnoses. DMD patients have an increased complication rate when compared to other neuromuscular disorders. ALI in our series was unique to DMD patients and we would recommend peri-operative vigilance for hepatotoxicity in these patients. Conflict Of Interest Statement: No conflict of interest

Aims

With recent progress in cancer treatment, the number of advanced-age patients with spinal metastases has been increasing. It is important to clarify the influence of advanced age on outcomes following surgery for spinal metastases, especially with a focus on subjective health state values.

STUDY DESIGN. Retrospective review of outcome of submuscular rod placement without apical fusion for the treatment of scoliotic deformities in children with severe co morbidities (ASA IV). METHODS. 6 children with progressive scoliosis (2 severe cerebral palsy, 2 congenital cyanotic heart disease, 1 Worster Drought syndrome, 1 Leigh's disease), underwent a serial and limited exposure of the lower and then the upper end of the spine, and insertion of pedicle screws, hooks and clamps. Two submuscularly rods were connected and distracted. Mean age was 13 years old, the mean preoperatively Cobb angle was 87° and the mean postoperatively Cobb angle was 62°. The mean operation time was 120 min and the peri-operative blood loss was 410 ml. Mean follow up is 15 months. RESULTS. There were no adverse peri-operative events. We anticipated late implant failure and revisions but to date only one construct has failed and revised without difficulties (clamps to pedicle screws). 1 patient complicated with increased spasms 1 year postoperatively. The benefits from this procedure were. a) the decreased peri-operative:. blood loss. operation time. respiratory stress. b) the faster patients recovery. c) the significant improvement regarding pain relief and sitting positioning. CONCLUSION. We believe that this procedure can be offered as a safe and viable alternative in selected patients who present with predicted high peri-operative mortality. To the best of our knowledge this technique is not described before

8 patients with cervical myelopathy treated by French-door laminoplasty and internal fixation. A novel technique of fixation is employed to provide immediate stability, pain relief and rapid mobilisation. To report the clinical and radiological outcomes of this new fixation device for French–door laminoplasty with minimum follow-up of 30 months. Hardware assisted laminoplasty has the potential advantage of instant stability and prevention of recurring stenosis. The use of titanium mini-plates has been described in open-door laminoplasty and now we describe this technique in French–door laminoplasty. 8 patients with cervical myelopathy secondary to congenital stenosis (2) and multi-level spondylotic myelopathy (6) underwent 2-4 level French–door laminoplasty and mini-plate fixation. The average follow-up was 46.5 months. Autogenous iliac crest bone graft was interposed between the sagittally split spinous processes and 16-18 holed titanium mini-plates were contoured into a trapezoidal shape and secured to the posterior elements with screws. Patients then mobilised without external support. The mean follow-up was 46.5 months. The mean improvement in NDI at final follow-up was 35% and mean improvement in VAS was 4 points. JOA score improved from a mean of 10 to a mean of 14.8 post-operatively. All patients had achieved a significant neurological improvement and pain relief. There were no post-operative hardware related complications, pseudarthrosis or neurological deterioration. French-door laminoplasty is an excellent alternative to laminectomy for treatment of young patients with cervical myelopathy. The use of titanium mini-plates not only provides instant stability and pain relief but also seems to minimize the risk of C5 nerve root palsy. Internal fixation appears to provide instant stability, early mobilisation and therefore reduces hospital stay and associated costs

Craniodiaphyseal dysplasia (CDD) is a rare sclerosing bone disorder, the severity of which depends on its phenotypic expression. Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation. We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment. Although the syndrome is rare, its pathophysiological and therapeutic considerations may be applicable to the management of stenosis of the spinal canal in other hyperostotic bone disorders

Introduction. Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity, affecting about 3% of school-aged children worldwide. This disorder occurs in otherwise healthy children who bear no obvious deficiencies in the components of the spinal column itself. The cause of AIS is poorly understood, as is implied by the name. Lesions of the bony composition of the vertebrae, the vertebral endplates, the paraspinous muscles, or the neurological system each have been proposed to explain disease pathogenesis. Progress has been hampered by the absence of an obvious AIS animal model. Consequently we have used genetic studies in human populations to identify factors underlying AIS susceptibility. The complex inheritance and population frequency of AIS suggest that many genetic factors are involved in this disease. To search comprehensively for such factors we previously undertook the first genome-wide association study (GWAS) of AIS susceptibility in a cohort of 419 families in Texas, USA. We found that chromosome 3 SNPs in the proximity of the CHL1 gene yielded strongest results, which we replicated in additional cohorts (rs10510181 OR 1·49, 95% CI 1·29–173, p=2·58×10–8). CHL1 is of interest because it encodes an axon guidance protein and is functionally related to the ROBO3 gene that causes hereditary gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Here we expanded the study to 702 Texas families. Methods. We tested more than 327 000 single-nucleotide polymorphisms (SNPs) across all human autosomes for association with disease. Results. Results of the study in 702 Texas families yielded evidence for association with SNPs in a second axon guidance gene, DSCAM, which encodes a protein in the same structural and functional class with Chl1 and Robo3 (rs2222973 combined OR 0·59, 95% CI 0·48–0·74; p=1·46×10–6). We additionally found AIS associations with loci in CNTNAP2, whose protein product interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Conclusions. These data support genetic variation in axon guidance genes as risk factors in AIS. Our results provide new insight into disease pathogenesis and suggest that late-onset scoliosis may be correlated with secondary neurological development