Split cord malformation

Split cord malformation

General information

The term split cord malformation (SCM) was first introduced in 1992 by Pang et al., in an attempt to resolve the confusion existing in the pathological definition and the clinical significance of previously existing terminologies in the literature, diastematomyelia and diplomyelia, and the inconsistent usage of these two terms 1).

The term split cord malformation (SCM) should be used for all double spinal cords, all of which appear to have a common embryologic etiology.


Split cord malformation (SCM) has a rich history and has intrigued physicians for over 200 years. Many well-known figures from the past such as Hans Chiari and Friedrich Daniel von Recklinghausen, both pathologists, made early postmortem descriptions of SCM. With the advent of MRI, these pathological embryological derailments can now often be detected and appreciated early and during life. Our understanding and ability to treat these congenital malformations as well as the terminology used to describe them have changed over the last several decades 2).

Classification

Pang et al. classified spinal cord duplication anomalies into types I and II. The first is characterized by two hemicords, each contained within its own dural sac, and separated by an osteocartillaginous septum. Type II is defined by two hemicords in the same dural sac, separated by a fibrous septum 3) 4).

Type I split cord malformation

Type 1.5 split cord malformation ?

Type 2 split cord malformation.


Much confusion still exists concerning the pathological definitions and clinical significance of double spinal cord malformations. Traditional terms used to describe the two main forms of these rare malformations, diastematomyelia, and diplomyelia, add to the confusion by their inconsistent usage, ambiguities, and implications of their dissimilar embryogenesis. Based on the detailed radiographic and surgical findings of 39 cases of double cord malformations and the autopsy data on two other cases, this study endorses a new classification for double cord malformations and proposes a unified theory of embryogenesis for all their variant forms and features. The new classification recommends the term split cord malformation (SCM) for all double spinal cords. A Type I SCM consists of two hemicords, each contained within its own dural tube and separated by a dura-sheathed rigid osseocartilaginous median septum. A Type II SCM consists of two hemicords housed in a single dural tube separated by a nonrigid, fibrous median septum. These two essential features necessary for typing, the state of the dural tube and the nature of the median septum, do not ever overlap between the two main forms and can always be demonstrated by imaging studies so that accurate preoperative typing is always possible. All other associated structures in SCM such as paramedian nerve roots, myelomeningoceles manqué, and centromedian vascular structures frequently do overlap between types and are not reliable typing criteria. The unified theory of embryogenesis proposes that all variant types of SCMs have a common embryogenetic mechanism. Basic to this mechanism is the formation of adhesions between ecto- and endoderm, leading to an accessory neurenteric canal around which condenses an endomesenchymal tract that bisects the developing notochord and causes formation of two hemineural plates. The altered state of the emerging split neural tube and the subsequent ontogenetic fates of the constituent components of the endomesenchymal tract ultimately determine the configuration and orientation of the hemicords, the nature of the median septum, the coexistence of various vascular, lipomatous, neural, and fibrous oddities within the median cleft, the high association with open myelodysplastic and cutaneous lesions, and the seemingly unlikely relationship with fore and midgut anomalies. The multiple facets of this theory are presented in increasing complexity against the background of known embryological facts and theories; the validity of each facet is tested by comparing structures and phenomena predicted by the facet with actual radiographic, surgical, and histopathological findings of these 41 cases of SCM 5).


A new classification system proposed by Mahapatra and Gupta further divides type I SCM into four categories: Ia, bony spur in the center with equally duplicated cord above and below the spur; type Ib, bony spur at the superior pole with no space above and a large duplicated cord below; Ic, bony spur at the lower pole with a large duplicated cord above; and Id, bony spur straddling the bifurcation with no space above or below the spur 6).

Treatment

The risk of neurological deficits developing increases with age; hence, all patients with SCM should be surgically treated prophylactically even if they are asymptomatic 7).

see Type I Split Cord Malformation treatment.

Outcome

SCMs can lead to progressively worsening scoliosis and gait difficulties if left untreated.

Case series

From 1990 to 2014, 37 patients were operated. Five situations lead to the diagnosis (orthopedic disorders (n = 8), orthopedic and neurological disorders (n = 16), pure neurological disorders (n = 5), no symptoms except cutaneous signs (n = 7), antenatal diagnosis (n = 1)). Scoliosis was the most common associated condition. The level of the spur was always under T7 except in one case. There were more type I (n = 22) than type II (n = 15) SCM.

Patients with preoperative neurological symptoms (n = 21) were improved in 71.4%. Five out of nine patients that had preoperative bladder dysfunction were improved. Eleven patients needed surgical correction of the scoliosis.

For us, the surgical procedure is mandatory even in case of asymptomatic discovery in order to avoid late clinical deterioration. In any case, the filum terminale need to be cut in order to untether completely the spinal cord. In case a surgical correction of a spinal deformity is needed, we recommend a two-stage surgery, for both SCM type. The SCM surgery can stop the evolution of scoliosis and it may just need an orthopedic treatment with a brace 8).


Over a 16-year period, Mahapatra encountered 300 cases of SCM at AIIMS. Over the same period, more than 1500 cases of NTD were managed. SCM was noticed in 20% of cases with NTD. Skin stigmata were noted in two-third of the cases, and scoliosis and foot deformity were observed in 50% and 48% cases, respectively. Motor and sensory deficits were observed in 80% and 70% cases, respectively. Commonest site affected was lumbar or dorsolumbar (55% and 23%, respectively). In 3% cases, it was cervical in location. Magnetic resonance imaging (MRI) scan revealed a large number of anomalies like lipoma, neuroenteric cyst, thick filum and dermoid or epidermoid cysts. All the patients were surgically treated. In type I, bony spurs were excised, and in type II, bands tethering the cord were released. Associated anomalies were managed in the same sitting. Patients were followed up from 3 months to 3 years.

Overall improvement was noticed in 50% and stabilization in 44% cases and deterioration of neurological status was recorded in 6% cases. However, 50% of those who deteriorated improved to preop status prior to discharge, 7-10 days following surgery.

SCM is rare and not many large series are available. They operated 300 cases and noticed a large number of associated anomalies and also multilevel and multisite splits. Improvement or stabilization was noted in 94% and deterioration in 6% cases. They recommended prophylactic surgery for our asymptomatic patients 9).


Mahapatra et al. in 2005 reported the first 254 cases of SCM treated surgically during a period of 16 years.

Patients’ demographic profiles, imaging studies, operative details, complications, and surgical outcomes were evaluated retrospectively. A new classification based on intraoperative findings is proposed. The mean age of the patients was 7.3 years (female/male 1.5:1). Type I SCM was seen in 156 patients (61.4%) and 98 patients (38.6%) had Type II SCM. Skin stigmata were present in 153 cases (60%); hypertrichosis, being the most common, was seen in 82 cases (32.3%). Asymmetrical lower-limb weakness and sphincter disturbances were present in 173 (68.1%) and 73 (33%) cases, respectively. Of the symptomatic cases, 39% (68 of 173) showed improvement in motor power, 57.9% (33 of 57) experienced sensory improvement, and 27.3% (20 of 73) regained continence. None of the 38 patients in the asymptomatic group had postoperative neurological deterioration. The neurological status was unchanged in 63% of the cases. A new subclassification of Type I SCM is proposed, based on the intraoperative location of a bone spur causing the split, which may have a bearing on surgical dissection and outcome. Based on the authors’ experience with 25 cases of Type I SCM, they have classified the disorder into four subtypes: Type Ia, bone spur located in the center with duplicated cord above and below the spur (12 cases); Type Ib, bone spur at the superior pole with no space above it (four cases); Type Ic, bone spur at the lower pole with large duplicated cord above (three cases); and Type Id, bone spur straddling the bifurcation with no space above or below the spur (six cases). The risk of injury to the hemicords is highest in the Id subtype (four of six patients in this group deteriorated neurologically in the present series, whereas none with subtypes Ia-c worsened).

This is the largest series on SCMs so far reported in the world literature The risk of neurological deficits developing increases with age; hence, all patients with SCM should be surgically treated prophylactically even if they are asymptomatic. This new classification is easy to use and remember and takes into account the use of intraoperative findings that may have a bearing on surgical outcome 10).


Retrospective analysis of 19 cases of SCM, thirteen were grouped under (Pang) type I and 6 in type II. Their ages ranged from 1 month to 9 years (mean 3.5 years). 14 of these were male children. The NOS without neurological signs was detected in 6 cases whereas pure neurological signs without NOS were seen in 8 patients. However, the rest 5 had a mixed picture of NOS and neurological dysfunction. Nine of 19 cases presented with cutaneous stigmata, mainly in the form of a hairy patch. 18 cases had other associated craniospinal anomalies i.e. hydrocephalus, meningomyelocele, syrinx, dermoid, teratoma, etc. Detethering of the cord was done in all cases by the removal of fibrous/bony septum. Associated anomalies were also treated accordingly. Follow up of these cases ranged from 6 months to 6 years. Six cases of NOS group neither showed deterioration nor improvement, and remained static on follow up. However, four of 8 children with neurological signs showed improvement in their motor weakness, and 1 in saddle hypoaesthesia as well as bladder/bowel function. In 5 cases of a mixed group, two had improvement in their weakness and one in hypoaesthesia, but no change was noticed in NOS of this group as well. Hence surgery seemed to be effective, particularly in patients with neurological dysfunction 11).


Proctor and Scott reviewed the results obtained in 16 patients in whom the senior author performed surgery over a 13-year period (average length of follow up almost 8 years).

Presentation, surgical approach, and the outcome are evaluated, and the long-term outcome of neurological status, pain, bowel/bladder disturbance, and spinal deformities are emphasized.

The primary conclusion is that patients with SCM generally tolerate surgery well and experience few complications. Neurological deterioration is rare except in cases in which retethering occurs, (two patients in this series). Although impaired bowel and bladder function was stabilized or improved and pain was reliably relieved postoperatively, preexisting vertebral column deformities usually progressed after surgery and, in most cases, required spinal fusion 12).


In 2000 Forty-eight patients of split cord malformation operated during a six years period were studied clinically and radiologically.

The mean age of symptomatic patients was more than that of asymptomatic ones (6.85 years vs 2.03 years). The dorsolumbar and lumbar regions were most frequently involved and in three cases the cervical spine was affected. Weakness of lower limbs (n=37), muscle atrophy (n=23) and gait disturbance were the most common indicators of motor system involvement. The sensory complaints were mainly hypoesthesia (n=16), trophic ulcer (n=4) and autoamputation (n=3). Hypertrichiosis was the most common cutaneous marker present alone or in combination with other markers in 21 cases. MRI, done in all cases, correctly established the diagnosis. Additional lesions causing tethering were seen in 50% cases and were simultaneously treated. Associated Chiari malformation was seen in 12%. Of the 42 symptomatic patients, 21 improved, in 17 (40%) the neurological deficits stabilized and 4 showed deterioration. CSF leak occurred in 4 patients and 3 had wound infections. Among the asymptomatic patients none had neurological deterioration postoperatively.

Split cord malformations are rare spinal cord disorders. Complete neural axis should be scanned at the first instance to determine associated lesions. Good results can be expected in about 90% patients with minimal complications 13).


Thirty-nine patients with split cord malformations (SCM) were studied in detail with respect to their clinical, radiographic, and surgical findings as well as their outcome data. Eight patients were adults and 31 patients were children. According to the classification endorsed by Part I of the SCM study, 19 patients had Type I SCM (6 adults and 13 children), 18 patients had Type II SCM (2 adults and 16 children), and 2 patients had composite SCM with both lesion types situated in tandem. Six SCMs were cervical, 2 were thoracic, and 31 were in the lumbar region. All 8 adults had pain and progressive sensorimotor deficits at diagnosis. Only 16 of the 31 children had symptoms, and among these, 14 had progressive sensorimotor deficits, but only 6 had pain. The difference in the clinical picture between adults and children is similar to that described in the tethered cord syndrome, except for left-right functional discrepancy, which was prominent in 8 children with SCM but rarely seen in tethered cord syndrome due to other causes. Cutaneous manifestations of either occult or open dysraphic states were present in all but 3 patients; hypertrichosis was by far the best predictor of an underlying SCM, being found in 56% in the series. Neurological deterioration in SCM was independent of the lesion type: the Type I:Type II ratio for symptomatic progression was 13:11. It was also independent of the location of the lesion: 67% of patients with cervical SCMs had symptomatic progression versus 64% of patients with thoracolumbar lesions. High-resolution, thin cut, axial computed tomographic myelography using bone algorithms was more sensitive than magnetic resonance imaging in defining the anatomical details of the SCM. Radiographic classifications of the SCM, using the nature of the median septum and the number of dural tubes as criteria, was always possible without ambiguity. However, whereas every Type I bone septum was identified preoperatively, only 5 Type II fibrous septa were revealed by preoperative imaging, even though a fibrous septum and/or other fibroneurovascular bands were found tethering the hemicords in every Type II case at surgery. Complete imaging studies also showed that all lumbar SCMs had low-lying coni and at least one additional tethering lesion besides the split cords, whereas only 1 of 7 cervical and high thoracic SCMs had a low conus and a second tethering lesion. The surgical goal for SCM was release of the tethered hemicords by eliminating the bone spurs, dural sleeves, fibrous septa, or any fibroneurovascular bands (myelomeningoceles manqué) that might be transfixing the split cord. Type I cases were technically more difficult and had a slightly higher surgical morbidity than Type II cases, especially if an oblique bone septum had asymmetrically divided the cord into one larger hemicord and one smaller, hence, very delicate, hemicord 14).

Case reports

Nazarali et al. reported on two patients who atypically presented with SCM in adulthood and reviewed previous reports 15).


A rare case of a child with a complex spina bifida with two different levels of split cord malformation (SCM) type 1 and single-level type 2, a nonterminal myelocystocele, coccygeal dermal sinus, bifid fatty filum and hydrocephalus, which substantiates the neurenteric canal theory and have further tried to highlight the importance of complete Magnetic resonance imaging (MRI) screening of the whole spine and brain with SCM to rule out other associated conditions. The patient was admitted with a leaking myelocystocele with bilateral lower limb weakness. MRI of the whole spine with a screening of brain was done. Patient underwent 5 operations in the same sitting- (According to classification given by Mahapatra et al.) removal of SCM type 1a at D7-8; removal of SCM type1c at L2-3; removal of SCM type 2 at D10; repair of nonterminal myelocystocele at D6-D10; low-pressure ventriculoperitoneal shunt on right side with excision of dermal coccygeal sinus; and, excision of bifid fatty filum. The clinic radiological findings in our patient further substantiate the multiple accessory neuroenteric canal theory in the development of a composite type of SCM. The physical and neurological signs of SCM and nonterminal myelocystocele should prompt the neurosurgeon to consider performing the screening MRI of the whole spine with the brain to rule out other composite types of SCM and hydrocephalus 16).


A 78-year-old woman presented for evaluation of back pain, urinary dysfunction, leg weakness and progressive equinovarus foot deformity. She reported that shortly after her birth in 1924, she underwent resection of a subcutaneous ‘cyst’ in the lower lumbar area. Seven years prior to evaluation at our institution, she had undergone bilateral total knee arthroplasty for osteoarthritis. After the procedure, she began to experience severe low back pain that radiated into her legs. Weakness of the foot inverters, urinary dysfunction and worsening bilateral equinovarus foot deformity developed in the years following the surgery. MRI revealed a split cord malformation with a tethered spinal cord. Because of the patient’s age and poor medical condition, her symptoms were managed conservatively. This case demonstrates symptomatic deterioration in an elderly patient with a tethered spinal cord after many years of clinical stability 17).


A 32-year-old man with the adult-onset of impairment of sacral functions with lumbar fibrous diastematomyelia is reported. Surgical release of the spinal cord was followed by improvement of the patient’s function 18).

References

1) , 5)

Pang D, Dias MS, Ahab-Barmada M. Split cord malformation: Part I: A unified theory of embryogenesis for double spinal cord malformations. Neurosurgery. 1992 Sep;31(3):451-80. Review. PubMed PMID: 1407428.
2)

Saker E, Loukas M, Fisahn C, Oskouian RJ, Tubbs RS. Historical Perspective of Split Cord Malformations: A Tale of Two Cords. Pediatr Neurosurg. 2017;52(1):1-5. PubMed PMID: 27806370.
3)

Pang D, Dias MS, Ahab-Barmada M. Split cord malformation: Part I. A unified theory of embryogenesis for double spinal cord malformations. Neurosurgery 1992;31:451-480.
4)

Pang D, Dias MS, Ahab-Barmada M. Split cord malformation. Part II: Clinical syndrome. Neurosurgery 1992;31:481-500.
6) , 7) , 10)

Mahapatra AK, Gupta DK. Split cord malformations: a clinical study of 254 patients and a proposal for a new clinical-imaging classification. J Neurosurg. 2005 Dec;103(6 Suppl):531-6. PubMed PMID: 16383252.
8)

Beuriat PA, Di Rocco F, Szathmari A, Mottolese C. Management of split cord malformation in children: the Lyon experience. Childs Nerv Syst. 2018 May;34(5):883-891. doi: 10.1007/s00381-018-3772-3. Epub 2018 Mar 26. Erratum in: Childs Nerv Syst. 2018 May 17;:. Pierre-Aurelien, Beuriat [corrected to Beuriat, Pierre-Aurélien]; Federico, Di Rocco [corrected to Di Rocco, Federico]; Alexandru, Szathmari [corrected to Szathmari, Alexandru]; Carmine, Mottolese [corrected to Mottolese, Carmine]. PubMed PMID: 29582170.
9)

Mahapatra AK. Split cord malformation – A study of 300 cases at AIIMS 1990-2006. J Pediatr Neurosci. 2011 Oct;6(Suppl 1):S41-5. doi: 10.4103/1817-1745.85708. PubMed PMID: 22069430; PubMed Central PMCID: PMC3208912.
11)

Kumar R, Bansal KK, Chhabra DK. Split cord malformation (scm) in paediatric patients: outcome of 19 cases. Neurol India. 2001 Jun;49(2):128-33. PubMed PMID: 11447430.
12)

Proctor MR, Scott RM. Long-term outcome for patients with split cord malformation. Neurosurg Focus. 2001 Jan 15;10(1):e5. PubMed PMID: 16749757.
13)

Jindal A, Mahapatra AK. Split cord malformations–a clinical study of 48 cases. Indian Pediatr. 2000 Jun;37(6):603-7. PubMed PMID: 10869139.
14)

Pang D. Split cord malformation: Part II: Clinical syndrome. Neurosurgery. 1992 Sep;31(3):481-500. Review. PubMed PMID: 1407429.
15)

Nazarali R, Lyon K, Cleveland J, Garrett D Jr. Split cord malformation associated with scoliosis in adults. Proc (Bayl Univ Med Cent). 2019 Mar 27;32(2):274-276. doi: 10.1080/08998280.2019.1573624. eCollection 2019 Apr. Review. PubMed PMID: 31191152; PubMed Central PMCID: PMC6541173.
16)

Khandelwal A, Tandon V, Mahapatra AK. An unusual case of 4 level spinal dysraphism: Multiple composite type 1 and type 2 split cord malformation, dorsal myelocystocele and hydrocephalous. J Pediatr Neurosci. 2011 Jan;6(1):58-61. doi: 10.4103/1817-1745.84411. PubMed PMID: 21977092; PubMed Central PMCID: PMC3173919.
17)

Pallatroni HF, Ball PA, Duhaime AC. Split cord malformation as a cause of tethered cord syndrome in a 78-Year-old female. Pediatr Neurosurg. 2004 Mar-Apr;40(2):80-3. PubMed PMID: 15292638.
18)

Chehrazi B, Haldeman S. Adult onset of tethered spinal cord syndrome due to fibrous diastematomyelia: case report. Neurosurgery. 1985 May;16(5):681-5. PubMed PMID: 3889701.

Diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma

see also Diffuse midline glioma H3 K27M-mutant.

Diffuse midline glioma H3 K27M-mutant includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.

Epidemiology

Approximately 300 children are diagnosed with diffuse intrinsic pontine gliomas (DIPG) each year, usually between the ages of 5 and 9.

They account for 10% to 25% of pediatric brain tumors.

The majority of DIPGs are astrocytic, infiltrative, and localized to the pons.

Etiology

The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). The results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors 1).

Results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation 2).

Clinical Features

The symptoms of DIPG usually develop very rapidly prior to diagnosis, reflecting the fast growth of these tumors. Most patients start experiencing symptoms less than three months—and often less than three weeks—before diagnosis. The most common symptoms include:

Rapidly developing problems controlling eye movements, facial expressions, speech, chewing, and swallowing (due to problems in the cranial nerves) Weakness in the arms and legs

Problems with walking and coordination.

Diagnosis

Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis 3).


After the start of the era of biopsy, DIPGs bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 4).


Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG).

A retrospective review of magnetic resonance imaging (MRI) scanning in a pure population of DIPG was undertaken. Baseline diagnostic MRI findings included; local tumour extension in upper medulla (74%) or midbrain (62%), metastatic disease (3%), basilar artery encasement (82%), necrosis (33%), intratumoural haemorrhage (26%), hydrocephalus (23%) and dorsal exophytic component (18%). Post-treatment MRI scans demonstrated increases in; leptomeningeal metastatic disease (16%), cystic change/necrosis (48%), enhancement (72%) and intratumoural haemorrhage (32%). Response rates were calculated according to both RECIST (4%) and WHO (24%) criteria. No MRI parameter in either the diagnostic or response scans had prognostic significance 5).


Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important.

Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post-radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin’s concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement.

The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders 6).

Biopsy

The place of stereotactic biopsy in the management of Diffuses Intrinsic Pontine Gliomas (DIPG) in children has changed over the years.

Due to the improvement of neurosurgical technics, it regained credit. Moreover, the era of targeted therapy with molecular and genomic discoveries paved the way to research protocol that requires a biopsy to include the patient. Nonetheless, stereotactic biopsy remains a surgical procedure with its risks. A complication has never been reported in case of a biopsy of a DIPG : metastatic seeding along the tract of the biopsy. Beuriat et al report the first two cases in the literature 7).

Nevertheless, most neurosurgical teams are reluctant to perform biopsy in pediatric patients, citing potential risks and lack of direct benefit. Yet, in reviewing 90 patients with and the published data on brainstem biopsy, these procedures have a diagnostic yield and morbidity and mortality rates similar to those reported for other brain locations. In addition, the quality and quantity of the material obtained confirm the diagnosis and inform an extended molecular screen, including biomarker study-information important to designing next-generation trials with targeted agents. Stereotactic biopsies can be considered a safe procedure in well-trained neurosurgical teams and could be incorporated in well-defined protocols for patients with DIPG 8).

Treatment

Outcome

Complications

Case series

As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), Bander et al. measured treatment-related volumetric alterations in the brainstem and ventricles.

Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem.

Children in the study had a mean age of 7.7 years (range 2-18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8-8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days.

CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm 9).

1)

Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, Rodriguez FJ, Raabe E, Nazarian J, Warren K, Quezado MM. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol. 2013 Sep;37(9):1357-64. doi: 10.1097/PAS.0b013e318294e817. PubMed PMID: 24076776; PubMed Central PMCID: PMC3787318.
2)

Taylor IC, Hütt-Cabezas M, Brandt WD, Kambhampati M, Nazarian J, Chang HT, Warren KE, Eberhart CG, Raabe EH. Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition. J Neuropathol Exp Neurol. 2015 Jun 25. [Epub ahead of print] PubMed PMID: 26115193.
3)

Coca HA, Cebula H, Benmekhbi M, Chenard MP, Entz-Werle N, Proust F. Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note. Neurochirurgie. 2016 Dec;62(6):327-331. doi: 10.1016/j.neuchi.2016.07.005. PubMed PMID: 28120771.
4)

Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.
5)

Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol. 2008 Feb;86(3):313-9. Epub 2007 Oct 2. PubMed PMID: 17909941.
6)

Singh R, Zhou Z, Tisnado J, Haque S, Peck KK, Young RJ, Tsiouris AJ, Thakur SB, Souweidane MM. A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume. J Neurosurg Pediatr. 2016 Jul 8:1-8. [Epub ahead of print] PubMed PMID: 27391980.
7)

Beuriat PA, Szathmari A, Di Rocco F, Kanold J, Mottolese C, Frappaz D. Diffuse Intrinsic Pontine Glioma in children : document or treat ? World Neurosurg. 2016 Jul 12. pii: S1878-8750(16)30533-2. doi: 10.1016/j.wneu.2016.07.011. [Epub ahead of print] PubMed PMID: 27422681.
8)

Puget S, Blauwblomme T, Grill J. Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book. 2012:629-33. doi: 10.14694/EdBook_AM.2012.32.629. PubMed PMID: 24451809.
9)

Bander ED, Tizi K, Wembacher-Schroeder E, Thomson R, Donzelli M, Vasconcellos E, Souweidane MM. Deformational changes after convection-enhanced delivery in the pediatric brainstem. Neurosurg Focus. 2020 Jan 1;48(1):E3. doi: 10.3171/2019.10.FOCUS19679. PubMed PMID: 31896089.

Tuberous sclerosis complex

Tuberous sclerosis complex

Tuberous sclerosis complex, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called “tubers,” in the brains of patients postmortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville’s disease.

Key concepts

● most cases are due to spontaneous mutation. Inherited cases are autosomal dominant. Incidence: 1 in 6K–10K live births.

● classic clinical triad: seizures, mental retardation, and sebaceous adenomas; the full clinical triad is seen in < 1/3 of cases.

● typical CNS finding: subependymal nodules (“tuber”)—a hamartoma.

● commonly associated neoplasm: subependymal giant cell astrocytoma (SEGA)

● 2 tumor suppressor genes: TSC1 (on chromosome 9q34) codes for hamartin and TSC2 (on chromosome 16p13) encodes tuberin

● CT shows intracerebral calcifications (usually subependymal).


Tuberous sclerosis complex (TSC), AKA Bourneville’s disease, is a neurocutaneous disorder characterized by hamartomas of many organs including the skin, brain, eyes and kidneys. In the brain, the hamartomas may manifest as cortical tubers, glial nodules located subependymally or in deep white matter, or giant cell astrocytomas. Associated findings include pachygyria or microgyria.

Tuberous sclerosis complex (TSC) was initially described approximately 150 years ago by von Recklinghausen in 1862 1).

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease usually diagnosed in childhood.

Subependymal giant cell astrocytomas (SEGA) are benign brain lesions occurring in up to 20% of patients with TSC.

Epidemiology

Studies estimate a frequency of 1/6000 to 1/10,000 live births and a population prevalence of around 1 in 20,000 2) 3).

Etiology

Autosomal dominant inheritance; however, spontaneous mutation accounts for the majority of cases.

Two distinct tumor suppressor genes have been identified: the TSC1 gene (located on chromosome 9q34) codes for TSC1 (AKA hamartin), and the TSC2 gene (on chromosome 16p13.3) codes for TSC2 (tuberin). Only 1 gene needs to be affected to develop TSC. These proteins work together to inhibit the activation of rapamycin (mTOR). Genetic counseling for unaffected parents with one affected child: 1–2% chance of recurrence 4) 5).

Clinical features

This rare multi-system genetic disease causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung and kidney disease.

classic clinical triad: seizures, mental retardation, and sebaceous adenomas; the full clinical triad is seen in < 1/3 of cases.

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option.


The diagnosis of TSC is based on clinical features, but the variability of phenotype and age at symptom onset makes this challenging.

In the infant, the earliest finding is of “ash leaf” macules (hypomelanotic, leaf-shaped) that are best seen with a Wood’s lamp. Infantile myoclonus may also occur.

In older children or adults, the myoclonus is often replaced by generalized tonic-clonic or partial complex seizures, which occur in 70–80%. Facial adenomas are not present at birth but appear in > 90% by age 4 yrs (these are not really adenomas of the sebaceous glands, but are small hamartomas of cutaneous nerve elements that are yellowish-brown and glistening and tend to arise in a butterfly malar distribution, usually sparing the upper lip).

Retinal hamartomas occur in ≈ 50% (central calcified hamartoma near the optic disc or a more subtle peripheral flat salmon-colored lesion). A distinctive depigmented iris lesion may also occur.

Diagnosis

Pathology

Subependymal nodules (“tubers”) are benign hamartomas that are almost always calcified, and protrude into the ventricles.

▶ Subependymal giant cell astrocytoma (SEGA). Almost always located at the foramen of Monro. Occurs in 5–15% of patients with TSC.

Treatment

Outcome

In a nationwide multi-center study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient 6).

Case series

Liu et al. reported a nationwide multicentre retrospective study and analyzed the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients’ clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients’ ages at surgery were 10.35 ± 7.70 years (range: 0.5-47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient 7).


Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests.

Eight of 110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample.

Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects 8).

Case reports

A novel technique is presented for the application of MRgLITT in a 6-month-old infant for the treatment of epilepsy associated with tuberous sclerosis complex (TSC) .

To Hooten et al. from the Tuberous Sclerosis Complex Clinic, Duke University, Durham, North Carolina; and University of Florida, Gainesville, knowledge this is the youngest patient treated with laser ablation. They used a frameless navigation technique with a miniframe tripod system and intraoperative reference points. This technique expands the application of MRgLITT to younger patients, which may lead to safer surgical interventions and improved outcomes for these children 9).

References

1)

von Recklinghausen F. Die Lymphelfasse und ihre Beziehung zum Bindegewebe. [German]. Berlin: A. Hirschwald; 1862.
2)

O’Callaghan F, Shiell A, Osborne J, Martyn C. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet. 1998;352:318–319.
3)

Sampson J, Scahill S, Stephenson J, Mann L, Connor J. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet. 1989;26:28–31.
4)

European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315.
5)

van Slegtenhorst M, deHoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808.
6) , 7)

Liu S, Yu T, Guan Y, Zhang K, Ding P, Chen L, Shan Y, Guo Q, Liu Q, Yao Y, Yang M, Zhang S, Lin Y, Zhao R, Mao Z, Zhang J, Zhang C, Zhang R, Yang Z, Qian R, Li Y, Zhang G, Yuan L, Yang W, Tian H, Zhang H, Li W, Zhang X, Yin J, Guo Y, Zou L, Qin J, Fang F, Wang X, Ge M, Liang S. Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain. 2020 Jan 18. pii: awz411. doi: 10.1093/brain/awz411. [Epub ahead of print] PubMed PMID: 31953931.
8)

Manara R, Brotto D, Bugin S, Pelizza MF, Sartori S, Nosadini M, Azzolini S, Iaconetta G, Parazzini C, Murgia A, Peron A, Canevini P, Labriola F, Vignoli A, Toldo I. Rhinencephalon changes in tuberous sclerosis complex. Neuroradiology. 2018 Jun 17. doi: 10.1007/s00234-018-2045-x. [Epub ahead of print] PubMed PMID: 29909560.
9)

Hooten KG, Werner K, Mikati MA, Muh CR. MRI-guided laser interstitial thermal therapy in an infant with tuberous sclerosis: technical case report. J Neurosurg Pediatr. 2018 Sep 28:1-6. doi: 10.3171/2018.6.PEDS1828. [Epub ahead of print] PubMed PMID: 30265228.
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