Abstract

Background:Rosai–Dorfman is a rare disease that usually occurs in young adults. It is characterized with massive painless cervical lymphadenopathy and histiocyte proliferation. Isolated intracranial involvement is extremely rare. Our aim is to present a new rare case of extranodal Rosai–Dorfman disease that involved the right optic nerve in a 4-year-old boy.

Case Description:A 4-year-old boy with right-sided convergent strabismus and amblyopia lasting for 1 year was treated at the Department of pediatric ophthalmology. Initial optical fundus examination was normal. Examination repeated after 1 year noted the atrophy of the optic nerve papilla. Visual evoked potentials of the right eye showed normal findings of prechiasmatic visual pathway with severe dysfunction of the right optic nerve. Magnetic resonance imaging (MRI) of the brain and orbits showed expansive changed and elongated right optic nerve with contrast enhancement, and smaller lesion in the right temporal operculum region visible in T2 and fluid-attenuated inversion recovery sequence. Through small eyebrow “keyhole” osteoplastic frontoorbital craniotomy the fusiform enlarged (to 2 cm) right optic nerve was identified, resected between the eyeball and optic chiasm, and transferred for pathohistological analysis. Early postoperative course had no complications. Histological, immunohistochemical, and ultrastructural analyses revealed extranodal Rosai–Dorfman disease. Right periorbital edema was verified on the 7^th postoperative day and regressed to supportive therapy. Control multi slice computed tomography (MSCT) and MRI of endocranium and orbits showed total tumor removal with no signs of complications.

Conclusion:Although rare, extranodular intracranial Rosai–Dorfman disease should be taken into account in the differential diagnosis of intracranial and intraorbital lesions, especially in the pediatric age group.

Keywords: Extranodal, optic nerve, pediatric tumor, Rosai–Dorfman disease

INTRODUCTION

Rosai–Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML) is an uncommon benign histiocytic proliferative disorder of unknown origin.[ 1 2 7 9 12 14 19 ] It predominantly affects the lymph nodes but can also be found extranodally in other organs, and usually presents with other constitutional symptoms such as fever, malaise, weight loss, and raised inflammatory markers.[ 1 2 7 9 12 14 19 ] Approximately, one-third of the patients have concurrent extranodal involvement, most commonly in the skin, salivary glands, and upper respiratory tract.[ 21 ] Nervous system involvement is rare and in most cases intracranial.[ 2 9 11 12 ] Only 18 cases of intracranial involvement have been described previously. In addition, only 4 cases described the lesion with involvement of the orbits. Our report documents the first case, to our knowledge, of optic nerve localization of RDD.

CASE DESCRIPTION

History and examination

A 4-year-old boy presented with right-sided convergent strabismus and amblyopia that lasted for 1 year and was admitted to the Department of Pediatric Ophthalmology. His medical history was unremarkable except for the thrombocytopenia treated at 2 years of age. Before admission, he had regular ophthalmological exams and was treated with corrective glasses. An eye examination was performed by an ophthalmologist. Visual acuity was normal on his left eye, but visual acuity on his right eye was poor, he did not have the sense of light. Both eye bulb motility was normal with good pupil function. Initial optical fundus examination was normal. The cover test was positive on his right eye with right-sided convergent strabismus. Visual field was not done because of the patient's age. On the last ophthalmologic control exam, due to the right-sided atrophy of the optic nerve papilla and amblyopia, performing visual evoked potentials (VEP) and magnetic resonance imaging (MRI) were recommended. VEP of the right eye showed normal findings of prechiasmatic visual pathway with severe dysfunction of the right optic nerve. MRI of the brain and orbits showed expansive changed and elongated right optic nerve with contrast enhancement; furthermore, a smaller lesion in the right temporal operculum region was visible in T2 and fluid-attenuated inversion recovery sequence, as well as a small oval lesion in the left cerebellar lobe [Figures 1 and 2 ]. Optic nerve glioma was considered to be the most likely radiological diagnosis.

Figure 1

(a, b) Preoperative T1 magnetic resonance (MR) images demonstrates expansive changed and elongated right optic nerve. (c) Preoperative coronal plane T1 gadolinium-enhanced MR image. (d) Preoperative sagittal plane T2 MR image

Figure 2

(a, b) Preoperative magnetic resonance imaging showing left cerebellar and right temporal intracranial lesions

Surgical technique

The position of the patient was supine, with the head turned to the left at 15°, leaving the eyebrow as the most prominent point. Skin was incised through the eyebrow, medially up to the supraorbital notch leaving the supraorbital nerve intact. With one small burr hole at the superior temporal line, small supraorbital bone flap was performed which was 3 cm in width and 2.5 cm in height using a craniotome, including linear extensions over the supraorbital arch. Periorbita was detached from the bone and the bony flap was pushed down toward the orbit until the orbital roof brakes. With slight elevation of the bone, dura was detached from the orbital roof and the whole bone flap including supraorbital arch was removed in one piece. Using a diamond drill, the whole orbital roof was drilled out, optic canal widely opened, and anterior clinoid removed extraduraly. Periorbit was incised longitudinally, including annulus of Zinni and the dura over the optic nerve and frontobasaly, meticulously dissecting orbital muscles and nerves before reaching the optic nerve. Almost the whole optic nerve was thickened, and was irregularly shaped 2 mm from the eyeball and up to the chiasm. The nerve with the infiltrating tumor was cut leaving the normal white tissue at the resected planes of the nerve. Macroscopically, the tumor was firm, avascular, and had a gray-yellow color infiltrating the whole width of the optic nerve. There was no bleeding at the resected planes of the nerve and dura and periorbit was partly sutured and sealed. Bone flap was attached using microscrews, and the wound was closed in the standard manner.

Postoperative course

Early postoperative course was uneventful, except right-sided periorbital hematoma that spontaneously regressed few days later. Later, the patient received corneal ulcer refractory to treatment with topical antibiotic drops and cream for 3 months, after which the amniotic membrane transplant was performed to heal the ulcer completely. After 3 years of follow-up, MRI showed complete tumor removal without any sign of recurrence [ Figure 3 ].

Figure 3

(a, b) Postoperative T2 images, axial and coronal plane. (c) Postoperative T1 axial plane image

Histopathological workup

Microscopic examination of the surgical sample revealed a mainly histiocytic lesion in a fibrous background admixed with lesser populations of lymphocytes and plasma cells. The histiocytic cells showed evidence of emperipolesis. Immunohistochemically, tumor cells were CD68 and S100 positive and negative for langerin and CD1a. The phenotype was consistent with RDD [Figures 4 and 5 ]. There were no microorganisms, necrosis, or granuloma formation. Because of the extremely rare diagnosis, especially on this localization, paraffin blocks of tumor tissue were sent to the Department of Pathology Brigham and Women's Hospital in Boston, USA, for a second opinion. They confirmed our diagnosis of RDD.

Figure 4

(a) Microscopic features; mainly histiocytes and a few chronic inflammatory cells in fibrous background (hematoxylin and eosin ×100). (b) Emperipolesis; an additional common histopathologic finding in Rosai–Dorfmann disease (hematoxylin and eosin ×400)

Figure 5

Immunohistochemistry: (a) Glial fibrillary acidic protein small fragments of brain tissue were positive whereas tumour was negative (×100). (b) CD68 positive histiocytic tumor cells (×400); (c) negative staining for CD1a (×100)

DISCUSSION

RDD is a rare histiocytic disorder initially described as a separate entity in 1969 by Rosai and Dorfman using the term SHML.[ 19 ] The causes of RDD are not fully understood, and treatment strategies can be different according to the severity of vital organ involvement. It is usually seen in young adult patients but may occur in any age group.[ 13 ] Patients presenting with isolated intracranial disease tend to be older.[ 6 ] Moreover, it is more common in men, with a possible predilection for African Americans, and the mean age at presentation is approximately 20 years.[ 7 9 19 ] The etiology is uncertain, although agents such as the Epstein-Barr or herpes viruses are important in the pathogenesis.[ 10 ] The neck lymph nodes are the most frequently involved, followed by inguinal, axillary, and mediastinal lymph nodes.[ 3 16 ] The most common extranodal sites are the skin, upper respiratory tract, and bones. Head and neck involvement—approximately 22% of extranodal disease—include involvement of the nasal cavity, the paranasal sinuses, the nasopharynx, submandibular glands, the parotid, the larynx, the temporal bone, the intratemporal fossa, the pterygoid fossa, the meninges, and the orbit.[ 3 18 ] The skin is also commonly affected. Half of the patients have another associated extranodal site. Orbit and ocular glove involvement have been reported, usually as a retroorbitary mass and proptosis.[ 8 ] To our knowledge, the present case is the first example of optic nerve localization caused by RDD. Intracranial RDD usually occurs without extracranial lymphadenopathy, and most intracranial lesions are attached to the dura with only few extending intraparynchemally. Central nervous system disease can present clinically and radiologically as meningioma, however, the presence of emperipolesis in the cerebrospinal fluid is usually diagnostic of RDD.[ 15 ] In our case, glioma was considered to be the most likely radiological diagnosis. Emperipolesis is not a unique phenomenon to RDD and has been seen in both normal and leukemic processes,[ 19 ] however, it appears to be a prerequisite for the diagnosis. The clinical course of RDD is unpredictable with episodes of exacerbation and remissions that could last many years. The disease is often self-limiting with a very good outcome, nevertheless 5–11% of patients die from their disease. In the present case, clinical presentation of RDD was right-sided convergent strabismus and amblyopia without painless cervical lymphadenopathy with fever, which has been seen in other patients. The presenting symptoms depended on the location of the lesions and were manifested by cranial nerve deficits or nonlocalizing symptoms of raised intracranial pressure or seizures. Laboratory features in RDD are often nonspecific. Leukocytosis, elevated sedimentation rate, and polyclonal hypergammaglobulinemia have been reported in most patients, but in our case there were no laboratory abnormalities.[ 7 20 ] The differential diagnosis of extranodal SHLM may be a challenge, and is based on the clinical and histological examination. Histology shows typical features, such as diffuse lymphoplasmatic infiltration, Russel bodies, foamy histiocytes, and histiocytes with phagocytosed lymphocytes within the cytoplasm (emperipolesis). Immunohistochemical features include positive S-100, alpha-antichymotrypsin and CD1a and CD68 antigens.[ 3 18 ] Imaging (computed tomography and MRI) may be used to assess disease extension. If there is cervical lymph node enlargement, fine needle aspiration biopsy or lymph node biopsies may be useful for the diagnosis.[ 10 ] The differential diagnosis is made with lymphoreticular malignancies such as lymphomas, Hodgkin's disease, malignant histiocytosis, and monocytic leukemia, all of which have similar histopathological features. Atypia in cytology and the aggressive clinical course establish the diagnosis in most case. Other histiocytoses, such as rhinoscleromas and Wegener's granulomatosis, may also be included in the differential diagnosis.[ 8 ] Treatment is controversial. In the majority of cases, RDD has a benign course and treatment is not necessary.[ 22 ] Therapy is required, however, for patients with extranodal RDD having vital organ involvement or those with nodal disease causing life-threatening complications.[ 18 ] The role of surgery is mostly in biopsies and to relieve obstruction.[ 10 ] Local recurrence is frequent following surgical resection. The role of radiotherapy is not well understood; some reports have described full resolution with this treatment, whereas others have shown no response.[ 4 5 ] Systemic corticosteroids are usually helpful in decreasing nodal size and symptoms, however, they can be immunosuppressive and recurrence of RDD lesions can occur after a short period of interruption.[ 21 ] Chemotherapy has resulted in controversial results. A possible efficacy of methotrexate and 6-mercaptopurine requires further investigation. Other reports have suggested using alpha-interferon, although its side effects have its limited use.[ 14 ] Furthermore, the efficacy of the anti-CD20 monoclonal antibody/rituximab has been described in one case.[ 17 ] We treated our patient with the surgical form of treatment, to which he responded well, without radiotherapy and others modalities. Because of the rarity of such cases, long-term clinical and radiological follow-up is mandatory. In summary, we described a new case of isolated optic nerve RDD causing optic nerve infiltration. It should be considered among the rare differential diagnosis of optic nerve infiltration disease.

CONCLUSION

Extranodular intracranial RDD should be taken into account in the differential diagnosis of intracranial and intraorbital lesions, especially in pediatric age group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

We thank Prof. Christopher D. M. Fletcher, MD, FRCPath, from the Department of pathology Brigham and Women's Hospital Boston, USA, for his support in diagnosis.

References

1. Al-Saad K, Thorner P, Ngan BY, Gerstle JT, Kulkarni AV, Babyn P. Extranodal Rosai-Dorfman disease with multifocal bone and epidural involvement causing recurrent spinal cord compression. Pediatr Dev Pathol. 2005. 8: 593-8

2. Andriko JA, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman disease isolated to the central nervous system: A report of 11 cases. Mod Pathol. 2001. 14: 172-8

3. Carbone A, Passannante A, Gloghini A, Devaney KO, Rinaldo A, Ferlito A. Review of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of head and neck. Ann Otol Rhinol Laryngol. 1999. 108: 1095-104

4. Carpenter RJ, Banks PM, Mc Donald TJ, Sanderson DR. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Report of a case with respiratory tract involvement. Laryngoscope. 1978. 88: 1963-9

5. Cooper SL, Chavis PS, Fortney JA, Watkins JM, Caplan MJ, Jenrette JM. A case of orbital Rosai-Dorfman disease responding to radiotherapy. J Pediatr Hematol Oncol. 2008. 30: 744-8

6. Deodhare SS, Ang LC, Bilbao JM. Isolated intracranial involvement in Rosai-Dorfman disease: A report of two cases and a review of the literature. Arch Pathol Lab Med. 1998. 122: 161-5

7. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Review of the entity. Semin Diagn Pathol. 1990. 7: 19-73

8. Goodnight JW, Wang MB, Sercarz JA, Fu YS. Extranodal Rosai-Dorfman disease of the head and neck. Laryngoscope. 1996. 106: 253-6

9. Hargett C, Bassett T. Atypical presentation of sinus histiocytosis with massive lymphadenopathy as an epidural spinal cord tumor: A case presentation and literature review. J Spinal Disord Tech. 2005. 18: 193-6

10. Hazarika P, Nayak DR, Balakrishnan R, Kundaje HG, Rao PL. Rosai-Dorfman disease of the subglottis. J Laryngol Otol. 2000. 114: 970-3

11. Hollowell JP, Wolfla CE, Shah NC, Mark LP, Whittaker MH. Rosai-Dorfman disease causing cervical myelopathy. Spine. 2000. 25: 1453-6

12. Huang YC, Than HY, Jung SM, Chuang WY, Chuang CC, Hsu PW. Spinal epidural Rosai-Dorfman disease proceeded by relapsing uveitis: A case report with literature review. Spinal Cord. 2007. 45: 641-4

13. Juskevicius R, Finlay JL. Rosai-Dorfman disease of the parotid gland, cytologic and histopathologic findings with immunohistochemical correlation. Arch Pathol Lab Med. 2001. 125: 1348-50

14. Kidd DP, Revesz T, Miller NR. Rosai-Dorfman disease presenting with widespread intracranial and spinal cord involvement. Neurology. 2006. 67: 1551-5

15. Krafet SK, Honig M, Krishnamurthy S. Emperipolesis in the cerebrospinal fluid from a patient with Rosai-Dorfman disease. Diagn Cytopathol. 2007. 36: 67-8

16. Lauwers GY, Perez-Atayed A, Dorfman RF, Rosai . The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): Review of 11 cases. Hum Pathol. 2000. 31: 380-5

17. Petschner F, Walker UA, Scmitt-Graf A. Catastrophic systemic lupus erythematous with Rosai-Dorfman sinus histiocytosis. Successful treatment with anti-CD20/rituximab. Dtsch Med Wochenschr. 2001. 126: 998-1001

18. Pulsoni A, Anghel G, Falcucci P, Matera , R Pescarmona, Ribersani M. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Report of a case and literature Review. Am J Hematol. 2000. 69: 61-71

19. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathological entity. Arch Pathol. 1969. 87: 63-70

20. Sanchez R, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: An analysis of 113 cases with special emphasis on its extranodal manifestations. Lab Invest. 1977. 36: 349-50

21. Scheel MM, Rady PL, Tyring SK, Pandya AG. Sinus histiocytosis with massive lymphadenopathy: Presentation as giant granuloma annulare and detection of human herpesvirus 6. J Am Acad Dermatol. 1997. 37: 643-6

22. Tian Y, Wang J, Li M, Lin S, Wang G, Wu Z, Ge M, Pirotte BJ. Rosai-Dorfman disease involving the central nervous system: Seven cases from one institute. Acta Neurochir. 2015. 157: 1565-71

Abstract

Background:Dysembryoplastic neuroepithelial tumors (DNETs) are benign tumors characterized by a cortical location; they result in symptoms of drug-resistant partial seizures in children. The development of DNETs is poorly understood because most of them are resected immediately upon diagnosis without any observation period owing to the intractable seizures.

Case Description:We report the first DNET case with the growth rate analyzed in the natural course of development for a period of 10 years. The patient was a right-handed man who was initially referred to another hospital with mild head injury when he was 8 years old. A tumor located in the right insular cortex was incidentally detected on magnetic resonance imaging (MRI) and followed-up with annual MRI for 10 years.

Conclusion:In this case, the volume of the DNET increased in direct proportion to the length of time in its clinical course. The tumor doubling time was approximately 10 years. This case suggests DNET is a slow-growing but not stable tumor.

Keywords: Dysembryoplastic neuroepithelial tumor, insular, growth analysis

INTRODUCTION

Dysembryoplastic neuroepithelial tumors (DNETs) are benign, hamartomatous tumors thought to arise from the cortical gray matter. They are mixed neuronal-glial tumors, classified as grade I by the World Health Organization (WHO). Progression or post-surgical recurrence of DNETs is perceived to be extremely rare. DNETs typically cause intractable seizures in children, and are removed surgically without observation.[ 1 10 ] Therefore, the natural course and development of DNETs is poorly understood. The DNET case reported here was observed for 10 years without surgery because of the absence of symptoms. The lesion demonstrated gradual growth. We report an analysis of the DNET growth rate for the first time.

CASE REPORT

Our patient was initially referred to another hospital with mild head injury when he was 8 years old. An intra-axial tumor located in the right insular cortex was incidentally detected on MRI. Surgical resection was waived and followed-up for 10 years until the patient was 18 years old because of slowly growing tumor without symptoms. At the end of the observation period, the tumor size was measured to be one and a half times the diameter measured on the first MRI scan. After the end of the follow-up period, he visited our hospital for intensive examination and treatment.

The patient had no neurological deficit. Computed tomography (CT) imaging showed a low-density lesion with no calcification located in the right insular cortex [ Figure 1a ]. T1-weighted MRI demonstrated a hypointense lesion in the right insular cortex [ Figure 1b ]. T2-weighted MRI showed a hyperintense lesion that corresponded with the hypointensity on the T1-weighted image [ Figure 1c ]. T1-weighted MRI with gadolinium administration did not show any enhanced lesions [Figure 1d and e ]. Arterial spin labeling study suggested decreased blood flow at the lesion [ Figure 1f ].

Figure 1

Axial computed tomography (CT) (a) and magnetic resonance imaging (MRI) scans (b-d, f) and coronal MRI scan (e). (a) CT scan shows a low-density lesion in right insular cortex with no calcification. (b) T1-weighted MRI demonstrates a hypointense lesion. (c) T2-weighted MRI shows a hyperintense lesion that corresponds with the hypointensity on the T1-weighted MRI image. (d, e) T1-weighted MRI with gadolinium administration did not demonstrate any enhanced lesion. (f) Arterial spin labeling study shows decreased blood flow at the lesion

The lesion located in the right insular cortex demonstrated gradual growth for 10 years [Figure 2a - d ]. The change in lesion volume was assessed using polygonal tracing with fusion. Fluid-attenuated inversion recovery (FLAIR) signals were assessed using the DICOM image viewer OsiriX (®) (v. 7.0; Pixmeo SARL, Bernex, Switzerland) by slice-by-slice region of interest tracings. The growth rate of this lesion was found to be almost directly proportional to time [ Figure 2e ].

Figure 2

(a-d) T2-FLAIR MRI scans in the axial plane from age 8 to 18 years show gradual growth. An inserted picture in the corner of images is a three-dimensional reconstructed model of the tumor in each figure. (e) A dot graph with an almost straight line shows that the increase in tumor volume is directly proportional to time

In order to remove the lesion and obtain histopathological diagnosis, an awake craniotomy was performed using cortical and subcortical stimulation mapping with a bipolar direct electrical stimulator at 3.5 mA/60 Hz biphasic current to monitor motor and somatosensory response, speech or language difficulties, and other higher brain functions.[ 6 ] An anarthria was induced by stimulation of the ventral precentral gyrus [ Figure 3a ]. Tumor resection was performed via a transopercular approach. Intraoperatively, the nature of the tumor was gray, soft, and jelly-like tissue with clear boundaries. Fiber structures in the peripheral zone were relatively well-defined and we promoted excision of the tumor using an ultrasonic surgical aspirator. A postoperative MRI showed gross total resection of the tumor [ Figure 3b ]. Postoperative course was uneventful without neurological deficits. No recurrence was recognized postoperatively for 12 months.

Figure 3

Intraoperative (a) and postoperative (b) images. (a) Intraoperative view after tumor resection during awake surgery. Tag 1 suggests the area where anarthria was induced on the ventral precentral gyrus by direct electrical stimulation. An inserted picture is the three-dimensional cortical view. (b) Fluid-attenuated inversion recovery magnetic resonance imaging performed 3 months after the operation shows gross total resection. Arrows indicate the Sylvian fissure

Histological examination of the hypointense area on T1-weighted MRI showed multiple cystic structures with myxomatous background and proliferation of oligodendroglia-like cells with oval nuclei in the wall of the cystic spaces [ Figure 4a ]. Neuronal elements featuring “floating neurons” were observed, indicating a glioneuronal lesion within the cystic cavity [ Figure 4b ]. Immunohistochemical analysis revealed intense positive staining for Olig2, S-100 and synaptophysin, and less reactivity for IDH-1 [ Figure 4c ]. The Ki-67 staining index (SI) was 1% [ Figure 4d ]. A combined deletion of 1p and 19q chromosomes was absent. The histological diagnosis was WHO grade I DNET.

Figure 4

Photomicrographs of the surgical specimen showing the hypointense lesion on T1-weighted magnetic resonance imaging. (a) Multiple cystic structures are observed on a mucinous background. Hematoxylin and eosin (H and E) staining, original magnification ×100. (b) High-power view of a, showing floating neurons (arrows) scattered in the cystic structure. H and E staining, ×200. (c) Negative staining for IDH1 mutation, ×100. Inset: Positive control (d) The Ki-67 staining index was 1%, ×100

DISCUSSION

This rare case of DNET was followed for 10 years with annual MRI. Our statistical analysis of growth rate showed that the tumor volume gradually increased in direct proportion to time. According to this analysis, the tumor doubling time was determined to be approximately 3473 days. To date, only a few studies on DNET growth pattern have been reported.[ 3 4 ] We report the first case of DNET growth rate analysis in its natural course over a period of 10 years.

DNETs are usually stable tumors. However, malignant transformation in DNETs results in rapid growth rates.[ 3 10 ] It is still debated whether DNET is stable at birth or exhibits gradual growth in cases without malignant transformation. Jensen et al. reported a case of DNET that was stable for 15 years.[ 7 ] Conversely, Alexander et al. reported a case of DNET in which the occipital lobe grew from 5.2 cm to approximately 10.4 cm, accompanied by the appearance of enhanced tumor lesions on MRI for 10 years.[ 1 ] In our patient, the volume of DNET increased in direct proportion to the length of time without the appearance of enhanced lesions on MRI during its clinical course.

The lesion was located in the right insular cortex in our patient. DNETs typically occur in the temporal lobe in 62%, the frontal lobe in 31%, the parietal and/or occipital lobe in 7% of cases,[ 4 ] and rarely in the periventricular white matter, basal ganglia, thalamus, brainstem, and cerebellum[ 12 ] including the pons and third ventricle.[ 8 ] To the best of our knowledge, this is the first report of DNET located in the insular cortex.

DNET is generally positive for Olig2, S-100, and synaptophysin. The genetic background of DNETs has not been systemically investigated. Loss of heterozygosity at 1p/19q and TP53[ 5 ] or IDH1[ 2 ] mutations were not detected in DNETs. However, Maria et al. reported a case with 1p/19q chromosomal deletion and IDH1 mutation.[ 11 ] Most DNETs show very low proliferative activity and Ki-67 SIs lower than 1%.[ 9 ] Our results agreed with these findings.

The patient underwent an awake craniotomy. Gross total resection of the lesion was achieved. We expected an extremely low risk of tumor recurrence.[ 11 ] This case indicated that partial resection of DNETs might result in the regrowth of residual lesion in direct proportion to the length of time. Therefore, we suggest that patients with partial or subtotal resection of DNET be followed-up for longer time after surgery.

Despite being recognized for only less than three decades, DNETs are becoming an important part of epilepsy neurosurgical practice. However, their natural growth rate remains poorly understood. We present this case to increase the knowledge related to the growth pattern of these tumors, and to suggest that the growth rate of DNETs is directly proportional to time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

We thank Erika Komura for assistance with preparation of the immunohistochemistry.

References

1. Alexander H, Tannenburg A, Walker DG, Coyne T. Progressive dysembryoplastic neuroepithelial tumour. J Clin Neurosci. 2015. 22: 221-4

2. Capper D, Reuss D, Schittenhelm J, Hartmann C, Bremer J, Sahm F. Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol. 2011. 121: 241-52

3. Daghistani R, Miller E, Kulkarni AV, Widjaja E. Atypical characteristics and behavior of dysembryoplastic neuroepithelial tumors. Neuroradiology. 2013. 55: 217-24

4. Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws ER, Vedrenne C. Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery. 1988. 23: 545-56

5. Fujisawa H, Marukawa K, Hasegawa M, Tohma Y, Hayashi Y, Uchiyama N. Genetic differences between neurocytoma and dysembryoplastic neuroepithelial tumor and oligodendroglial tumors. J Neurosurg. 2002. 97: 1350-5

6. Herbet G, Lafargue G, Almairac F, Moritz-Gasser S, Bonnetblanc F, Duffau H. Disrupting the right pars opercularis with electrical stimulation frees the song: Case report. J Neurosurg. 2015. 123: 1401-4

7. Jensen RL, Caamano E, Jensen EM, Couldwell WT. Development of contrast enhancement after long-term observation of a dysembryoplastic neuroepithelial tumor. J Neurooncol. 2006. 78: 59-62

8. Leung SY, Gwi E, Ng HK, Fung CF, Yam KY. Dysembryoplastic neuroepithelial tumor. A tumor with small neuronal cells resembling oligodendroglioma. Am J Surg Pathol. 1994. 18: 604-14

9. Mano Y, Kumabe T, Shibahara I, Saito R, Sonoda Y, Watanabe M. Dynamic changes in magnetic resonance imaging appearance of dysembryoplastic neuroepithelial tumor with or without malignant transformation. J Neurosurg Pediatr. 2013. 11: 518-25

10. Moazzam AA, Wagle N, Shiroishi MS. Malignant transformation of DNETs: A case report and literature review. Neuroreport. 2014. 25: 894-9

11. Thom M, Toma A, An S, Martinian L, Hadjivassiliou G, Ratilal B. One hundred and one dysembryoplastic neuroepithelial tumors: An adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol. 2011. 70: 859-78

12. Yang AI, Khawaja AM, Ballester-Fuentes L, Pack SD, Abdullaev Z, Patronas NJ. Multifocal dysembryoplastic neuroepithelial tumours associated with refractory epilepsy. Epileptic Disord. 2014. 16: 328-32

Abstract

Background:Bowel perforation is a serious but rare complication after a ventriculoperitoneal shunt (VPS) procedure. Prior studies have reported spontaneous bowel perforation after VPS placement in adults of up to 0.07%. Transanal catheter protrusion is a potential presentation of VPS bowel perforation and places a patient at risk for both peritonitis and ventriculitis/meningitis via retrograde migration of bacteria. This delayed complication can be fatal if unrecognized, with a 15% risk of mortality secondary to ventriculitis, peritonitis, or sepsis.

Case Description:We describe a unique case of a patient with distal VPS catheter protrusion from the anus whose bowel perforation did not cause clinical sequelae of infection. We were able to manage the patient without laparotomy.

Conclusions:A subset of patients can be managed without laparotomy and only with externalization of the ventricular shunt with antibiotics until the cerebrospinal fluid cultures finalize without growth.

Keywords: Bowel perforation, complications, ventriculoperitoneal shunt

INTRODUCTION

Peritoneal complications of ventricular shunt placement (VPS) are uncommon along with serious events.[ 1 7 9 14 ] Spontaneous bowel perforation after VPS has been reported with an incidence of 0.01–0.07% with a high mortality of up to 15%.[ 9 14 ] However, it still remains an underappreciated potential complication. There has been a shift toward the assistance of general surgery for the laparoscopic placement of the distal shunt tubing, and it is unclear if this affects the rate of bowel perforation.

Regardless of prompt recognition of this uncommon condition, important and delayed recognition can have significant consequences for patient care.

CASE REPORT

A 29-year-old male with shunted congenital hydrocephalus of unknown etiology with previous revisions in infancy and as a young child initially presented to the neurosurgery clinic with worsening headaches and complaints of blurred vision for more than 18 months. Computerized tomography (CT) of the head demonstrated a slight increase in his ventricular size; physical evaluation noted mild chronic papilledema and reduced visual acuity in his left eye, which was baseline following a car accident a few years earlier. He had a right parietal VPS in place; shunt series X-rays showed no shunt disconnections. In addition, abdominal X-rays demonstrated a retained peritoneal distal catheter from his previous shunt revision operations. Given the concerns for shunt failure, he underwent shunt exploration and revision for management. During the shunt revision surgery, the valve was found to be nonfunctional and was replaced; the retained peritoneal distal catheter was also removed laparoscopically by the general surgery team. His initial postoperative course was uncomplicated, and he was discharged on postoperative day 1 with decrease in his headaches and improvement in his subjective complaint of blurry vision.

He again presented 17 months later with continual headaches, decrease in vision, and increased ventricular size. This time he was noted to have acute papilledema and worsened visual acuity in his right eye. Given the concern regarding the age of the ventricular and distal catheter in his right parietal system, which had been placed at 4 months of age, it was determined that the placement of a new shunt system would be the best clinical option. He underwent another VPS revision with placement of a new right frontal VPS shunt and a new distal peritoneal catheter placed laparoscopically by the general surgery team [ Figure 1 ]. His initial postoperative course was uncomplicated, and the patient's headaches decreased, however, he did experience a lasting deficit in his visual acuity. Two months postoperatively, he presented to the emergency room with complaints of an object intermittently protruding from his rectum. At this initial emergency room evaluation, his rectal exam was unremarkable; on shunt series X-rays, the distal catheter was within the peritoneal cavity [ Figure 2 ]. The patient was subsequently discharged without neurosurgical consultation.

Figure 1

Postoperative abdominal X-ray film following the patient's second shunt revision demonstrating appropriate shunt placement. As noted, the peritoneal portion was placed laparoscopically by general surgery and was visualized to be within the peritoneal space

Figure 2

Initial evaluation in the emergency department demonstrating shunt catheter placement in the abdomen, which was originally interpreted as intraperitoneal

One month later, he presented with continued complaints of an object intermittently protruding from his rectum. During the emergency room evaluation, a neurosurgical consultation was obtained and the rectal exam revealed that the distal peritoneal catheter was protruding through his anus. X-rays corroborated the physical exam [ Figure 3a ]; CT imaging clearly revealed the distal peritoneal catheter within the large colon and rectum [ Figure 3b ]. On examination, the patient had no signs of peritonitis or meningitis, and he described no abdominal pain, feeding concerns, fevers, worsening headaches, or blurry vision.

Figure 3

(a) Abdominal shunt series X-ray showing the distal peritoneal catheter protruding through the rectum (arrow), and (b) abdominal computed tomography showing the distal peritoneal catheter within the bowel (arrow)

INTERVENTION PERFORMED

Because the patient was clinical asymptomatic except for the distal catheter protrusion through the anus, the general surgery team was consulted, and we decided to expose and externalize the distal catheter at the clavicle with simultaneous removal of the remaining distal catheter through the previous laparoscopic abdominal incision in a manner described previously.[ 1 ] Cerebrospinal fluid (CSF) taken at the time of the externalization of the shunt did not show any organisms on gram stain or subsequent bacterial growth on culture, with a normal glucose level of 72 mg/dL and a normal protein level of 23 mg/dL.

POSTOPERATIVE COURSE

The patient was placed on a triple antibiotic regiment of flagyl, vancomycin, and cefepime; daily CSF cultures from the externalized shunt revealed no bacterial growth. After 5 days of negative cultures, he underwent removal of all previous hardware and placement of a new right frontal ventriculoatrial shunt. His antibiotic regimen was continued for 1 day and he was discharged on postoperative day 2 without further antibiotics. At the patient's 6 month postoperative visit, he was doing well with no signs of infection and decreased headaches.

DISCUSSION

At our institution, it is common practice to enlist the assistance of general surgery to place the distal catheter laparoscopically. The reason for this is the theoretical advantage of visualizing the distal catheter within the peritoneal space, thus reducing the likelihood of incorrect placement; it also allows for a small incision and good wound healing at the distal site. However, as with any laparoscopic procedure, it is possible that a bowel injury was caused at the time of operation. The reported incidence of laparoscopic-induced bowel perforation is 0.22%, and most are recognized at the time of surgery.[ 12 ] There have been no reports of shunt bowel perforation with a laparoscopic approach to placement of the distal catheter. At this time, spontaneous bowel perforation appears to be the most likely cause, however, as laparoscopic approaches become more common, it will be important to pay close attention to the incidence of this uncommon complication.

The exact pathogenesis of spontaneous bowel perforation is unclear having been first reported by Wilson and Bertran[ 13 ] in two pediatric patients. Since the initial report, there have been approximately 90 documented cases in the literature regarding VPS-induced bowel perforation. In cases that have warranted surgical intervention, or by autopsy, the authors have described an encasing fibrotic scar anchoring the tubing to an area of the bowel and causing ulceration, and theoretically, eventual perforation.[ 3 ]

Clinical presentation may be straightforward with 44% of the patients having abdominal pain, vomiting, and fever, and 50% with clinical signs of meningitis.[ 4 6 14 ] Abdominal radiology can be diagnostic in a majority of these cases, and both X-ray and CT have been used with success.[ 4 5 11 ] Notably though, almost half of the patients with distal catheter bowel perforation may present without abdominal pain or signs of infection within the abdomen or shunt, which may hinder accurate diagnosis. Further complicating the clinical presentation of VPS-bowel perforation is the delayed nature of its presentation from the original surgery and the uncommon nature of this complication. Its presentation is so rare that colleagues outside the neurosurgical field may not be aware of this entity.[ 2 4 ] As with our patient, initial evaluation with abdominal shunt series X-rays 1 month prior to definitive diagnosis was interpreted as unremarkable and only on re-evaluation was the concern raised that the distal peritoneal catheter may be within the bowel based on the pattern of the distal catheter following the transverse and descending colon [ Figure 2 ].

Management of bowel perforation is highly individualized and dependent upon the presenting signs and symptoms of the patient. Immediate externalization is necessary to maintain shunt patency, as well as to limit the retrograde spread of bacteria along the shunt system which can cause ventriculitis or meningitis.[ 6 ] If there is a concern of abdominal abscess or peritonitis, laparotomy is the preferred treatment choice to manage the bacterial infection.[ 8 11 ] However, in cases where there is no evidence of peritoneal involvement and the patient's exam remains benign, it is believed that the fistulous opening should close spontaneously after removal of the catheter.[ 10 14 ] As we demonstrated here, this subset of patients can be managed without laparotomy and only with externalization of the ventricular shunt with antibiotics until the CSF cultures finalize without growth. Importantly, when re-shunting a patient, we highly recommend choosing a different terminus outside the abdominal cavity, as there remains the concern that the factors leading to bowel perforation are still present, such as the atrium (as in our case) or pleura.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Abu-Dalu K, Pode D, Hadani M, Safar A. Colonic complications of ventriculoperitoneal shunts. Neurosurgery. 1983. 13: 167-9

2. Akcora B, Serarslan Y, Sangun O. Bowel perforation and transanal protrusion of a ventriculoperitoneal shunt catheter. Pediatr Neurosurg. 2006. 42: 129-31

3. Brownlee JD, Brodley JS, Schaefer IK. Colonic perforation by ventriculoperitoneal shunt tubing: A case of suspected silicon allergy. Surg Neurol. 1998. 49: 21-4

4. Ferreira PR, Bizzi JJ, Amantea SL. Protrusion of ventriculoperitoneal shunt catheter through the anal orifice. A rare abdominal complication. J Pediatr Surg. 2005. 40: 1509-10

5. Hornig GW, Shillito J. Intestinal perforation by peritoneal shunt tubing: Report of two cases. Surg Neurol. 1990. 33: 288-90

6. Ibrahim AW. E-coli meningitis as an indicator of intestinal perforation by V-P shunt tube. Neurosurg Rev. 1998. 21: 194-7

7. Sathyanarayana S, Wylen EL, Baskaya MK, Nanda A. Spontaneous bowel perforation after ventriculoperitoneal shunt surgery: Case report and a review of 45 cases. Surg Neurol. 2000. 54: 388-96

8. Schulhof LA, Worth RM, Kalsbeck JE. Bowel perforation due to peritoneal shunt. A report of 7 cases and a review of the literature. Surg Neurol. 1975. 3: 265-9

9. Sells CJ, Loeser JD. Peritonitis following perforation of the bowel: A rare complication of a ventriculoperitoneal shunt. J Pediatr. 1973. 83: 823-4

10. Sharma A, Pandey AK, Radhakrishnan M, Kumbhani D, Das HS, Desai N. Endoscopic management of anal protrusion of ventriculo-peritoneal shunt. Indian J Gastroenterol. 2003. 22: 29-30

11. Snow RB, Lavyne MH, Fraser RA. Colonic perforation by ventriculoperitoneal shunts. Surg Neurol. 1986. 25: 173-7

12. van der Voort M, Heijnsdijk EA, Gouma DJ. Bowel injury as a complication of laparoscopy. Br J Surg. 2004. 91: 1253-8

13. Wilson CB, Bertan V. Perforation of the bowel complicating peritoneal shunt for hydrocephalus. Report of two cases. Am Surg. 1966. 32: 601-3

14. Yousfi MM, Jackson NS, Abbas M, Zimmerman RS, Fleischer DE. Bowel perforation complicating ventriculoperitoneal shunt: Case report and review. Gastrointest Endosc. 2003. 58: 144-8

Abstract

Background:A neural tube defect (NTD) is a common congenital anomaly with an incidence of 6.57–8.21 per 1000 live births. Patients usually present early because of obvious swelling or due to neurological deficit. However, neglecting the obvious cystic swelling on the back till its transformation into malignant tumor is rare.

Case Description:We describe a case of malignant transformation of meningocele in a 60-year-old man. Magnetic resonance imaging showed sacral meningocele. Neurological examination revealed intact motor and sensory examination with normal bladder and bowel function. There were no signs of meningitis and hydrocephalus. Excision was done and biopsy revealed it as squamous cell carcinoma.

Conclusion:Meningocele should be treated early and possibility of malignant change should be kept in mind in neglected cases presenting in adulthood.

Keywords: Adult, meningocele, neural tube defects, squamous cell carcinoma

INTRODUCTION

A neural tube defect (NTD) is a common congenital anomaly with an incidence of 6.57–8.21 per 1000 live births.[ 1 3 ] Patients usually present early because of obvious swelling or due to neurological deficit. However, neglecting the obvious cystic swelling on the back till adulthood is rare. To the best of our literature search, we could find only few such cases.[ 2 4 5 6 7 ]

CASE REPORT

A 60-year-old man presented with complaints of discharge from a swelling in the sacral area. At the time of birth he was noted to have a sacral meningocele for which he was advised surgery, however, his family had refused and the wound surface slowly became abraded and exudated repeatedly over a period of years. One month before the admission, the swelling started discharging foul smelling fluid and increased in size. Inspection showed a swelling in the sacral region of 5 cm in diameter, consisting of cauliflower-shaped swelling with yellowish slough [ Figure 1 ]. The area smelled foul and was constantly draining serosanguinous fluid. Neurological examination revealed intact motor and sensory examination with normal bladder and bowel function. There were no signs of meningitis and hydrocephalus. Magnetic resonance imaging (MRI) showed sacral meningocele with sinus tract [Figure 2a and b ]. The tumor was excised, dural attachment was removed, and dura was closed again [ Figure 3 ].

Figure 1

Adult sacral meningocele with yellowish slough over it

Figure 2

(a, b) Magnetic resonance imaging of the spine (T1, T2 sagittal view) showing sacral meningocele

Figure 3

Operative photograph showing the swelling being excised

Pathological finding

The tissue sections were stained in hematoxylin and eosin (H and E) stain, and the histopathology study revealed tumor cells arranged in sheets and nests with keratin pearl formation [ Figure 4 ], suggestive of well-differentiated squamous cell carcinoma. On high power examination, these tumor cells were large with high nuclei/cytoplasmic ratio and prominent nucleoli.

Figure 4

Photomicrograph shows tumor cells arranged in sheets and central keratin pearl (marked arrow), which is suggestive of it being squamous cell carcinoma (H and E stain, ×400)

Postoperative course

The postoperative recovery was uneventful and the wounds healed by primary intention. Further, the patient was sent to the oncology department for adjuvant therapy. Postoperatively, the patient has been on follow-up for a year without any recurrence.

DISCUSSION

A meningocele is a congenital anomaly of neural arch fusion in association with an open neural tube defect, and is characterized by protrusion of spinal meninges which contain cerebrospinal fluid without involvement of the neural tissue. Most meningoceles are surgically repaired during the new-born period or at least in childhood. The incidence of survival is low without intervention, and hence, adult meningoceles are rarely seen. Life expectancy at birth is shorter in myelomeningocele patients, although effective treatment for hydrocephalus and intermittent catheterization for the management of the neurogenic bladder can improve the quality of life for these patients. Posterior lumbosacral meningocele cases have rarely been reported. The long-term follow up results for adults with sacral myelomeningocele are not as good as in children because other neurological abnormalities such as hydromyelia, syringomyelia, tethered cord, Chiari malformations, and hydrocephalus accompany this lesion.[ 3 ]

A search of the literature revealed four cases similar to the one we have described. Saskun et al.[ 6 ] biopsied a neglected case of lumbosacral myelomeningocele who presented with fungating growth. Histology showed squamous cell carcinoma and radiotherapy was instituted. In the case reported by Thorp,[ 7 ] surgical treatment was chosen initially for a 26-year-old man with a carcinoma at the site of a lumbar meningomyelocele. Six months after resection, the tumor recurred and was treated with radiotherapy. Later, the tumor appeared again, necessitating further surgery. Three weeks postoperatively, the patient the patient died of septicemia. In the case described by Pope and Todorovl,[ 5 ] a squamous cell carcinoma developed at the site of a cervical meningomyelocele in a 37-year-old man. This lesion was easily excised, without complications because the defect was a meningocele, and hence did not contain neural elements or connect with the spinal canal. Hong- Zhou et al.[ 2 ] excised a cauliflower-shaped lumbosacral myelomeningocele in an 11-year-old boy, who had the swelling since birth. It turned out to be squamous cell carcinoma on histology. Our patient presented as a neglected case of sacral meningocele with a discharge from the swelling and normal neurological examination. Excision of the mass was done and biopsy revealed squamous cell carcinoma.

MRI is a good investigation choice for evaluating the meningocele sac in the sagittal plane, and to observe the spinal cord itself, as well as the possible congenital anomalies associated with it.[ 2 4 ]. In meningocele cases, neurological involvement are not seen as often as in myelomeningocele lesions, however, the local signs of sacral nerve involvement are seen as pain in both legs and bladder dysfunction. Taking this into consideration, somatosensory evoked potentials (SSEP) can be used in these patients as in myelomeningoceles.[ 4 ]

One must be aware of possible neoplastic change in untreated meningomyelocele after years of mechanical irritation and chronic bacterial infection. This seems to be a probable cause in our case. The defect, lacking a protective epithelial cover, must be viewed regularly with a high degree of suspicion, as with other chronic ulcers. Squamous cell carcinoma is a well-known complication of burn and chronic venous ulcer, pilonidal sinuses, longstanding bacterial and fungal infections, vaccination scars, and even tattoos.[ 6 ]

Once change is noted, biopsies should be done to establish a histological diagnosis. If malignancy is established, an intensive search for metastases, lymph node involvement, and local invasion must be made for proper staging and subsequent treatment.[ 6 ]

CONCLUSION

In conclusion, meningocele should be treated as soon as diagnosed and possibility of malignant change should be kept in mind in neglected cases presenting in adulthood.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Cherian A, Serena S, Bullock RK, Antony AC. Incidence Of Neural Tube Defects In The Least-Developed Area Of India: A Population-Based Study. Lancet. 2005. 366: 930-1

2. Duan HZ, Zhang Y, Zhang JY, Bao SD, Zhou CQ. A Case Report of Squamous Cell Carcinoma Arising In a Patient with Meningomyelocele. Beijing Da Xue Xue Bao. 2009. 41: 489-91

3. Laharwal MA, Sarmast AH, Ramzan AU, Wani AA, Malik NK, Arif SH. Epidemiology of the neural tube defects in Kashmir valley. Surg Neurol Int. 2016. 7: 35-

4. Ozdemir NG, Atci IB, Antar V, Yllmaz H, Bitirak G, Katar S. Lumbosacral Meningocele In Adulthood. Cukurova Med J. 2015. 40: 131-5

5. Pope M, Todorov AB. Cutaneous squamous cell carcinoma as a rare complication of cervical meningocele. Birth Defects. 1975. 11: 336-

6. Saskun JM, Fisher BK. Squamous Cell Carcinoma Arising In a Meningomyelocele. Can Med Assoc J. 1978. 119: 739-41

7. Thorp RH. Carcinoma Associated With Myelomeningocele. Case Report. J Neurosurg. 1967. 27: 446-8

Abstract

Background:Ventriculoperitoneal (VP) shunt is a day-to-day procedure performed by a neurosurgeon. The most frequent associated complications are obstructive and infectious. Although rare, there are well-reported complications related to the poor positioning of the distal catheter, with perforation of organs and tissues. Still rarer are the complications related to the migration of this catheter.

Case Description:We describe an atypical case of VP shunt postoperative by normal pressure hydrocephalus. After well-documented proper positioning of the distal catheter into the intraperitoneal cavity, it protruded into the subcutaneous space. Even on a new documented satisfactory abdominal tomography, this catheter migrated back again to the subcutaneous tissue.

Conclusion:We did not find plausible explanation for this rare event.

Keywords: Catheters, cerebrospinal fluid shunts, normal pressure hydrocephalus, postoperative complications, surgically-created structures, ventriculoperitoneal shunt

INTRODUCTION

Placement of a ventriculoperitoneal (VP) shunt is the most common treatment for hydrocephalus.[ 6 ] It is a routine, common, and effective procedure in Neurosurgery.[ 2 ] Complications of VP shunts may occur anywhere along their course from the cerebral ventricle to the peritoneal cavity.[ 6 ] Valvular dysfunction secondary to the obstruction of proximal catheter is relatively frequent in the emergency room. However, non-infectious obstruction of distal catheter is exceptional.[ 9 ] Rare complications such as migration of the peritoneal catheter into the stomach, liver, gallbladder, vagina, scrotum, bladder, bowel, colon, pulmonary artery, diaphragm, cardiac ventricle, cervical area, umbilicus, rectum, anus, and mouth have been described in the literature. We report a case of a male patient with normal pressure hydrocephalus (NPH) submitted to VP shunt. The distal catheter protruded from the intraperitoneal cavity and lodged in the subcutaneous tissue, leading to collection of cerebrospinal fluid (CSF). The same thing occurred after another surgery for catheter repositioning. During both times, control computed tomography (CT) scans had recorded proper positioning of all shunt systems. This unusual complication is extremely uncommon. According to our records, there is no case cited in the past.

CASE REPORT

A male patient, 63-year-old, with no known comorbidities and a cocaine user, presented with over 1 year of classic triad of dementia, urinary incontinence, and ataxia march. The diagnosis of NPH was confirmed by CT scan, with Evans index of 0.62, as shown in Figure 1 . Therapeutic test (tap test) was positive for improvement of symptoms after 50 mL drain of CSF by lumbar puncture. He was submitted to ventriculoperitoneal shunt uneventfully. In our hospital, we routinely perform CT scans of the skull and abdomen as postoperative control, and both showed the entire system to be positioned properly [Figures 2 and 3 ]. However, on the second postoperative day, the patient presented with clinical worsening, with recurrence of early symptoms, and an abdominal collection was identified by superficial palpation. New abdomen CT identified the distal catheter protruding from the peritoneal cavity and housed beneath the subcutaneous tissue, producing a collection of CSF, as shown in Figure 4 . During further surgery to reposition the catheter, it was identified immediately below the skin after the incision, and no other pathological findings were noteworthy [Figures 5 and 6 ]. The shunt was otherwise functioning, however, there was a subcutaneous collection filled with a turbid CSF. New control CT showed the catheter well positioned in the peritoneal cavity [ Figure 7 ] and the patient symptoms improved. However, again 2 days after the last surgery, a superficial collection in the abdomen was identified, similar to the previous event. Another CT scan suggested the same event, with prolapsed and allocated catheter in abdominal subcutaneous and a collection of CSF, as illustrated in Figure 8 . New surgical repositioning of the entire DVP system was performed uneventfully, with appropriate control scans [Figures 9 and 10 ].

Figure 1

Computed tomography scan showing Evans index of 0.62, confirming the diagnosis of normal pressure hydrocephalus

Figure 2

Computed tomography scan after ventriculoperitoneal shunt with the catheter well positioned in the anterior horn of the right lateral ventricle

Figure 3

Abdomen tomography after ventriculoperitoneal shunt with the catheter well positioned in the peritoneal cavity

Figure 4

Abdomen tomography two days later, with the catheter lodged in the subcutaneous tissue, and cerebrospinal fluid collection in the same space

Figure 5

Aspect of coiling of the distal catheter after opening the abdominal incision

Figure 6

Distal catheter functioning wrapped in the subcutaneous space resulting in collection of cerebrospinal fluid

Figure 7

Abdomen tomography after repositioning of the distal catheter spread into the peritoneal cavity with no other complications

Figure 8

Abdominal tomography 2 days after the second surgery demonstrating new protrusion of the catheter from the peritoneal cavity into the subcutaneous space

Figure 9

Final control CT scan, with the ventricular catheter in the proper position

Figure 10

Final control abdomen tomography, with the peritoneal catheter in proper position

The patient was discharged on the fifth postoperative day of the second surgical shunt revision. No further problems were noted during regular follow-ups at the outpatient office, with significant clinical improvement in gait and bladder control, although with no marked cognitive improvement. CT scan showed reduction of brain ventricles globally. He had clean and dry operative wounds, functioning valve to palpation; and the abdomen flat, flaccid, and not painful on palpation.

DISCUSSION

Infectious and obstructive are the most frequent complications after shunt surgery.[ 1 8 ] Other types are less common, and eventually occur due to technical errors during brain ventricular puncture, opening the intraperitoneal cavity and the catheter tunneling between the two points.

There are several cases reports of distal catheter migration to cardiac ventricle.[ 2 ] The hypothesis is an incidental perforation of internal jugular vein during tunnelization, added to negative inspiratory pressure and orthograde, as well as slow blood flow that may draw the catheter proximally through vein and eventually to the heart or even to the pulmonary artery.[ 2 4 6 8 ] These could be resolved with a pericardial window by cardiac surgeons[ 4 ] by an endovascular approach, either guided by fluoroscopy through the internal jugular vein, or via femoral and inferior vena cava.[ 2 6 ]

Other documented complication of VP drainage is effusion of CSF through pleura (hydrothorax), peritoneum (ascite) and peritoneum-vaginal processus (hydrocele),[ 7 9 ] all for absorption issues and normally in children.

In a large series of 1585 VP shunts, only 0.7% developed large abdominal cysts, and the associated causes were infection, particularly by Staphylococcus epidermidis and multiple-shunt revisions. Simple parencentesis and replacement of the shunt usually are sufficient treatment for this complication, if infection is not present.[ 5 ]

Our case had a complication not as serious as the aforementioned because there was no perforation of the hollow viscus or penetration of involved organs, and there was no infection. Nevertheless, the involved mechanisms with twice protrusion of distal catheter are not easily explicated.

One revision in 2013 of 12 cases of upward VP catheter migration postulated the following hypothesis.[ 1 ] (1) Reabsorption of subgaleal fluid may generate negative pressure, dragging the distal tubing proximally; (2) “Windlass effect,” with some granulation tissue or valve placed below the scalp, which acts as an anchoring point, and the patient's repeated head motion allows the distal tubing to be pulled in a proximal direction; (3) Increased abdominal pressure during Valsalva maneuver may act as a pushing force for distal tubing to migrate upward; (4) The memory of devices placed in packaging allows the tubing to recoil, as explained by the “memory phenomenon;”[ 3 ] (5) Unishunt catheters with a spring coil mechanism and no interposed valves or flushing devices are more frequently involved in migration. Shunt migration depends on various factors such as the type of catheter and reservoir used (for example, shunt migration in children is more frequent). None of the migration hypotheses are clearly defined but many similar cases include the “windlass effect.”[ 1 ]

One of these cases was a child with proximal migration of the VP catheter and extrusion of the ventricular catheter. This resulted in the entire VP shunt along with the shunt chamber lying in a subgaleal pocket in the occipital region in a tightly coiled manner. This coiling was very similar in appearance to that of the pre-insertion shunt in the packaging when it was supplied; hence, it was postulated that the migration was secondary to retained “memory” of the shunt tubing.[ 3 ]

Regardless of what mechanism was involved in the case of our patient, we did not find any cases in the literature with the occurrence of two consecutive extrusions of distal catheter. Further, we did not find references about protrusion only for abdominal subcutaneous space. We noted that in both instances there were imaging studies documenting the good positioning of the entire system previously.

CONCLUSIONS

We emphasize the importance of careful and proper placement of the distal catheter during the tunneling procedure to prevent complications, as well as the importance of carrying out control tests to document the satisfactory placement of the entire shunt system.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Cho KR, Yeon JY, Shin HJ. Upward migration of a peritoneal catheter following ventriculoperitoneal shunt. J Korean Neurosurg Soc. 2013. 53: 383-5

2. Chong JY, Kim JM, Cho DC, Kim CH. Upward migration of distal ventriculoperitoneal shunt catheter into the heart: Case report. J Korean Neurosurg Soc. 2008. 44: 170-3

3. Dominguez CJ, Tyagi A, Hall G, Timothy J, Chumas PD. Sub-galeal coiling of the proximal and distal components of a ventriculo-peritoneal shunt. An unusual complication and proposed mechanism. Childs Nerv Syst. 2000. 16: 493-5

4. Frazier JL, Wang PP, Patel SH, Benson JE, Cameron DE, Hoon AH. Unusual migration of the distal catheter of a ventriculoperitoneal shunt into the heart: Case report. Neurosurgery. 2002. 51: 819-22

5. Gutierrez FA, Raimondi AJ. Peritoneal cysts: A complication of ventriculoperitoneal shunts. Surgery. 1976. 79: 188-92

6. Hermann EJ, Zimmermann M, Marquardt G. Ventriculoperitoneal shunt migration into the pulmonary artery. Acta Neurochir. 2009. 151: 647-52

7. Kim JH, Roberts DW, Bauer DF. CSF hydrothorax without intrathoracic catheter migration in children with ventriculoperitoneal shunt. Surg Neurol Int. 2015. 23(Suppl 11): S330-3

8. Manix M, Sin A, Nanda A. Distal ventriculoperitoneal shunt catheter migration to the right ventricle of the heart--A case report. J La State Med Soc. 2014. 166: 21-5

9. Rivero-Garvía M, Barbeito Gaído JL, Morcillo J, Márquez Rivas J. Shunt dysfunction secondary to peritoneal catheter migration to the scrotum. Arch Argent Pediatr. 2013. 111: e14-6

Commentary

1. Center for World Health, Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA E-mail: jalazareff@mednet.ucla.edu

The natural history of a surgical complication has always been a puzzle. We surgeons tend to believe that the complication is the derailment of a neat set of events, and when it happens, we search for the culprit.

Following this logic, “Rare complication of ventriculo peritoneal shunt: catheter protrusion to subcutaneous tissue-Case report” can be read as an improper closure of the peritoneal wall, or an increase in abdominal pressure that perhaps was combined with a minimally imperfect stitching of the wound. If so, a heartfelt praise for the authors honesty would be enough.

However, I propose that complications reports should be read assuming, without reservations, that those directly involved in the surgical procedure performed it up to the more stringent standard. Hence, there is no smoking gun in anybody hands. And this seems to be the conclusion of the authors unless until they retract and state that careful and proper placement of the distal catheter during the tunneling procedure to prevent complications, as well as the importance of carrying out control tests to document the satisfactory placement of the entire shunt system. But, I ask, do we not do it all the time? Did they not do it the first time? Of course they did it, of course we all do it in every case. And still the events recur. To the authors of the paper it happened twice on the same patient. And I feel it is a disservice to what nature is trying to tell us to treat this report as the report of a complication. The epistemological question of the complication is, has the complication a different set of rules? Philosophy is the process of interrogating nature, with surgical complications we surgeons interrogate ourselves.

Descartes stated that a stopped watch had a different ontology than a working one. Perhaps we could borrow the analogy and apply it to the surgical complications, certainly not to those were an egregious mistake was committed (those are rarely if ever reported) but those as the one reported here that lead us to pause and ponder the phenomenon as an independent entity not necessarily a continuum from the original procedure.

Keywords: Medulloblastoma, pediatric, posterior fossa syndrome

ILLUSTRATIVE CASE

A 4-year-old boy presented with papilledema and nystagmus. He had developed eye deviation, clumsiness, and episodes of dizziness starting 6 months prior to presentation, which progressed in frequency. Following an episode of emesis, he was brought to our attention. One week prior to presentation, the patient had one episode of emesis in the morning. His development had been notable for speech delay, with expressive language limited to speaking in short phrases without full sentence formation; he otherwise had normal growth and motor development.

Physical examination was significant for sluggish and dilated pupils, agitation, crying, and attention difficulty. Computer tomography (CT) scan of the brain revealed a large posterior fossa mass arising from the vermis with multiple calcifications and associated obstructive hydrocephalus. Magnetic resonance imaging (MRI) with and without contrast of the brain showed a mass with patchy enhancement and associated metastatic lesions located throughout the cerebellar hemispheres [ Figure 1 ]. MRI of the spine demonstrated two focal enhancing nodules of spinal cord in the cervical and thoracic spine.

Figure 1

Preoperative MRI Brain, T1 post-gadolinium in sagittal (a) and axial (b) sections from patient in the example case. The large midline medulloblastoma arises from the cerebellar vermis and compresses the fourth ventricle, causing obstructive hydrocephalus. There is nodular leptomeningeal spread throughout the posterior fossa

Once in the operating room, a frontal external ventricular drain was placed prior to positioning the patient prone for a midline suboccipital craniotomy with transvermian approach splitting the inferior aspect of the vermis. The tumor was highly vascular and noted to be involving the floor of the fourth ventricle, bilateral foramina of Luschka, and left cerebellar peduncle, precluding a complete resection. Histopathology confirmed a medulloblastoma with subsequent molecular definition of a non-WNT(wingless)/non-SHH(sonic hedgehog) subgroup.

Postoperatively, the patient exhibited decreased responsiveness, mutism, fixed downward gaze, and inability to follow commands. Postoperative imaging did not demonstrate any hemorrhage [ Figure 2 ]. He was dependent on cerebrospinal fluid (CSF) drainage, requiring a ventriculoperitoneal shunt on postoperative day 14. He had an extended postoperative course complicated by shunt infection but eventually was able to undergo adjuvant radiation and chemotherapy. Following craniospinal proton radiotherapy, he improved in his mental status and purposeful interaction and regained three-word speech. However, significant disease burden still persisted on imaging [ Figure 3 ].

Figure 2

Postoperative MRI Brain, T1 post-gadolinium in sagittal (a) and axial (b) sections. The medial portion of the lesion has been largely resected, but the lesion remains in the bilateral cerebellar hemispheres, totaling >1.5 cm²

Figure 3

Post-radiotherapy MRI Brain, T1 post-gadolinium in sagittal (a) and axial (b) sections. There has been some interval improvement of leptomeningeal spread and nodular lesions. However, there has been recurrence of disease in the fourth ventricle

OVERVIEW OF MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common posterior fossa tumor in children, presenting at a mean age of 9 years and, more commonly, in males (ratio 2:1).[ 2 ] It usually presents with obstructive hydrocephalus and resultant symptoms, which may also be accompanied by ataxia, cranial neuropathies, brainstem dysfunction, or nerve root/spinal cord compression from metastatic disease. Symptoms are often progressive over weeks to months, and it is not uncommon for patients to have an extended symptomatic period prior to initial diagnosis. Metastatic disease is commonly present at diagnosis (40%), and imaging of the entire craniospinal axis is an essential part of the initial diagnostic evaluation. Most cases of MB arise sporadically but are also linked to a number of syndromes, including Gorlin, Li-Fraumeni, and Turcot syndromes.

Molecular subgrouping

In addition to traditional histologic classification [classic, desmoplastic/nodular (DNMB), MB with extensive nodularity (MBEN), large cell/anaplastic (LCA)), MB has been classified into four distinct molecular subgroups according to transcriptional profiling studies.[ 41 ] The consensus four subgroups, which include WNT, SHH, Group 3, and Group 4, have been correlated to both clinical outcomes and histologic appearance.[ 2 41 ] These genetically defined molecular subgroups form a crucial aspect of the forthcoming World Health Organization 2016 guidelines, which divides MB into WNT, SHH-TP53 wild type, SHH-TP53 mutant, non-WNT/non-SHH, and MB-NOS.[ 31 ] Unfortunately, molecular studies, while available, remain isolated to large tertiary centers, even in developed countries.

Genetics

The WNT and SHH classifications identify the underlying oncopathogenic pathway, whereas Groups 3 and 4 retain generic designations pending elucidation of underlying cellular pathobiology. WNT tumors result from unregulated WNT signaling leading to increased beta-catenin-mediated increase in transcriptional activity and consequent tumorigenesis. They are associated with monosomy 6, germline APC mutations (Turcot syndrome), somatic CTNNB1 mutations, and nuclear positivity for β-catenin.[ 17 48 ] Oncogenesis of SHH MBs results from upregulation of sonic hedgehog signaling as a consequence of loss of function of the tumor suppressors suppressor of fused gene (SUFU) and patched-1 (PTCH1). Other events implicated in pathogenesis of SHH MBs include mutations of PTCH1, PTCH2, SUFU, and SMO, as well as amplification of GLI1 and GLI2.[ 7 8 26 27 28 37 39 40 ]

The precise oncopathogenic mechanisms for non-WNT/SHH tumors are still under investigation. Altered MYC and KDM6A signaling has been implicated in Groups 3 and 4 MBs. Whereas MYC is often overamplified in Group 3 MBs, Group 4 MBs are occasionally characterized by MYCN and CDK6 amplification. Isochromosome 17q is characteristic of Group 4 tumors but is also occasionally observed in Group 3 MBs, making it poorly specific. An alternative proposed marker for Group 4 lesions is KCNA1.[ 26 ]

Whereas molecular subgrouping of MB is based on differential gene transcriptional profiles, the different subgroups are recapitulated by subgroup-specific differential heterogeneity of cis-regulatory elements in the epigenome.[ 21 ] Based on these studies, it has been proposed that Group 4 MBs may arise from cells in the deep cerebellar nuclei of the cerebellar nuclear transitory zone or the upper rhombic lip.[ 21 ] Probing and further delineating epigenetic and gene regulatory differences may serve not only as better molecular subgrouping classification metrics but also the dual purpose of uncovering oncopathogenesis of different types of MB as well as of offering novel therapeutic targets.

Another compelling area of investigation in the genetics of MB is recurrent disease. Much of our understanding of the molecular and genetic profiles of MB is derived from experiments with treatment naïve and primary site disease. However, much like other malignancies, there is mounting evidence that suggests clonal selection and genetic divergence may play an important role in MB recurrence.[ 25 ] Although it has been demonstrated that molecular subgroups (WNT, SHH, Group 3, Group 4) are preserved in both metastatic and recurrent disease, for recurrence this may be insufficient to guide molecularly targeted therapies because significant genetic divergence, including increased mutational burden with both loss and gain of actionable molecular targets, has been demonstrated.[ 25 44 ]

Histologic correlation

There is an association between molecular subgroup and histologic type. For instance, 97% of WNT MBs are of the classic histologic variant.[ 19 ] However, this correlation is not absolute; in infants, children, and adults, 89%, 25%, and 100% of DNMBs were of the SHH molecular subgroup, respectively.[ 19 ] LCA tumors in infants are most commonly Group 3 lesions, however, in other ages they are evenly distributed across molecular subgroups.

Epidemiologic correlation

WNT, SHH, Group 3, and Group 4 MBs account for 10%, 30%, 25%, and 35% of MBs overall, respectively, with a 1:1 M:F ratio for WNT and SHH subgroups, and a 2:1 male predominance for non-SHH/WNT tumors. WNT tumors are typically seen in children and adults, whereas Group 3 tumors are more often seen in infants and children. SHH and Group 4 tumors are seen across all age groups, with the former exhibiting a bimodal age distribution, most typically occurring in patients <4 and >16 years of age.[ 10 ]

Surgical treatment

Extent of resection

The extent of resection indicated in MBs largely depends on the unique anatomy of the tumor and what can be done safely and without the incurrence of neurological deficit, as with all tumors in the eloquent areas of brain. Although no clinical trials have been designed to specifically evaluate the role of surgery for MB, there have been many studies supporting a relationship of extent of resection with event-free survival. The most influential is likely a retrospective analysis of 233 children involved in a randomized controlled trial of differing chemotherapy regimens by Albright et al. determining that a radiographically measured residual tumor less than 1.5 cm³ was associated with improvement in 5-year PFS of greater than 20% in patients with M0 disease and an 11% difference for all patients irrespective of age, M stage, or any other measured factors.[ 3 ] However, there have also been a number of studies that question a definitive association between the extent of resection and survival. Possibly, the most compelling of these studies was a recent retrospective analysis of 787 patients by Thompson et al. They demonstrated that the benefit of increased extent of resection is largely attenuated after taking into account molecular subtype and not significant when comparing STR (>1.5 cm³) versus NTR (<1.5 cm³) or gross total resection (GTR; no radiographic residual) versus NTR (<1.5 cm³).[ 43 ] In addition, aggressive resection of brainstem disease is not indicated owing to the high potential for morbidity incurred with this approach as well as the high sensitivity of the tumor to radiation and chemotherapy. For tumors involving the brainstem, investigators have found no difference in outcome between GTR and residual tumor <1.5 cc.[ 46 ]

Hydrocephalus

Following resection, between 10 and 40% of the patients have hydrocephalus requiring CSF diversion.[ 2 20 33 ] Riva-Cambrin et al. developed the Canadian Preoperative Prediction Rule for Hydrocephalus (CPPRH) for use in the preoperative prediction of shunt dependence, which can aid in surgical planning and patient counseling.[ 33 ] Our patient had a CPPRH score of 7/10 and, thus, a predicted risk of hydrocephalus of 79.9%. It is important to expedite shunt placement and not to delay adjuvant therapies, especially if leptomeningeal spread or metastases have occurred.

Adjuvant therapies

Risk stratification and radiotherapy

Traditionally, children older than 3 years of age are stratified into average and high-risk prognostic groups based on the presence of metastatic disease and post-resection residual less or greater than 1.5 cm³. “High-risk” MB is defined as having any one of the following characteristics: >1.5 cm³ postoperative residual, evidence of radiographic metastases, or presence of leptomeningeal disease/CSF seeding, with the remaining patients defined as “average-risk.”[ 2 ] Those less than 3 years of age constitute a unique group in which current standard of care is chemotherapy alone as first-line adjunctive therapy, with radiation therapy eschewed in order to avoid the very poor neurocognitive outcomes associated with typical doses of craniospinal irradiation (CSI) in such young patients.

Under the above scheme, “high-risk” patients undergo posterior fossa or surgical bed radiation (54–55.8 Gy) with high-dose CSI (36.0 Gy) followed by adjuvant chemotherapy, whereas “average-risk” patients undergo posterior fossa or surgical bed radiation (54–55.8 Gy) with reduced-dose CSI (23.4 Gy) followed by adjuvant chemotherapy.[ 2 ] However, molecular subgrouping is already being applied to clinical trials of varied adjuvant therapy schemes, and this classic scheme is likely to be modified or supplanted by a scheme reliant on molecular subgroups, as suggested in a recent consensus paper by Ramaswamy et al.[ 31 ]

Chemotherapy

Cytotoxic chemotherapy may be used in the initial treatment, maintenance therapy, or for recurrent disease. It may be radiation sparing, which would allow one to eschew the use of radiation in children <3 years of age and permit dose-reduction in older patients. Various regimens exist for initial treatment, with standard therapy being post-radiation cisplatin-based chemotherapy for 4–9 cycles.[ 42 ]

Many previous trials investigating chemotherapy and radiation regimens have compared outcomes based on the histologic type. However, the histologic types and molecular subgroups have not been completely congruent. Following the new stratification of MB by molecular subgroup, inroads have been made to tailor therapies to these pathways or predict response to traditional therapy.[ 47 ] In cases where tumor characteristics or metastases preclude adequate resection, biopsy followed by targeted chemotherapy may serve as a favorable alternative.[ 46 ]

Specifically targeted chemotherapies based on pathways believed to be involved in oncogenesis are a promising future application of molecular subgrouping. At present, molecularly targeted agents for each of the four molecular subgroups are being studied in either clinical and pre-clinical models—the most well-studied of these being smoothened (SMO) receptor antagonists, such as vismodigib, that have demonstrated some utility in both preclinical and clinical models.[ 9 ]

Alternative strategies include sensitization of MB tumor cells to chemotherapeutic treatment. For example, thiostrepton, an antagonist of FOXM1 (an oncogene shown to be upregulated in a variety of malignancies), was shown to sensitize MB cells to cisplatin in vitro.[ 22 ]

Options for recurrent disease are more limited. A regimen of ifosfamide, cisplatin, and etoposide has been investigated but may be limited by significant attendant toxicities, most notable for profound myelosuppression.[ 18 ] An alternative regimen combines bevacizumab and irinotecan with or without temozolomide, with an objective response rate of 55% at 6 months and may be better tolerated.[ 1 ] Further studies are required to identify an efficacious regimen with tolerable toxicity for recurrent medulloblastoma, perhaps targeted to molecular subgroup.

Prognosis and outcomes

The overall prognosis of MB is relatively good compared to other high-grade tumors, with a 5-year overall survival of approximately 70%.[ 38 ] Prognostic factors include age at diagnosis, post-resection residual, histologic type, presence of metastasis, and molecular subgroup. Positive prognostic markers include DNMB and MBEN histologic types, WNT subgroup tumors, and expression of beta-catenin in the nucleus[ 11 13 ] and TrkB.[ 16 35 ]

Histological phenotype has classically been very important in prognostication, especially in young children in whom it is highly predictive of outcome. Favorable results can be seen in DNMBs, which account for half of MB cases seen in children ≤3 years old.[ 46 ] In another study, DNMB and MBEN accounted for more than half of the cases in patients <3 years old and had a 5-year overall survival of ~53% compared to ~17% for the classic variant of MB.[ 23 ] DNMB and MBEN are also unique in that complete remission is a realistic and realizable goal with resection and postoperative chemotherapy.[ 14 15 34 36 ] In patients >3 years old, MB histology still retains prognostic significance, with significant differences in outcome for DNMB versus classic versus large cell/anaplastic types.

The WNT subgroup has a very favorable prognosis, with only a 10% probability of metastasis at diagnosis and a 5-year overall survival of 95–100%. SHH MBs carry a slightly greater risk of metastasis than WNT MBs but less than the Groups 3 and 4 subgroups. Prognosis of SHH tumors is inversely correlated with age, with 10-year overall survival of 77%, 51%, and 34% in infants, children, and adults, respectively.[ 32 ] The presence of TP53 mutations in SHH tumors, unlike its presence in the WNT subgroup MBs, carries an additional poor prognostic risk.

Non-WNT/SHH (Groups 3 and 4) MBs are more likely to be metastatic than WNT and SHH subgroups, with approximately 30% of the patients having metastasis at diagnosis. Group 4 tumors carry an intermediate prognosis with 5-year progression-free survival of 95%, with negative risk modifiers including MYCN amplification and presence of metastasis.[ 19 32 ] A categorically poor prognosis is carried by Group 3 MBs, with a 10-year overall survival of 39% and 50% in infants and children, respectively; these tumors are associated with large cell/anaplastic histology and MYC amplification.[ 29 ] These and other distinguishing features are summarized in Table 1 .

Table 1

Summary of characteristics and prognosis of the four recognized subgroups of medulloblastoma

A meta-analysis examining event-free survival/disease-free survival favored the inclusion of chemotherapy in treatment of pediatric MB when omitting, but not when including, disease progression as an event.[ 24 ] The authors could not discount a benefit for chemotherapy in the treatment of MB, but also could not make firm positive recommendations for the same. The decision regarding whether or not to include chemotherapy in the treatment of a specific patient and what intensity to use should be individualized based on patient risk factors and tumor characteristics (i.e., molecular subgroup, histology, presence of metastasis).

Posterior fossa syndrome

The posterior fossa syndrome (PFS), also known as cerebellar mutism syndrome, is a complication that occurs in 8–24% of infratentorial brain tumor resections.[ 12 ] PFS usually presents between 1 and 2 days postoperatively and is characterized as a triad of cerebellar mutism, ataxia or axial hypotonia, and affective symptoms such as irritability and emotional lability. These children are commonly inconsolable, apathetic, and/or hypokinetic. While the pathophysiology is poorly understood, there are some purported mechanisms, including disruption of the dentate-thalamo-cortical (DTC) pathway, which has been identified on diffusion tensor imaging of patients affected with PFS.[ 5 ] Specifically, Avula et al. have shown, across several imaging analyses, possible involvement of the proximal efferent cerebellar pathway (pECP), which interconnects the dentate nucleus, superior cerebellar peduncle, and midbrain tegmentum.[ 4 ] The DTC and pECP constitute a sufficiently large area that may account for the anatomic heterogeneity of lesions associated with PFS.

While some studies have suggested vermian injury as the cause of PFS,[ 30 ] equivocal data exist for this hypothesis.[ 45 ] While potentially associated with a variety of posterior fossa tumors and even hemorrhagic AVMs,[ 6 ] MB appears to be associated with the highest risk for development of PFS. While some recent progress has been made regarding the anatomical pathways associated with PFS, a wide variety of partially supported hypotheses still exist regarding the pathophysiology, including postoperative vasospasm, axonal injury, neuronal dysfunction, thermal injury, and postoperative edema.[ 5 ]

CONCLUSION

MB is one of the most well-studied and frequently encountered CNS malignancies with a relatively good response to current treatments. However, there remains a subset of patients with poor outcomes despite numerous studies trying to optimize chemotherapy and radiation regimens. The current understanding of MB biology has vastly outpaced breakthroughs in treatment over the past 5–10 years, and application of this knowledge holds promise for continued improvements in outcomes for the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords: Cerebral cavernous malformation, cavernous angioma, cavernous hemangioma, vascular lesion, neurovascular, intracranial

CASE REPORTS

Case 1

A 2-year-old Hispanic girl presented with a 3-day history of vomiting followed by a sudden onset of right facial droop and right eye ptosis. She had achieved normal developmental milestones until then. In retrospect, she had several months of occasional left leg weakness causing falls. There was no history of seizures. She had a family history with two second-degree relatives with cerebral cavernous malformations (CCMs) of the cerebrum and brainstem. She had not received prior imaging or screening. Genetic testing revealed a heterozygous mutation in the KRIT1 gene.

Computerized tomography (CT) of the head demonstrated multiple hemorrhagic lesions of different ages, with the largest being a 3 × 2.5 cm lesion in the right thalamus with mesencephalic extension, along with 1 cm lesions in the left forceps minor and right atrium. There was obstructive hydrocephalus without intraventricular hemorrhage [ Figure 1a ].

Figure 1

Evolution of hemorrhage from familial cavernous malformation (Case 1). (a) Computerized tomography (CT) of head at presentation, showing 2.5 × 3 cm hemorrhagic CM in right thalamic-mesencephalic junction. (b) Magnetic resonance imaging (MRI) of the brain, axial gradient echo sequence showing the same. (c) Expansion of hemorrhage to 3.5 × 3 × 3 cm. (d) CT head, sagittal section, day 9, showing further extension in the craniocaudal dimension. (e) Preoperative MRI brain, axial gradient echo sequence, showing lesion growing to 3.3 cm anteroposterior × 3.7 cm transverse × 3.7 cm craniocaudal. (f) Postoperative CT head showing complete resection of lesion and hematoma

An external ventricular drain (EVD) was placed. Magnetic resonance imaging (MRI) of the brain characterized these lesions as CCMs [ Figure 1b ]. Due to the deep and eloquent location of the hemorrhage, the initial plan was directed toward supportive care and rehabilitation. Over 2 weeks of supportive care, the patient's neurologic status declined, and she required intubation. The lesions exhibited continued episodic hemorrhage with rupture into the ventricular system [Figure 1c and d ]. The hemorrhage extended deeper into the midbrain and pons, causing a complete third nerve palsy, quadriplegia, and obtundation. The hematoma eventually presented to the surface of the tectal plate, allowing a direct surgical corridor for access [ Figure 1e ]. Evacuation of the hematoma and right thalamic-mesencephalic CCM was performed via a midline supracerebellar–infratentorial approach [ Figure 1f ]. The patient recovered some right-sided motor function. Ventilator support and EVD were both weaned successfully. She continues with postoperative rehabilitation.

Case 2

A 7-year-old girl presented with diplopia, ataxia, and headaches. Imaging revealed a hemorrhagic right middle cerebellar peduncle lesion suggestive of a solitary CCM [ Figure 2a ]. Her presenting deficits resolved within a week, and she received a brief course of physical therapy with serial follow-up. In the following month, the patient had acute headache and ataxia. Repeat imaging showed extension of the hemorrhagic lesion past the ependymal surface into the lateral fourth ventricle without obstructive hydrocephalus [Figures 2b and c ]. Surgery was timed 4 weeks following the acute hemorrhage to allow for rehabilitation and evolution of the hematoma cavity. She underwent suboccipital craniotomy with complete resection of the CM [ Figure 2d ]. The patient had excellent postoperative recovery without deficits; she was more active and energetic than the year prior to surgery.

Figure 2

Evolution of hemorrhage in brainstem cavernous malformation (Case 2). (a) Computerized tomography (CT) of the head at presentation showing hemorrhage in right middle cerebellar peduncle that does not extend to the pial surface. (b) CT head 1 month later during recurrence of symptoms shows worsened perilesional edema and progression toward the ependymal surface of the fourth ventricle. (c) Magnetic resonance imaging (MRI) of the brain T1-weighted sequence with contrast at the time of second hemorrhage demonstrates surgical corridor made possible by hemorrhage extending to the right lateral recess of fourth ventricle. (d) Postoperative MRI demonstrates complete resection of lesion

REVIEW

Epidemiology

The epidemiology of CCMs, or cavernomas, is an area of extensive investigation in adults. However, less data exist regarding their incidence and prevalence in the pediatric age group. Moreover, a prior false assumption of an exclusively congenital etiology may have led to an underestimation of the overall hemorrhage risk. The development of CCMs appears to increase with age, reaching a plateau in late adolescence, as demonstrated by Al-Holou et al. in 2012.[ 3 ] They reported a prevalence of ~0.2% in infants and an overall prevalence of ~0.6% in children. Males and females are equally affected in the pediatric and adult populations.[ 3 34 35 ] According to studies by Gross et al. in 2011 and 2015, among children with CCMs, 10% of cases are familial and approximately 17% have multiple lesions.[ 34 35 ] Also evident is an apparent racial disparity in etiology, with the familial form accounting for half of the cases in Hispanic patients and only 10–20% of affected Caucasians.[ 22 63 ]

The overall incidence for the development of new CCMs in children is correlated with their pre-existing cavernoma burden. Gross et al. reported incidences of approximately 1.2% per patient per year and 2.5% per lesion per year; that is, the presence of multiple CMs confers a greater risk of de novo cavernoma-genesis compared with patients with solitary CMs (7.1% versus 0.6% per lesion per year).[ 34 ] Prior radiation also appears to confer a risk of de novo CCM formation, representing 9% of pediatric CCMs. Patients harboring CCMs who subsequently received radiation developed further CCMs at a rate of 2.6% per lesion per year,[ 34 ] usually with a latency period of 9 years until detection.[ 55 ]

Histopathology

Cavernous malformations (CMs) are hamartomatous, cystically-dilated vascular spaces composed of a single layer of endothelium with possible infrequent subendothelial cells, without elastic lamina or smooth muscle cells, embedded in a collagenous extracellular matrix.[ 9 17 64 ] The endothelial cells characteristically lack tight junctions. The rudimentary vessels coalesce to form a compact mulberry-like mass devoid of intervening neural parenchyma, distinguishing them from capillary telangiectasias and arteriovenous malformations (AVMs).[ 35 64 ] On gross pathology, they are well-demarcated vascular masses measuring up to several centimeters. CMs may exhibit reactive astrogliosis, calcification, and hemosiderin deposition, with the latter being a consequence of recurrent hemorrhages.

Clinical presentation and diagnosis

Approximately 85% of CMs are supratentorial in children (92% lobar, 8% deep). The remainder are located infratentorially (57% brainstem, 43% cerebellar), with rare occurrence in the spinal cord.[ 34 ] CCMs may remain asymptomatic for the lifetime of the patient in both children and adults. In the pediatric population, clinical presentation of CCM includes hemorrhage (62%), seizures (35%), and incidental radiographic finding (26%). A bleeding episode is followed by thrombosis of the lesion and subsequent recanalization, predisposing to recurrent hemorrhage.[ 72 80 ] Presentation by hemorrhage is more common among brainstem CMs (80%), which also have higher annual re-hemorrhaging rates (17% versus 11% for CMs overall).[ 34 48 ] Patients may or may not have neurological sequelae.

By definition, all CCMs exhibit varying degrees of microhemorrhage, as evidenced by hemosiderin deposition. When located in noneloquent areas of the brain, slightly larger degrees of hemorrhage may be tolerated. Concern arises when CCMs occur in critical brain regions, such as the brainstem, where even small hemorrhages may compromise vital functions.

The overall risk for CCM hemorrhage in the pediatric population is approximately 0.5% per lesion per year.[ 3 4 29 34 35 43 ] A history of prior hemorrhage is perhaps the most important risk factor, shown in one study to confer an overall annual hemorrhage risk of 11.3%.[ 4 6 9 29 34 35 43 ] Recurrent hemorrhages have a tendency to “cluster,” usually seen within 2–3 years of the index hemorrhage event.[ 6 34 ]

Imaging

CT scanning has poor sensitivity for detection of CCMs. T2-weighted MRI, especially gradient echo (GRE) or susceptibility weighted imaging (SWI) sequences, possesses the greatest sensitivity for detection of CCMs and reveals a mixed signal core and surrounding low signal rim, often with evidence of microhemorrhages. Brain MRI screening is indicated for first-degree relatives of patients with CMs with two or more affected family members.

Developmental venous anomalies (DVAs) are seen in up to 20% of patients with CMs,[ 35 54 59 ] and have been suggested to confer an increased risk of CCM hemorrhage risk in past studies.[ 61 ]

Genetics and etiopathogenesis

CCMs may occur sporadically or be transmitted in an autosomal dominant fashion with variable penetrance; the familial type has been reported to account for roughly half of the cases in Hispanics and up to one-fifth of the cases in Caucasians, and is also associated with a greater annual risk of symptomatic bleeding.[ 10 16 37 40 63 80 ] It has been shown that many cases thought to be sporadic do, in fact, harbor familial mutations.[ 23 47 ] Multiple lesions are present in 84% of the familial cases and up to one-third of the sporadic cases.

Three genetic loci have been associated with and account for ~80% of familial CCM: CCM1/Krit1, CCM2/MGC4607, and CCM3/PDCD10.[ 19 25 51 ] CCM1 was definitively localized and mapped to chromosome 7q21-q22,[ 66 67 ] CCM2 to 7p15-p13,[ 19 ] and CCM3 to 3q25.25-27.[ 19 ] Multilocus analysis reveals 40%, 20%, and 40% of familial CCM are linked to CCM1, CCM2, and CCM3, respectively.[ 19 ] Penetrance of CCM1, CCM2, and CCM3 mutations is approximated at 60–88%, 100%, and 63%, respectively.[ 19 21 ] Several different loss-of-function mutations have been identified in CCM1-3, suggesting that their products function as tumor suppressors. A fourth locus has been postulated to be present at 3q26.3-q27.2.[ 8 19 ] Other candidate genes include ZPLDC1, found mutated in a single patient with CCM, and those encoding ephrin-B2[ 74 ] and Notch[ 76 ] proteins.

Furthermore, single nucleotide polymorphisms (SNPs) of inflammatory and immune response genes have been associated with different features of CCM natural history, including disease burden and severity of risk of intracerebral hemorrhage; identified SNPs include IL-1RN, TGFBR2, CHUK, SELS, CD3G, IGH, and IGL. This information may have implications for risk stratification and treatment planning.

A Knudsonian two-hit hypothesis has been presented to account for all cases of CCM. This appears to hold true for the familial form, wherein an inherited germline CCM mutation and a single acquired somatic mutation in the homologue affects cavernoma-genesis,[ 42 ] which has been demonstrated for CCM1-3.[ 2 30 31 ] In the sporadic form of the disease, the Knudsonian two-hit hypothesis posits the acquisition of two somatic mutations in homologous genes, which has never been directly shown, and thus remains to be explained. One theory is that, in the setting of vascular insult, such as trauma or radiation shown to predispose to cavernoma-genesis,[ 34 55 ] context-dependent haploinsufficiency of a CCM gene may occur. In this model, a single functional copy of a CCM gene in the normal uninjured state would be sufficient to prevent cavernoma genesis by maintaining vascular integrity and blunting unmitigated cellular proliferation via actions of CCM protein products (see Molecular Pathogenesis). Injury may create a greater requirement for larger amounts of this protein product to keep rho-associated protein kinase (ROCK) signaling and other pathways in check when a single functional copy of a CCM gene becomes inadequate (haploinsufficiency).

Molecular pathogenesis

The molecular pathogenesis of CCMs is linked to the gene products of CCM1, CCM2, and CCM3, which are also known as Krev Interaction Trapped 1 (Krit1), malcavernin, and PDCD10, respectively. Table 1 summarizes the effects of these mutations.

Table 1

Summary of pathogenesis of mutations in the cerebral cavernous malformation (CCM) genes associated with familial cavernous malformations (CM)

CCM1 encodes Krit1, a microtubule-associated protein that also interacts with Rap1A, ICAP-1, and a variety of other proteins. Rap1A is a Ras-family GTPase involved in cellular differentiation and morphogenesis, as well as regulation of cellular polarity and cytoskeletal organization.[ 58 65 ] It is expressed in endothelial and vascular smooth muscle cells.[ 77 ] Among the proposed functions of Krit1 is localization of Rap1A to specific subcellular compartments. An abnormality of this nature in vascular smooth muscle cells may result in perturbation of endothelial cell organization[ 38 67 ] or affect the stability of endothelial adherens junctions.[ 26 81 83 84 ]

In addition, Krit1 may contribute to regulation of transmembrane β1-integrin-mediated signal transduction and cell-cell as well as cell-extracellular matrix (ECM) signaling, both of which are critical in the formation of microtubules and, in turn, endothelial structure/function and angiogenesis. An important intermediary protein in β1-integrin-mediated signal transduction is ICAP-1, which binds the cytoplasmic domain and links it to the cytoskeleton. Further, ICAP possesses binding sites for Krit1, which may play a regulatory function in the β1-integrin/ICAP-1 interaction.[ 81 83 ] CCM1 mutations prevent Krit1/ICAP-1 association and, thus, may effect cavernoma-genesis consequent to defective transmembrane protein-mediated signaling involved in the angiogenesis and organization of vascular endothelium.[ 83 ]

Krit1 also interacts with malcavernin, a scaffold protein that associates with mitogen-activated protein kinase (MAPK)-extracellular-regulated kinase (ERK) kinase 3 (MEKK3), a pathway critical in the regulation of endothelial proliferation and migration, adhesion, and cytoskeletal regulation.[ 52 81 82 ] The malcavernin/MEKK3 complex promotes the nuclear-to-cytoplasmic translocation of Krit1/ICAP-1, which associates to form a ternary complex that regulates p38 MAPK activity;[ 82 ] malcavernin mutations alter the phosphotyrosine binding domains by which Krit1 associates. P38 MAPK promotes endothelial proliferation via promotion of VEGF and COX-2 signaling, while also negatively modulating differentiation and apoptosis via promotion of Bad (an inhibitor of MEK1/2 and ERK1/2) and inhibition of Bcl-x (an inhibitor of the caspase cascade).[ 12 20 ]

Programmed cell death 10 gene (PDCD10) encodes for a protein involved in apoptosis and associates with both Krit1 and malcavernin.[ 8 ] PDCD10 also affects cellular proliferation and growth via interaction with MST4 kinase and the MAPK and ERK pathways.[ 50 ] PDCD10 has been proposed to function in the pruning of newly formed blood vessels. A perturbation in this mechanism may effect cavernoma-genesis.

CCM1-3 share their ability to negatively modulate RhoA/Rho kinase;[ 12 ] loss-of-function mutations result in upregulated ROCK signaling. ROCK increases the synthesis of microtubules and phosphorylates myosin light chains, leading to increased cell contractility, which promotes disruption of endothelial intercellular adhesion, leading to the formation of abnormally dilated leaky vessels.[ 11 33 71 76 79 ] Thus, CCM genes contribute to the maintenance of vascular integrity through negative modulation of ROCK [ Figure 3 ]. This may offer a promising therapeutic target for CCMs;[ 49 ] direct pharmacological inhibition of ROCK using Fasudil has been demonstrated in both in vitro and animal models.[ 71 ] Another target could be RhoA, whose hyperactivation could be inhibited by HMG-CoA reductase inhibitors such as statins.[ 49 ] Human trials appear to be the next step in the future; there are no open clinical trials as of May 2016. An increased risk of hemorrhage in zebrafish is reported, but not in murine or mammalian models.[ 27 ] Short hairpin RNA (shRNA) silencing of ROCK has been used in vitro[ 11 ] and, in theory, may also be targeted to locally treat CCMs.

Figure 3

Summary of main pathways of cavernoma-genesis and potential targeted therapies. The molecular pathogenesis of familial cavernomas centers around modulation of Rho Kinase (ROCK), which modulates microtubule synthesis. This, in turn, alters contractility of endothelial cells, intercellular adhesion, and vascular integrity. Loss of vascular integrity allows cavernoma-genesis

Treatment

Standard management options for CCMs have classically included observation and surgical removal.[ 41 ] Asymptomatic lesions are generally treated conservatively. Surgery is indicated for accessible symptomatic lesions. Complete resection eliminates the risk of hemorrhage from that particular lesion but may risk neurological morbidity, especially for CCMs located in eloquent cortex or brainstem.[ 24 75 ] Assessment of optimal surgical timing and approach is important to minimize treatment morbidity.

Especially for deep-seated CCMs in the pons or brainstem, surgeons typically prefer to wait for the CCM lesion to present to a surgically accessible surface without the need for direct surgical dissection through eloquent tracts.[ 1 ] In addition, the timing of microsurgery is optimal several weeks after hemorrhage to allow perilesional edema to subside, as well as hematoma contents to evolve and soften.[ 15 62 ]

Surgical resection of CMs in the setting of epilepsy is a topic of continuing investigation. In this scenario, the hemosiderin ring associated with CCMs is associated with epileptogenic potential[ 44 45 ] and is generally recommended to be resected along with the CCM lesion.[ 7 36 46 70 ] High rates of seizure control (73–85%) can be attained with complete resection of the hemosiderin ring.[ 14 28 69 ] Use of intraoperative electrocorticography (ECoG) has also been correlated with more favorable seizure outcomes, increasing seizure freedom from 77% without ECoG to 90% with ECOG-directed resection at 6 months postoperatively,[ 73 ] though in other studies the benefit has not reached statistical significance.[ 28 ] Englot et al. have postulated that this may be due to a selection bias of ECoG use in patients with more severe epilepsy or lesions in eloquent regions.[ 13 28 ] However, safety of full resection of hemosiderin-stained tissue may be limited in eloquent areas such as those subserving motor or language function. Hemosiderin resection is typically not performed in brainstem CCMs.[ 24 ]

Evolution of minimally invasive therapies

Stereotactic radiosurgery (SRS) has been reported by some groups as a potential treatment option.[ 5 60 85 ] However, any reported decrease in the risk of hemorrhage appears to occur at 2 years after SRS; thus, it is difficult to discern whether this reflects true therapeutic benefit versus the natural history of decreased hemorrhage rates after initial “clustering” of hemorrhage events.[ 5 39 57 60 ] Because arteriopathy is not an etiology of CCM, some experts contend that the use of SRS for CCMs does not have an explanation grounded in biological basis.[ 13 ]

Magnetic resonance-guided focused ultrasound (MRgFUS) has been reported as a novel minimally invasive procedure for the treatment of central nervous system pathologies, including CCMs.[ 68 ] This treatment focuses multiple intersecting ultrasonic waves to overcome the attenuation of wave energy by the skull and prevents overheating of nontargeted foci in a manner analogous to SRS.[ 32 ] Known mechanisms of therapeutic efficacy include local thermal rise, acoustic cavitation, and immunomodulation.[ 18 ] The treatment is guided by magnetic resonance thermal imaging, which confirms correct targeting and sufficient heating to effect ablation. In the treatment of vascular malformations, such as CCMs, MRgFUS may theoretically be used to activate the release of anti-angiogenic or endothelial-targeting nanoparticles carried on microbubbles. Limitations include difficulty in focusing ultrasonic waves in paraconvexity regions and long procedure duration due to the need for MRI acquisition or large lesions requiring multiple sonications. It must be stressed that, to date, this technology has had neither widespread application nor long-term follow-up.

Another minimally invasive treatment option for CCMs may include MR-guided laser interstitial thermal therapy (MRgLITT), also called MR-guided stereotactic laser ablation (MRgSLA). MRgSLA has been used in the treatment of tumors, epilepsy, and chronic pain syndromes. A non-negligible risk of focal neurologic deficits has been reported, especially for deep targets.[ 56 ] MRgSLA has been used successfully at Texas Children's Hospital to treat hypothalamic hamartomas, with high rates of control of gelastic seizures and a low complication rate.[ 78 ] Application of MRgSLA for ablation of CCMs has been demonstrated in a series of 5 adults with medically intractable epilepsy associated with CCMs with abolition of disabling seizures in 4 patients at 12 to 28 months’ postintervention.[ 53 ] CCM ablation was confirmed immediately following the procedure, and follow-up imaging (6–21 months) revealed perilesional necrotic encephalomalacia, consistent with the intent to effect extended lesionectomy. Because there are no long-term treatment outcomes and experience is limited, thus far, critical evaluation and further study are needed.

CONCLUSION

CCMs are a common cause of intracranial hemorrhage in the pediatric population. A significant proportion of CCMs identified in pediatric patients, especially those with a history of symptomatic hemorrhage, may be associated with a familial subtype with identifiable genetic mutations in genes CCM1, CCM2, or CCM3. Future research will further identify genetic pathophysiology, risk of rupture, and risk of CCM formation based on genotyping. Surgery remains the gold standard of treatment. Directions for future evaluation include minimally invasive procedures, as well as potential for an increased role of medical management using targeted molecular therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords: Arteriovenous malformation, cavernoma, cavernous malformation, intracerebral hemorrhage, intracranial hemorrhage, neurovascular

INTRODUCTION

Pediatric stroke is a relatively rare occurrence, with an annual incidence of 1.2–13 cases per 100,000. Hemorrhagic strokes account for half of these cases.[ 28 ] In adults, hemorrhagic strokes are predominantly hypertensive in etiology. However, in the pediatric population, they are frequently associated with vascular lesions such as AVMs (47%), arteriovenous fistulas, or CMs [ Table 1 ].[ 21 ] Other causes of ICH in adults, such as amyloid angiopathy or drug-related vascular damage, are rarely seen in the pediatric population. Workup of pediatric ICH should include vascular imaging consisting of either CTA or DSA. An MRI of the brain should be obtained to detect CMs, which are angiographically occult. MR angiography may lack the sensitivity to allow for visualization of the smaller vessels that may be involved with some of these lesions.[ 25 ] In a series of 137 patients with ICH described by Hino et al., 9% were found to have an “occult” vascular lesion that was not visualized on first angiogram. The clinical index of suspicion should guide the workup further if a causative lesion cannot be identified upon initial imaging. This may include repeat DSA, which is considered the gold standard for the assessment of vascular lesions. In the setting of clinically symptomatic hemorrhage, any vascular lesion, including AVM, CM, capillary telangiectasias, or developmental venous anomalies, may present in occult fashion, though AVM is most common.[ 7 ]

Table 1

Most common etiologies of spontaneous intracerebral hemorrhage in adults and children

ILLUSTRATIVE CASES

Case 1

A 7-year-old girl presented with acute onset headache, aphasia, and right hemiparesis. She was found to have a large left temporal intracerebral hemorrhage (ICH) and underwent emergent decompressive craniectomy without direct evacuation of hematoma [ Figure 1a ]. Postoperative imaging studies, including magnetic resonance imaging (MRI) and digital subtraction angiogram (DSA), failed to show a causative lesion [Figures 1b and c ]. She went to rehab and had considerable improvement of her aphasia and hemiparesis. Six weeks later, repeat imaging with DSA was performed after resolution of the initial hemorrhage, which also failed to show an associated vascular lesion. Because of the high index of clinical suspicion for arteriovenous malformation (AVM), a third angiogram was performed at 4 months post-hemorrhage. This showed a small left temporal AVM with a small nidus and early draining vein, which was the likely culprit of the patient's initial hemorrhage [ Figure 1d ]. Because of its small size, the lesion was not visualized on MRI or computed tomography (CT) angiogram; thus, radiosurgery was not a treatment option. Endovascular embolization was considered but deemed a poor option due to the high degree of difficulty in accessing the feeding vessel and concerns of the durability of treatment in this young patient. Because of the difficulty in localization, DynaCT was performed with the catheter in the feeding vessel from the inferior branch of the left MCA. This allowed preoperative study, planning, and intraoperative neuronavigation.[ 26 ] The lesion was successfully resected in total, and cranioplasty was performed in the same setting. Postoperative DSA demonstrated complete extirpation of the AVM, with tissue confirmation by pathology. The patient made an excellent recovery. She is ambulatory without focal motor deficit and has regained normal language function.

Figure 1

Left frontal hemorrhagic lesion from Case 1. (a) Computed tomography of the head at presentation showed a 9 × 4 × 4 cm hematoma with midline shift. (b) Magnetic resonance imaging brain, T2 sequence showed surrounding vessels but no definite arteriovenous malformation nidus around the large hematoma. (c) Left internal carotid artery digital subtraction angiogram at presentation, without evidence of vascular malformation. (d) Left internal carotid artery digital subtraction angiogram at 4 months post-hemorrhage reveals a left temporal Grade 1 arteriovenous malformation (arrow)

Case 2

A 9-year-old girl presented with acute onset of headache and obtundation. CT of the head demonstrated a large right cerebellar hemorrhage with tonsillar herniation, brainstem compression, and obstructive hydrocephalus [ Figure 2a ]. CT angiography (CTA) was suspicious for a vascular lesion. In emergent fashion, ventriculostomy was placed, followed by posterior fossa decompression. Because of the suspicion of a vascular lesion requiring further characterization, suboccipital decompression with craniectomy and dural decompression and minimal subtotal resection of the hematoma were performed. After surgical stabilization, the patient underwent DSA and MRI, which revealed an AVM, fed by branches of the right anterior and posterior inferior cerebellar arteries (AICA and PICA) [Figure 2b and c ]. She returned to the operating room the next day for definitive resection of the AVM. Postoperative DSA confirmed complete extirpation of the ruptured AVM and surrounding hematoma [ Figure 2d ]. Ventriculostomy was subsequently weaned, and the patient recuperated with rehabilitation. At one-year follow-up, the patient was independent with activities and had returned to school.

Figure 2

Right cerebellar hemorrhagic lesion from Case 2. (a) Computed tomography of the head at presentation showed a large hemorrhage of the right cerebellar hemisphere with displacement of the fourth ventricle. (b) Magnetic resonance imaging brain, T2 sequence showed perilesional edema and some associated vessels. (c) Right vertebral artery injection DynaCT, coronal view, showed an arteriovenous malformation with feeders from the right anterior and posterior cerebellar arteries. (d) Postoperative angiogram, AP projection, showed no residual malformation

Case 3

A 14-year-old girl presented with acute onset of headache, nausea, and vomiting for 1 day. She had similar but mild symptoms 2 weeks prior. She had a generalized seizure upon arrival to the hospital. CT of the head revealed a large 5 cm left frontal hemorrhage with mixed density and significant mass effect with exuberant perilesional edema [ Figure 3a ]. She was intubated for diminished sensorium and subsequently deteriorated as a result of uncal herniation. CT of the head with contrast demonstrated a lesion that appeared to be consistent with a tumor, though not definitive [ Figure 3b ]. She was taken for emergent decompressive craniectomy for stabilization. Subsequently, she returned to her prior neurological baseline. She proceeded to undergo MRI and MRA of the brain, which were suggestive of a cavernous malformation (CM) rather than a hemorrhagic tumor [ Figure 3c ]. The lesion was completely resected [ Figure 3d ], followed by replacement of her bone flap. Pathology confirmed hemorrhage and CM. The patient made an excellent functional recovery, with resolving mild abulia secondary to her dominant frontal lobe injury.

Figure 3

Left frontal hemorrhage from Case 3. (a) Computed tomography of the head showed a large left frontal intracerebral hemorrhage with subfalcine shift and perilesional edema. (b) Computed tomography with contrast showed partial enhancement of the lesion without any vascular feeders. (c) Magnetic resonance imaging brain, gradient echo sequence, showed a central lesion with surrounding hemorrhage, suggestive of cavernous malformation. (d) Postoperative magnetic resonance imaging brain with contrast showed complete resection of the lesion and hematoma, with resolution of mass effect

MANAGEMENT

Upon initial diagnosis of intracerebral hemorrhage on noncontrast CT, workup and treatment should be initiated without delay. The guidelines for the treatment of spontaneous ICH were last updated in 2010; these recommendations also apply to pediatric patients [ Table 2 ].[ 22 ] Based on institutional availability and clinical suspicion, workup should proceed with both vascular imaging (CTA or DSA) and MRI of the brain. Some authors have reported that MRI, MRA, and MRV are sufficient to diagnose vascular lesions in up to 66% of patients.[ 19 ] We suggest that MR vascular studies be supplemented with their CT-based counterparts if clinical suspicion is high for the improved resolution and sensitivity of CTA as MR imaging has a false-negative rate of 7%.[ 19 ] Intensive care and monitoring are indicated. Conservative management with supportive care may be appropriate for self-limited hemorrhage without progressive mass effect or elevated intracranial pressure (ICP).

Table 2

Summary of guidelines for management of spontaneous intracerebral hemorrhage

SURGICAL NUANCES

Several surgical options exist for managing acute ICH requiring intervention. First and foremost are the evaluation and management of “ABCs:” Airway, breathing, and circulation. If high intracranial pressure is present, it must be addressed with external ventricular drainage, evacuation of the hematoma, and/or decompressive craniectomy with expansile duraplasty depending on the clinical situation and the location of the hemorrhage. If there is suspicion of underlying AVM, limited evacuation of the hematoma is advised only if necessary in cases of mass effect because aggressive evacuation of the hematoma may precipitate AVM re-rupture. The thrombus cap over the rupture site can be tenuous.[ 16 ] In non-eloquent areas or in the posterior fossa where mass effect can be significant, evacuation of hematoma is typically undertaken with care, cognizant that an underlying AVM may be present.

In hemorrhages seemingly admixed with eloquent brain tissue, our experience supports a large craniectomy with expansile duraplasty in cases of significant cerebral edema, without surgical destruction of eloquent areas. This allows for the possibility of recovery of function. Direct removal of the hematoma and the vascular malformation at initial surgery may not be possible due to high ICP and incomplete workup due to clinical instability, and thus, incomplete appreciation for the anatomy and localization of the lesion, as described in Case 1. Craniectomy or minimal evacuation of hematoma, followed by a more lesion-tailored approach with the support of diagnostic imaging, may be prudent in these cases. In contrast to ruptured aneurysms that have a high short-term risk of re-rupture, thus warranting urgent securement, ruptured AVMs and cavernomas have relatively low acute re-rupture rates, which allow slightly more conservative management.[ 8 9 ] This permits the benefit of proceeding to surgery under optimal circumstances with adequate imaging and a medically optimized, stable patient. Multiple-modality imaging should be used, and in the case of equivocal findings, repeat imaging is indicated as obscuring hemorrhage resolves. Modern management can include the use of intraoperative indocyanine green videoangiography (ICG-VA) or intraoperative DSA in a hybrid OR-angiography suite.

ARTERIOVENOUS MALFORMATIONS

AVMs are the most common cause of ICH in children. They carry an annual risk of hemorrhage of approximately 3.2%, a 5–10% mortality rate, and a 50% risk of neurological morbidity.[ 4 23 ] The large majority of AVMS are clearly evident on DSA, although several authors dating back several decades have described angiographically “occult” AVMs that were obscured following rupture.[ 24 27 ] Hypotheses for this phenomenon include possible lesional thrombosis, compressive occlusion of lesion from hematoma, transient vasospasm, or small nidus.[ 24 ] The Lawton supplementary scale has been used in recent years as an adjunct to the well-established Spetzler–Martin grading scale for assessment of surgical risk in AVMs.[ 14 17 ] The Lawton supplementary scale validates the experience that pediatric patients and lesions with previous hemorrhage carry lower surgical morbidity. This helps to further guide the treatment decision-making in AVM-associated pediatric ICH. While SRS may play a role in lesions with unacceptably high surgical risk,[ 1 ] the risk of short-term hemorrhage and lesional persistence is concerning in pediatric patients with a higher cumulative lifetime risk of hemorrhage.[ 13 ] With a 20% failure rate of primary SRS therapy, radiosurgery is best used as an adjunct to a more definitive cure in the pediatric patient.[ 10 ] Endovascular embolization, frequently performed with Onyx or n-BCA at our center, usually plays an adjunct role to surgical resection but is not used as the primary treatment modality.

Postoperative surveillance of AVM

AVMs in children are fraught with a high recurrence rate (as high as 14%),[ 23 ] especially in lesions with a diffuse nidus[ 15 ] or deep venous drainage. There are no definitive guidelines for postoperative surveillance, however, undoubtedly, DSA has the highest resolution and sensitivity. Although surveillance patterns vary greatly, at our institution we recommend intraoperative/immediate postoperative DSA, followed by 1-year DSA, yearly CTA, and DSA every 3 years until age 18. Concerns over morbidity of the procedure are discussed, though the overall procedural complication rate is less than 1%.[ 18 ] A recent series suggests that MRA, although benign in the sense of radiation and contrast exposure, has reduced sensitivity.[ 23 ] CTA is considered as a noninvasive surveillance tool with higher sensitivity at recurrent AVM detection than MRA[ 23 ] and is used at our institution at yearly intervals between surveillance DSA performed at 3 years intervals.

CAVERNOUS MALFORMATIONS

CMs represent 20–25% of spontaneous ICH in children.[ 12 ] CM-associated ICH is generally smaller and has better outcomes compared to ICH from AVM. Rarely, CM-associated ICH can produce significant mass effect and may even be fatal.[ 2 ] Various factors have been associated with symptomatic hemorrhage risk. Chief among them are prior hemorrhage, brainstem location, and associated developmental venous anomalies (DVAs). The natural history of CMs includes temporal clustering of hemorrhages, often seen within the first 3 years of a herald bleed. This known grouping of hemorrhages should be an important consideration in management.[ 9 ] Unhemorrhaged lesions have an annual bleeding rate of <2%, whereas previously hemorrhaged lesions can have much higher rates (4.5–22.6%).[ 3 ] The appearance on MRI has been described in four classes by Zabramski et al.[ 30 ] While the classical “popcorn” appearance (Zabramski Type 2) is the most common, it is important to be familiar with the more atypical appearances as well. CMs are angiographically silent; thus, MRI is the only way to visualize them. Large ICH from CMs can obscure the lesion itself, making initial diagnosis challenging at times.[ 11 29 ] The initial hemorrhage can sometimes take months to fully resolve. In pediatric patients with ICH, it is imperative to maintain a high index of suspicion for causative vascular lesions and to continue aggressive diagnostic workup given the relatively high incidence in this population.[ 5 ] Therefore, MRI following the resolution of the acute hemorrhage is mandatory to rule out underlying vascular lesions. Advanced MRI sequences, such as gradient echo (GRE) and susceptibility weighted imaging (SWI), have a better sensitivity for blood and may better characterize the lesion[ 6 ] or identify other lesions in the setting of multiple CMs. Specifically, because there are no intrinsic 180-degree refocusing pulses in gradient echo sequences (as compared to a spin echo sequences), GRE images are more sensitive to the dephasing and signal losses that result from paramagnetic blood products. SWI further increases sensitivity to dephasing from these blood products by incorporating and mathematically amplifying this phase information in the image generation process. Cavernomas typically have hemosiderin rings on T2-weighted sequences.

CONCLUSION

Intracerebral hemorrhage in children requires special consideration in management compared to the same in adults. The rate of associated vascular malformations, including but not limited to AVMs and CMs, is high. These should be considered during initial evaluation, hematoma management, and surgical management of the offending lesion.[ 20 ]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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2. Al-Holou WN, O’Lynnger TM, Pandey AS, Gemmete JJ, Thompson BG, Muraszko KM. Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr. 2012. 9: 198-205

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4. Blauwblomme T, Bourgeois M, Meyer P, Puget S, Di Rocco F, Boddaert N. Long-term outcome of 106 consecutive pediatric ruptured brain arteriovenous malformations after combined treatment. Stroke. 2014. 45: 1664-71

5. Clatterbuck RE, Moriarity JL, Elmaci I, Lee RR, Breiter SN, Rigamonti D. Dynamic nature of cavernous malformations: A prospective magnetic resonance imaging study with volumetric analysis. J Neurosurg. 2000. 93: 981-6

6. de Champfleur NM, Langlois C, Ankenbrandt WJ, Le Bars E, Leroy MA, Duffau H. Magnetic resonance imaging evaluation of cerebral cavernous malformations with susceptibility-weighted imaging. Neurosurgery. 2011. 68: 641-

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9. Gross BA, Du R, Orbach DB, Scott RM, Smith ER. The natural history of cerebral cavernous malformations in children. J Neurosurg Pediatr. 2015. p. 1-6

10. Hoh BL, Ogilvy CS, Butler WE, Loeffler JS, Putman CM, Chapman PH. Multimodality treatment of nongalenic arteriovenous malformations in pediatric patients. Neurosurgery. 2000. 47: 346-

11. Ide C, De Coene B, Baudrez V. MR features of cavernous angioma. JBR-BTR. 2000. 83: 320-

12. Jordan LC, Hillis AE. Hemorrhagic stroke in children. Pediatr Neurol. 2007. 36: 73-80

13. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Awan NR. Stereotactic radiosurgery for arteriovenous malformations, part 2: Management of pediatric patients. J Neurosurg Pediatr. 2012. 9: 1-10

14. Kim H, Abla AA, Nelson J, McCulloch CE, Bervini D, Morgan MK. Validation of the supplemented Spetzler-Martin grading system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. Neurosurgery. 2015. 76: 25-31

15. Klimo P, Rao G, Brockmeyer D. Pediatric arteriovenous malformations: A 15-year experience with an emphasis on residual and recurrent lesions. Childs Nerv Syst. 2007. 23: 31-7

16. Lawton MT.editorsSeven AVMs: Tenets and Techniques for Resection. New York: Thieme; 2014. p.

17. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010. 66: 702-13

18. Lin N, Smith ER, Scott RM, Orbach DB. Safety of neuroangiography and embolization in children: Complication analysis of 697 consecutive procedures in 394 patients. J Neurosurg Pediatr. 2015. 16: 432-8

19. Liu AC, Segaren N, Cox TS, Hayward RD, Chong WK, Ganesan V. Is there a role for magnetic resonance imaging in the evaluation of non-traumatic intraparenchymal haemorrhage in children?. Pediatr Radiol. 2006. 36: 940-6

20. Meretoja A, Strbian D, Putaala J, Curtze S, Haapaniemi E, Mustanoja S. SMASH-U: A proposal for etiologic classification of intracerebral hemorrhage. Stroke. 2012. 43: 2592-7

21. Meyer-Heim AD, Boltshauser E. Spontaneous intracranial haemorrhage in children: Aetiology, presentation and outcome. Brain Dev. 2003. 25: 416-21

22. Morgenstern LB, Hemphill JC, Anderson C, Becker K, Broderick JP, Connolly ES. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010. 41: 2108-29

23. Morgenstern PF, Hoffman CE, Kocharian G, Singh R, Stieg PE, Souweidane MM. Postoperative imaging for detection of recurrent arteriovenous malformations in children. J Neurosurg Pediatr. 2015. p. 1-7

24. Ogilvy CS, Heros RC, Ojemann RG, New PF. Angiographically occult arteriovenous malformations. J Neurosurg. 1988. 69: 350-5

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Keywords: Spinal lipoma, lipomyelomeningocele, spinal dysraphism, pediatric

ILLUSTRATIVE CASES

Case 1

A 3-month-old boy was referred to neurosurgery when a subcutaneous bulge in the lower lumbar region was incidentally noted. Initial workup included an ultrasound of the region that was concerning for spinal dysraphism, including sacral agenesis and an associated intraspinal mass. These findings prompted a lumbosacral magnetic resonance image (MRI), which confirmed the diagnosis of lipomyelomeningocele. The patient was clinically asymptomatic, with normal strength in his lower extremities, no evidence of hydrocephalus, and normal bowel and bladder function. Because he was meeting developmental milestones, he was managed observantly with annual clinical exams, which remained normal. At 3 years of age, he underwent urodynamic studies, which were unremarkable, and he was able to successfully toilet train. At around this time, his parents reported transient morning stiffness in the back and lower legs, which would resolve by the afternoon. This prompted a repeat MRI [ Figure 1 ], which demonstrated the development of a syrinx in the lumbar region of the spinal cord. Surgical debulking and untethering of the lipomyelomeningocele was discussed with the parents, along with the associated risks and potential benefits, and, ultimately, the decision was made to continue expectant management. At 5 years of age, he remains clinically asymptomatic and continues to meet developmental milestones.

Figure 1

(a) T1 (left) and T2 (right) sagittal sections of an MRI showing the presence of a caudal lipomyelomeningocele with an associated lumbar syrinx (arrows) in a clinically asymptomatic patient. (b) Selected T2 axial sections as identified by the color coding on the sagittal image in A

Case 2

An 11-day-old girl with an uncomplicated birth was noted by her parents to have a lump on her lower back, prompting further workup by her pediatrician. A physical exam revealed a 4–5 cm soft, nontender mass in the lumbar spine with hyperpigmented changes [ Figure 2 ]. An ultrasound was performed, which showed the absence of sacral lamina and dorsal elements with an associated intraspinal mass and bilateral hydronephrosis. She subsequently underwent an MRI showing a spinal dysraphism of the sacrum associated with a large cystic intraspinal mass, concerning for a lipomyelomeningocele versus a terminal lipomyelocystocele. Her motor exam showed normal strength in both lower extremities but poor deep tendon reflexes and a slightly distended abdomen. Further urological workup revealed the presence of grade 4 vesicoureteral reflux for which she was started on a clean intermittent catheterization protocol. After a thorough discussion about the risks and benefits of operative intervention, she was taken to the operating room (OR) for debulking of the lipomatous mass and untethering. Electrical stimulation and neuromonitoring were used to monitor function. The dural tube was reconstructed using a synthetic patch duroplasty. No cyst was encountered during the debulking. There were no intraoperative complications, however, 1 week postoperatively she developed a cerebrospinal fluid (CSF) leak, which precipitated a Klebsiella wound infection. She returned to the OR for irrigation and debridement, placement of a lumbar drain, and revision of the dural closure. Postoperatively, she remained intubated and prone for 1 week, at which point the lumbar drain was removed and she was extubated. She had no further leakage from the wound and was discharged approximately 5 weeks after her first surgery. At 18-months’ postoperative follow-up, her wound was well healed, and she retained normal strength in her bilateral lower extremities. She progressed to grade 5 vesicoureteral reflux with moderate hydronephrosis without urinary tract infections, managed by clean intermittent catheterization every 3 hours.

Figure 2

(a) Photograph demonstrating a lumbar mass and associated hyperpigmentation. (b) T1 (left) and T2 (right) sagittal sections of an MRI showing the lumbosacral dysraphism and associated cystic lumbar mass. (c) Selected T2 axial sections as identified by color coding on the sagittal image in A

INTRODUCTION

Lipomyelomeningocele (LMMC) is a closed neural tube defect in which neural elements are incorporated into a spinal lipoma. This is an uncommon defect, occurring in 3–6 patients per 100,000 live births.[ 14 ] Clinical decision-making regarding treatment is complicated by the varied pathology and the spectrum of presentations. Herein, LMMC embryology, morphology, treatment options, and outcomes are reviewed.

Embryology

Central nervous system development consists of primary and secondary neurulation. During primary neurulation, the notochord induces folding of the neural plate to form the neural tube, which extends in both the rostral and caudal directions. The ectoderm overlying the neural tube separates to ultimately form the skin dorsal to the spine, a process known as dysjunction. Mesoderm around the neural tube differentiates into the posterior vertebral elements, fat, and paraspinal musculature. In premature dysjunction, mesoderm can migrate into the neural tube before it is fully closed, disrupting the neurulation process. This mesoderm then differentiates into fat and forms a border between the neural placode and the now entrapped lipoma. As development continues, meninges form around the neural tube except at the placode-lipoma interface, leaving a dorsal diaschisis traversed by a lipoma. This often results in a distinct transition point between normal planes and anatomy, anteriorly, and the lipoma, posteriorly.[ 13 ]

In secondary neurulation, a caudal mass of mesenchymal mesoderm cavitates and fuses with the primary neural tube, forming the spine below S2. After fusion of the primary and secondary neural tubes, mesoderm can migrate caudally and interfere with secondary neurulation in a mechanism similar to the disruption of primary neurulation. Secondary neurulation differs phylogenetically and is incompletely understood. Humans lack mature tail structure and have less complexity of secondary neurulation comparatively. In chick embryos, dynamic histology describes a coalescing of radially oriented tubules around a central lumen, ultimately cavitating within the caudal cell mass and joining the primary neurulated structure. Prevailing theories involve morphogenetic determinants, with candidate genes including sonic hedgehog and Pax transcription factors.[ 10 ] Environmental factors are posited to interfere with the enfolding mechanism of secondary neurulation including folate deficiency, viremia, and teratogens as examples; however, little incidence data supports this supposition.[ 8 ]

The morphology of spinal lipomas is thought to be determined by which of the two neurulation processes is affected. Regardless of the morphology, in LMMC the placode-lipoma junction lies outside the spinal canal with dorsal extension of the meninges through an accompanying bony defect, in contrast to residing inside the canal, as seen in a lipomyelocele.[ 29 ] After the lipoma exits the dural defect, it continues through a fascial defect to communicate with subcutaneous tissue. This tethers the spinal cord and restricts its ability to ascend normally, making it susceptible to stretch injury during spine growth or repetitive ischemic insults resulting from flexion/extension movements.[ 15 21 24 ]

Classification

Traditionally, spinal lipomas have been classified into three groups based on the location of the neural placode–lipoma junction: Dorsal, caudal, and transitional, known as the Chapman classification[ 3 5 ] [ Figure 3 ]. In dorsal spinal lipomas, the junction is on the dorsal aspect of the lumbar spinal cord and spares the conus medullaris. The dorsal root entry zone (DREZ) and neural elements are displaced lateral and ventrolateral to the placode–lipoma junction, respectively. The nerve roots emerge from the spinal cord tissue anterior to the junctional zone, where the lipoma, dura, and conus medullaris converge. In contrast, the conus is involved with caudal lipomas, and neural elements are located rostral to the junction. In caudal lipomas, the fatty tissue can extend from within the central canal caudally, where the fat is intermixed with nerve roots. The distal cord thus appears progressively larger in diameter toward the caudal aspect. Other findings may include a restrictive transverse fibrous band at the level of the last intact lamina. Transitional lipomas have characteristics of both dorsal and caudal types, with viable nerve roots passing through the lipoma tissue. These lesions tend to be asymmetric, with a rotational component on the spinal cord. The placode–lipoma junction is thus typically rotated. In addition, Pang et al. described a chaotic type, which has an irregular border between the placode and lipoma. Fat extends around the spinal cord and onto its ventral aspect, obscuring the DREZ. Most LMMCs are of the dorsal or transitional type.[ 30 ]

Figure 3

Classification of lipomas of the conus medullaris, as described by Chapman. Dorsal, caudal, and transitional types (right to left)

Premature dysjunction is necessary for all types of spinal lipomas, except the chaotic type. Primary and secondary neurulation is disrupted in the dorsal and caudal types, respectively, whereas both are affected in the transitional type. The chaotic type is thought to involve only secondary neurulation, where mesenchymal cells may become mixed with the caudal stem cell mass.

Presentation

Spinal lipomas and LMMCs are frequently associated with cutaneous and musculoskeletal abnormalities in addition to sensorimotor deficits and urological dysfunction.[ 29 ] Cutaneous lesions include subcutaneous lipomas, capillary hemangiomas, complex dimples, and hypertrichosis, whereas complex malformations, such as dermal appendages, are rare.[ 12 15 ] Musculoskeletal findings include scoliosis, unilateral or bilateral foot deformities, such as pes cavus, club feet, or abnormal rotation, or asymmetry of the foot or leg. Any of these findings should prompt consideration of an underlying embryomorphic etiology. Urological dysfunction, such as incontinence, frequency, urgency, and urinary tract infections, are also commonly associated. Neurological symptoms frequently correspond to those expected of a tethered cord syndrome, such as back or leg pain at rest that worsens with activity, in addition to weakness, sensory disturbances, or gait abnormalities.[ 9 ]

At birth, neurological symptoms may be absent in nearly half of the cases.[ 16 ] As the infant ages and axial growth occurs, the infant may experience progressive loss of neurological function.[ 19 ] Often, a change in the pattern of bladder and bowel function is the presenting symptom of LMMC.[ 9 ] As axial growth continues, lower limb, and sacral motor and sensory dysfunction, such as radicular pain, leg spasticity, foot deformities, and gait abnormalities, can develop.[ 17 ] Consequently, older children who escape early detection of LMMC are more likely to present with more pronounced urological and neurological complaints.[ 2 ] In addition to the symptomatic progression that correlates with axial growth, morphology of the defect also plays a large role in the presentation of LMMC patients. Symmetric malformations without a rotational component to the lipoma–placode interface tend to cause bilateral neurological or orthopedic abnormalities, which present at a later age. In contrast, asymmetric malformations tend to cause unilateral functional abnormalities and present earlier in life, usually on the side to which the neural placode was rotated.[ 2 ] Finally, LMMCs can become symptomatic from spinal stenosis secondary to mass effect as the lipomatous malformation increases mass over time.[ 30 ]

LMMC can be associated with additional pathologies, including Chiari malformation type 1 (13%), spina bifida (14.4%), split cord malformations (3.1%), associated dermal sinuses (3.1%), dermoid or epidermoid cysts (3.1%), diastematomyelia (3.1%), terminal hydromyelia (3.1%), anal stenosis (1.0%), and Down syndrome (1.0%).[ 18 23 33 ]

DIAGNOSTIC STUDIES

Ultrasound is an effective screening tool because it is low risk and widely available, however, it has limited use after the initial diagnosis or following surgical treatment and should not be relied upon as the sole preoperative assessment.[ 22 ] A detailed MRI is the definitive imaging evaluation for spinal-neural lipomas. The anatomical detail of the placode-lipoma junction can be shown in relation to the normal spinal cord. Plain radiographs or computed tomography (CT) imaging may be useful to assess for scoliosis and evaluate the spine's bony anatomy during preoperative planning.

MANAGEMENT

Historical studies have shown that surgical interventions may briefly stabilize or relieve neurological symptoms but ultimately fail to improve upon the natural history of LMMCs.[ 6 21 23 28 34 ] Symptoms are typically progressive and worsen with age. Kulkarni et al. shed light on the natural history, citing a 33% risk of symptom deterioration with conservative management versus 46% for surgical treatment at nine-year follow-up.[ 28 ] One downfall of this study was that the conservative group was prospectively followed, whereas the surgical cohort was treated in the 1970s and retrospectively analyzed. Nevertheless, this study has changed the outlook and management of asymptomatic patients previously thought to require surgical intervention. The argument against surgical intervention for asymptomatic spinal lipomas was reinforced again in a 2012 London study that found a 40% cumulative risk of deterioration at 10 years.[ 35 ]

Surgical intervention may provide temporary relief or lessening of symptoms by releasing tension on the spinal cord, however, there is a risk of retethering with subsequent return or progression of neurologic symptoms, with reported rates of 5–50%. In a study by Colak et al. of 94 patients who underwent initial repair of a LMMC, 20.2% required subsequent operations for symptomatic retethering, with an average follow-up of 52 months after surgery. Of these reoperated patients, 6.4% exhibited repetitive symptomatic tethering, which became more difficult to treat and with shorter times between return of symptoms. Colak concluded that even after an adequate initial operation, symptomatic retethering is a common problem and that no current duraplasty graft material entirely prevents this from occurring.[ 7 ] There has been a confusing array of studies showing progression of neurologic symptoms after surgery to be lower,[ 4 ] similar to,[ 3 6 ] or worse than[ 11 ] the natural history. Cochrane et al. suggested that the variance in these results may be due to differences in the symptoms assessed, the duration of follow-up, the type of malformation, and timing of surgery.[ 6 ] Many experts argue for conservative treatment, with close clinical evaluations and surgical intervention only as patients develop worsening symptoms, as the natural history is similar or marginally better than the long-term outcome of surgically-treated patients.

A recent retrospective review attempted to identify radiological correlates predicting neurological decline. Over 16 years, a 24-patient population with LMMC that underwent an observational management strategy at a single institution was dichotomized into those experiencing early (less than 18 months) and late (18–30 months) neurological deterioration. Nine patients experiencing early deterioration were more likely to have large intradural lipomatous masses, which grew within the first year to exert regional mass effect on neural structures and were associated with a large expanded syrinx. Early decliners were more likely to present with motor deficits, whereas 15 patients experiencing late neurological decline presented with mixed urologic and motor deficits.[ 32 ] This study supports prophylactic untethering in infants with large intradural lipomas with syrinx, which exert mass effect on neural structures.

Several factors are thought to affect the treatment outcome of LMMCs. Age, gender, morphology, the presence and severity of neurological symptoms, and absence or presence of an associated spinal cord syrinx are all taken into consideration. Of these, morphology is considered the most crucial factor affecting outcome. For example, transitional lipomas appear to have a higher rate of retethering after surgery than dorsal and caudal types.[ 7 ] It is unclear if this is related to a factor intrinsic to the embryology or related to lesional complexity precluding adequate untethering.[ 30 31 ] It is also hypothesized that these factors may affect the outcome through a common pathway described by Pang et al. as the postoperative cord-to-sac ratio, which his group noted to be directly correlated to the progression or return of neurologic symptoms.[ 30 ] They suggested that cord retethering is a result of too little space in the dural sac for the spinal cord. This forces into close proximity any remaining residual lipoma surface with the normal spinal cord, which can then adhere. If the lipoma is completely removed and space within the dural sac is increased, they posited there is less chance of the cord contacting the dura or the “sticky” lipoma surface and retethering.

The traditional surgical technique described in historical studies involves partial resection of the lipoma to avoid injury to the neural placode, followed by untethering of the cord, then apposition of the edges of the placode, and finally duraplasty.[ 1 ] This technique, however, does not dramatically affect the cord-to-sac ratio. Pang et al. suggested a more aggressive approach involving total or near-total resection of the lipoma, complete reconstruction of the neural placode, followed by expansile duraplasty, preferably using bovine pericardium.[ 30 ] Using their technique, they showed no neurologic deterioration in 88.1% of patients over 20 years of follow-up, compared to 34.6% risk of progression over 10 years in patients with only partial resection. This included lipomas of all types, including symptomatic, asymptomatic, unoperated, and redo subgroups. Progression free survival (PFS) for asymptomatic unoperated spinal lipomas with this aggressive resection method was 98.8% over 20 years. Multivariate analysis of their data showed cord-to-sac ratio to be the only independent factor predicting outcome. These results have not been reproduced in any other series to date, however, they are compelling numbers for those who hold that surgical intervention can improve upon the natural history of LMMCs, whether or not symptoms are present.

A radically different approach to the treatment of tethered cord comes in the form of vertebral column shortening, which offers an alternative method for relieving tension on the spinal cord without risking injury to the neural placode and possibly stabilizing or improving neurological outcome.[ 20 ] The three-column osteotomy typically involves T12 or L1, and the average reduction in height is approximately 20 mm. Potential surgical complications include pseudoarthrosis, neurological injury, and significant perioperative blood loss. Kokubun et al. used this surgical method to treat eight patients (ages 15–54 years), 3 of which had previous conventional untethering procedures.[ 26 ] Six patients remained stable, and 2 patients experienced neurological decline over an average follow-up of 6.2 years. For these patients with decline, it is unclear if additional height reduction is needed, or perhaps changes within the neural placode occur independent of tension produced by the tethering. Although thought to be a relatively safe treatment option when used by experienced surgeons, its use should be limited to symptomatic patients with recurrent tethering despite conventional surgical detetherings, until studies with larger patient numbers can demonstrate its safety and effectiveness as a primary treatment option.

Regardless of the type of surgical intervention, the use of operative microscope is recommended, and intraoperative neurophysiological monitoring should be performed. There are a number of various neurophysiologic measures that can be used, and institutional practice may dictate what is available. Whatever monitoring type is chosen, the goal remains to avoid unintended injury to intact nervous structures, which may be hidden by or attached to the LMMC.[ 25 27 ]

As mentioned earlier, management of symptomatic LMMCs may not always entail surgical untethering. Complex variants of the transitional or chaotic spinal lipomas associated with isolated urological symptoms or orthopedic deformities may be observed because these abnormalities are less likely to improve with surgical intervention. They also carry a higher risk of unsuccessful untethering and incomplete lipoma resection, which may lead to an increased risk of neurological deterioration after surgery.

After careful evaluation, “simple” LMMCs with symptoms or any LMMC with an associated sensorimotor deficit should be considered for possible surgical intervention. Caudal and dorsal spinal lipomas are typically more amenable to surgical treatment than the rest. Immediate postoperative complication rates range from 10–30% and include infection, CSF leak, or neurological deterioration.[ 1 23 ]

LMMCs associated with embryomorphic malformations of other systems may represent the more severe end of the spectrum of congenital defects. For example, OEIS (omphalocele, exstrophy, imperforate anus, spinal defects) and VATER (vertebral defects, anal atresia, tracheoesophageal fistula, renal abnormalities) represent associated multisystem abnormalities, which complicate management and are beyond the scope of this review.

CASES IN CONTEXT

Table 1 summarizes the salient details of Cases 1 and 2, along with the resultant clinical decision. Case 1 included incidental identification of an asymptomatic caudal LMMC with associated syrinx and without intradural mass effect. The patient had normal motor and urological exams, with only the development of leg tightening over 2 months. The clinical and radiographic data were combined into a clinical decision rule supported by the literature, and the patient has been stable through observational treatment. Case 2 is defined radiographically by caudal LMMC with large associated syrinx and mass effect on intradural neural structures. The patient also exhibited signs of tethering, including diminished deep tendon reflexes and abdominal distention, along with intercurrent embryomorphic malformations of the spine and renal system. In the presentation for Case 2, the literature supports untethering and debulking, which was performed. The patient had essentially static symptoms without significant worsening or improvement on follow-up at 18 months.

Table 1

Clinical decision-making for patients with lipomyelomeningocele

CONCLUSION

LMMC management remains a challenge. The selected cases demonstrate important factors integrated within a clinical decision rule. Although there is no high-quality clinical outcome data to provide guidance regarding the treatment options for LMMCs, conservative management of asymptomatic patients is appropriate. Clearly progressive symptomatic patients should be considered for surgical untethering with the goal of managing symptoms, with the patient and family prepared for an iterative process. Patients with static neurological deficits should be managed observationally. Prophylactic surgery may, theoretically, prevent the onset of neurological deterioration or stabilize and reverse early-onset symptoms at diagnosis, especially in infants with large intradural lipoma and associated syrinx, which compress neural structures, however, this has not been shown to offer immunity against further deterioration. When surgical management is elected, experts advocate aggressive resection of the lipoma, along with reconstruction of the placode and large expansile duraplasty, but the literature shows this is technically difficult and may not greatly improve upon the natural history of LMMCs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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2. Atala A, Bauer SB, Dyro FM, Shefner J, Shillito J, Sathi S. Bladder functional changes resulting from lipomyelomeningocele repair. J Urol. 1992. 148: 592-4

3. Blount JP, Elton S. Spinal lipomas. Neurosurg Focus. 2001. 10: e3-

4. Byrne RW, Hayes EA, George TM, McLone DG. Operative resection of 100 spinal lipomas in infants less than 1 year of age. Pediatr Neurosurg. 1995. 23: 182-6

5. Chapman PH. Congenital intraspinal lipomas: Anatomic considerations and surgical treatment. Childs Brain. 1982. 9: 37-47

6. Cochrane DD. Cord untethering for lipomyelomeningocele: Expectation after surgery. Neurosurg Focus. 2007. 23: E9-

7. Colak A, Pollack IF, Albright AL. Recurrent tethering: A common long-term problem after lipomyelomeningocele repair. Pediatr Neurosurg. 1998. 29: 184-90

8. Copp AJ, Stanier P, Greene ND. Neural tube defects: Recent advances, unsolved questions, and controversies. Lancet Neurol. 2013. 12: 799-810

9. Cornette L, Verpoorten C, Lagae L, Plets C, Van Calenbergh F, Casaer P. Closed spinal dysraphism: A review on diagnosis and treatment in infancy. Eur J Paediatr Neurol. 1998. 2: 179-85

10. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, Speer MC. Human neural tube defects: Developmental biology, epidemiology, and genetics. Neurotoxicol Teratol. 2005. 27: 515-24

11. Dorward NL, Scatliff JH, Hayward RD. Congenital lumbosacral lipomas: Pitfalls in analysing the results of prophylactic surgery. Childs Nerv Syst. 2002. 18: 326-32

12. Drolet B. Birthmarks to worry about. Cutaneous markers of dysraphism. Dermatol Clin. 1998. 16: 447-53

13. Finn MA, Walker ML. Spinal lipomas: Clinical spectrum, embryology, and treatment. Neurosurg Focus. 2007. 23: E10-

14. Forrester MB, Merz RD. Descriptive epidemiology of lipomyelomeningocele, Hawaii, 1986-2001. Birth Defects Res A Clin Mol Teratol. 2004. 70: 953-6

15. Guggisberg D, Hadj-Rabia S, Viney C, Bodemer C, Brunelle F, Zerah M. Skin markers of occult spinal dysraphism in children: A review of 54 cases. Arch Dermatol. 2004. 140: 1109-15

16. Hertzler DA, DePowell JJ, Stevenson CB, Mangano FT. Tethered cord syndrome: A review of the literature from embryology to adult presentation. Neurosurg Focus. 2010. 29: E1-

17. Hoffman HJ, Hendrick EB, Humphreys RP. The tethered spinal cord: Its protean manifestations, diagnosis and surgical correction. Childs Brain. 1976. 2: 145-55

18. Hoffman HJ, Taecholarn C, Hendrick EB, Humphreys RP. Management of lipomyelomeningoceles. Experience at the Hospital for Sick Children, Toronto. J Neurosurg. 1985. 62: 1-8

19. Hoving EW, Haitsma E, Oude Ophuis CM, Journee HL. The value of intraoperative neurophysiological monitoring in tethered cord surgery. Childs Nerv Syst. 2011. 27: 1445-52

20. Hsieh PC, Stapleton CJ, Moldavskiy P, Koski TR, Ondra SL, Gokaslan ZL. Posterior vertebral column subtraction osteotomy for the treatment of tethered cord syndrome: Review of the literature and clinical outcomes of all cases reported to date. Neurosurg Focus. 2010. 29: E6-

21. Huang SL, Shi W, Zhang LG. Surgical treatment for lipomyelomeningocele in children. World J Pediatr. 2010. 6: 361-5

22. . International Society of Ultrasound in O, Gynecology Education C. Sonographic examination of the fetal central nervous system: Guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’. Ultrasound Obstet Gynecol. 2007. 29: 109-16

23. Kanev PM, Lemire RJ, Loeser JD, Berger MS. Management and long-term follow-up review of children with lipomyelomeningocele, 1952-1987. J Neurosurg. 1990. 73: 48-52

24. Kannu P, Furneaux C, Aftimos S. Familial lipomyelomeningocele: A further report. Am J Med Genet A. 2005. 132A: 90-2

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26. Kokubun S, Ozawa H, Aizawa T, Ly NM, Tanaka Y. Spine-shortening osteotomy for patients with tethered cord syndrome caused by lipomyelomeningocele. J Neurosurg Spine. 2011. 15: 21-7

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Abstract

Background:Neck pain is a major public health concern that has been extensively studied in adults but not in children and adolescents. Therefore, the purpose of this article is to explore musculoskeletal neck pain in children and adolescents, as well as to discuss its possible risk factors and complications.

Methods:Participants were patients under 18 years of age, who had presented to the clinic (Beirut, Lebanon) in 2015, with nonspecific neck pain. They were examined and asked to evaluate and localize the pain. Neck positioning during various activities along with other complications were explored. Patients reporting pain associated with congenital or systemic diseases and fractures were excluded.

Results:Two-hundred-and-seven children and adolescents presented with nonspecific neck pain. Musculoskeletal neck pain with spasm was diagnosed in 180 patients (N = 180). Participants did not show any findings on physical examination and radiological studies, and had no comorbidities. More females (57%) than males (43%) and more adolescents (60%) than children (40%) were affected. All the 180 participants (100%) reported flawed flexion of their back and neck while studying and/or using smartphones and tablets. Eye symptoms were reported in 21% of the cases, and parents of most participants (82%) reported a change in the psychological and social behavior of their children.

Conclusions:Musculoskeletal neck pain is an important disease in children and adolescents with numerous risk factors contributing to its development. Increased stresses regarding the cervical spine may lead to cervical degeneration along with other developmental, medical, psychological, and social complications.

Keywords: Adolescents, children, neck flexion, neck pain, smartphones, text neck

INTRODUCTION

Neck pain is a major public health problem in modern societies.[ 4 14 ] It can originate from any structure in the neck including intervertebral discs, ligaments, muscles, facet joints, dura, and nerve roots.[ 3 ] Potential causes can be tumors, infection, inflammatory diseases, and congenital disorders. In most cases, however, no systemic illness can be detected, and the complaint is labeled as musculoskeletal neck pain.[ 2 ]

Prevalence data have shown that, in a general population, the 1-year incidence of neck pain can be as high as 40%.[ 1 ] The World Health Organization (WHO) has ranked neck pain and other musculoskeletal diseases at 4^th and 10^th, respectively, among all health conditions for years lived with disability.[ 32 ] These conditions were also acknowledged as the key drivers of the increase in years lived with disability over the past 20 years.[ 32 ] In addition, data from the WHO Global Burden of Disease study showed that neck pain is the 8^th ranked reason for most years lived with disability for 15–19 year olds of any health condition, which is higher than well-known adolescent public health problems such as asthma, alcohol use, drug use, and road injury.[ 21 ]

Although the epidemiology, burden, and treatment of musculoskeletal pain have been extensively explored in adults, the same is not true for children. The lack of clinical research pertinent to children and adolescents has been emphasized by multiple studies.[ 7 15 25 26 29 ] Emerging evidence shows that children, especially adolescents who report persistent pain, are at an increased risk of chronic pain as adults.[ 5 19 23 ] Moreover, many musculoskeletal illnesses follow a long-term pattern of recurring exacerbations and remissions, with the most consistent predictor of a new episode being the experience of a previous episode.[ 30 ]

As the surge in prevalence of musculoskeletal conditions occurs in childhood and adolescence, it may be necessary to investigate the condition at these stages of life.[ 24 ] Understanding aspects and risk factors surrounding the initial onset provides the best opportunity to develop efficacious treatments, and is central to any efforts at primary prevention.

Therefore, the purpose of this article is to explore musculoskeletal neck pain in children and adolescents under 18 years of age, and to discuss possible risk factors and complications related to this pain.

MATERIALS AND METHODS

This study explored cases that presented to our clinic in Beirut, Lebanon, in 2015 with nonspecific neck pain. Demographic information including age, sex, level of education, use of technology, and study habits were collected from individuals and their parents.

Interviewed individuals were under 18 years of age. Those whose ages ranged between 8 and 11 years were considered children, and those whose ages ranged between 12 and 17 years were considered adolescents. Patients were asked to localize the pain on themselves and on a model provided to them. Neurological assessment was conducted to test for sensory and motor deficits. Individuals were also asked about their pertinent daily habits, studying conditions, sitting positions, and sleeping positions. Further investigation explored the use of technology such as cell phones, tablets, computers, and television; participants were asked to show their usual neck position when engaged in these activities. All interviewees underwent radiological studies by radiography to rule out scoliosis or any other pathologies at the cervical spine level. In addition, psychological and social symptoms were investigated.

For the purposes of this study, we did not include patients reporting pain associated with congenital or systemic diseases, such as scoliosis. We also excluded patients reporting pain resulting from frank injuries, such as fractures, and pain following surgical interventions. Chronic neck pain was defined as continuous neck complaints for more than 6 months.

RESULTS

In total, 207 children and adolescents presented with nonspecific neck pain. All patients reported having cervical neck pain of more than 6 months’ duration that radiates dorsally down the back and to the shoulders. None had sensory or motor deficits. Twenty-seven patients were found to have dorsolumbar scoliosis and were excluded from the study. The remaining 180 patients did not show any finding on physical examination and radiological studies, and had no comorbidities. They were diagnosed with musculoskeletal neck pain with spasm, and were the focus of our study (N = 180). Ages ranged between 8 and 17 years, with a mean age of 14 years. Demographics of the children and adolescents participating in the study are presented in Table 1 .

Table 1

Demographics of the children and adolescents participating in the study (N=180)

All the 180 participants (100%) reported flawed flexion of their back and neck while studying. They also admitted to using smartphones and/or tablets. When asked to demonstrate how they used these devices, all participants (100%) showed strong flexion of the neck (≥45 degrees) when engaged in the activity. Children and adolescents in our sample spent an average of 5 and 7 hours a day, respectively, on their smartphones and handheld devices. Table 2 shows the pain sites, eye symptoms, and psychological and social effects that were found in the children and adolescents.

Table 2

Pain location, eye symptoms, and psychological and social effects in the children and adolescents participating in the study (N=180)

A change in behavior, defined by a change in daily habits and usual social interactions, as noticed by parents, was reported in 147 young participants (82%). They were described as having become more irritable and alienated. Parents of 115 participants (64%) reported that their grades in school have been declining.

DISCUSSION

Musculoskeletal neck pain in children and adolescents is very common. Almost 87% (180 of 207) of the children and adolescents presented in our study were diagnosed with musculoskeletal neck pain. Other studies and reviews have shown 1-year incidences of 28% and 40% for neck pain.[ 1 22 ]

All our participants reported flexing their back and neck while studying. Ariëns et al.[ 1 ] found a positive relationship between neck flexion and neck pain, suggesting an increased risk of neck pain for individuals studying with the neck at a minimum of 20° of flexion for more than 70% of the studying time. Moreover, all our participants showed strong flexion of the neck when using smartphones. “Text neck,” a 21^st-century syndrome, is a term derived from the onset of cervical spinal degeneration resulting from the repeated stress of frequent forward head flexion while looking down at the screens of mobile devices and “texting” for long periods of time.[ 31 ] Text neck is becoming more common as more people, especially teens and adolescents, hunch over smartphones.[ 6 ] It is estimated that 75% of the world's population spends hours daily hunched over their handheld devices with their heads flexed forward.[ 19 ] In our sample, children and adolescents spent averages of 5 and 7 hours a day, respectively, with their heads tilted over reading and texting on their smartphones and handheld devices. Cumulatively, this is an average of 1825 and 2555 hours a year, respectively, of excess stresses seen in the cervical spine area. Hansraj adds that it is possible that a high school student may spend an extra 5000 hours in poor posture.[ 18 ]

The weight put on the spine dramatically increases when flexing the head forward at varying degrees [ Figure 1 ]. A full-grown head weighs 4.54 to 5.44 kg in the neutral position.[ 18 ] As the head tilts forward, the forces seen by the neck surges to 12.25 kg at 15°, 18.14 kg at 30°, 22.23 kg at 45°, and 27.22 kg at 60°.[ 18 ] The frequent forward flexion causes changes in the cervical spine, curvature, supporting ligaments, tendons, and musculature, as well as the bony segments, commonly causing postural change and pain felt in the neck and other associated areas.[ 31 ]

Figure 1

A chart depicting the stress and weight put on the neck and spine as a result of hunching over a smartphone and handheld devices at varying degrees. The neck flexion angle is the angle between the global vertical and the vector pointing from C7 to the occipitocervical joint. A full-grown head weighs 5 kg in the neutral position. As the head bends forward, the weight seen by the neck increases to 18 kg at 30° and 27 kg at 60°

The effects of forward flexion of the neck transcend pain to contribute to more associated complications. Often times, the effects of prolonged neck flexion can contribute to nearsightedness, eye strain, or dry eyes, as the eyes are forced to focus on an object placed nearby.[ 8 ] New research suggests a link between forward leaning postures that people use while texting, studying, surfing the web, emailing, and playing video games, and hyperkyphosis, which is associated with pulmonary disease and cardiovascular problems.[ 9 ] It is suggested that when someone drops their head and rounds their shoulders while looking at a smartphone or a tablet, it is harder for them to take a full breath because of the restriction to their muscles.[ 9 ] In addition, the ribs cannot move properly; thus, the heart and lungs cannot function to their full effectiveness.[ 9 ] Most times, children and adolescents do not know they could be doing serious long-term damage to their body because the short-term effects are not as noticeable. It is only in later life that the effects can seriously affect the quality of life. This increases fears that younger people, who are society's biggest users of smartphones and tablets, could be facing a future of pain and disability, or even taking years off of their life expectancy.

Emre et al.[ 10 ] indicate that computers, wireless internet, cell phones, and televisions emit an extremely low-frequency electromagnetic field. Electromagnetic radiation can cause difficulty sleeping, dizziness, headaches, tingling in the hands, ringing in the ears, eye pain, “unexplained” cardiac conditions, electrosensitivity, low immunity, attention deficit hyperactivity disorder, and autism.[ 20 ] When electrical properties are considered, the absorption of electromagnetic radiation through a child's head can be over two times greater, and absorption of the skull's bone marrow ten times greater, than in adults.[ 16 ]

Parents of most of our participants reported that their children have become more isolated and easily irritable. In addition, their grades in school have been negatively affected. Children who use more than the expert recommended 1–2 hours per day of technology, have a 60% increase in psychological disorders.[ 28 ] As mentioned previously, children and adolescents in our sample spent averages of 5 and 7 hours a day, respectively, on their smartphones and handheld devices. It is indicated that the more time students spend consuming media, and the more violent its contents are, the worse their grades in school, even when controlling for vital factors such as family, education, or immigrant background.[ 27 ] In addition, spending too many hours on handheld devices and smartphones will negatively affect children and adolescents’ communication skills, particularly with regard to face-to-face communication skills, bullying, and teasing.[ 17 ]

The lack of validated instruments to measure musculoskeletal neck pain and its consequences in children and adolescents is a limitation in similar studies. This is due to the fact that it becomes difficult to draw conclusions and compare between different samples, populations, and cultures. In addition, the method of administration is critical because self-administered instruments cannot be conducted among illiterate and young children, and the need for a parent to collect information may hinder the pain evaluation process.

Future studies should aim to find a unified instrument to measure musculoskeletal neck pain, and validation across cultures should occur. The pathways and mechanisms for the association of pain experienced in childhood and pain experienced in adulthood are unknown. It can be hypothesized that a physiological or behavioral trigger is set when a child has a particular painful experience, which predisposes them to pain as an adult. Genetic susceptibility may also underlie the experience of pain. Future studies can aim to explore these mechanisms. Moreover, there is a particular need for studies to investigate the nature of the relationships between neck pain and other adverse health risk factors.

CONCLUSIONS

Musculoskeletal neck pain is a common multifactorial disease in children and adolescents, implying that there are numerous risk factors contributing to its development. Bending the head, neck, and shoulders over cell phones and handheld devices, along with distorted neck positioning when sitting, studying, and watching television, can lead to incrementally increased stresses in the cervical spine area. These stresses may lead to early wear, tear, degeneration, and possibly surgeries. Other developmental, medical, psychological, and social complications are also of concern. While it is nearly impossible to avoid the habits and technologies that cause these issues, young individuals should make an effort to perform activities with a neutral spine and to avoid neck flexion for hours each day.[ 11 12 13 14 ] Cervical spine surgeons, pediatric neurologists, public health advocates, and social workers should run campaigns to raise awareness on musculoskeletal neck pain and its medical, psycholgical, and societal consequences, and methods of prevention and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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25. McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007. 21: 403-25

26. Michaleff ZA, Kamper SJ, Maher CG, Evans R, Broderick C, Henschke N. Low back pain in children and adolescents: A systematic review and meta-analysis evaluating the effectiveness of conservative interventions. Eur Spine J. 2014. 23: 2046-58

27. Mössle T, Kleimann M, Rehbein F, Pfeiffer C. Media use and school achievement–boys at risk?. Br J Dev Psychol. 2010. 28: 699-725

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29. Rodgers A. Managing chronic pain in children and adolescents. BMJ. 2002. 324: 1570-6

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31. Last accessed on 2016 Aug 29. http://text-neck.com/.

32. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015. 386: 743-800

Abstract

Background:Hurler Syndrome is the most severe phenotype of mucopolysaccharidosis type I. With bone marrow transplant and enzyme replacement therapy, the life expectancy of a child with Hurler syndrome has been extended, predisposing them to multiple musculoskeletal issues most commonly involving the spine.

Case Description:This is the case report of a 6-year-old male with Hurler syndrome who was diagnosed with Chiari I malformation and cervicothoracic syringomyelia on a preoperative magnetic resonance imaging (MRI) for his thoracolumbar kyphosis. This report details the successful management of a Chiari I malformation and syringomyelia with posterior fossa decompression in a child with Hurler syndrome.

Conclusion:Children born with MPS I can have complex spine issues that require surgical management. The most common orthopedic spinal condition for these patients, thoracolumbar kyphosis, requires evaluation with an MRI before performing surgery. This resulted in the diagnosis of a Chiari I malformation and syringomyelia in our patient with Hurler syndrome. This was successfully treated with decompression of the posterior fossa.

Keywords: Chiari I Malformation, Hurler syndrome, mucopolysaccharidosis type I, posterior fossa decompression, syrinx

INTRODUCTION

Mucopolysaccharidosis type I (MPSI) is an autosomal recessive lysosomal storage disease caused by deficient or absent activity of the α-L-iduronidase enzyme (IDUA), which catalyzes the degradation of the glycosaminoglycans (i.e., dermatan and heparan sulfates), the most severe form of which is Hurler syndrome (HS).[ 25 ] Without treatment, patients with HS suffer from multisystem manifestations including mental retardation, skeletal deterioration, severe cardiopulmonary disease, hepatosplenomegaly, visual impairment, and deafness, usually leading to death within the first decade of life.[ 8 ] The advent of allogeneic hematopoietic stem cell transplantation from bone marrow, peripheral blood, or unrelated umbilical cord has resulted in the reversal of organomegaly, preservation of neurocognitive development, and improved hearing, vision, and cardiopulmonary function in most transplanted patients.[ 1 8 9 13 18 20 21 ] With improvement in treatment, not only is the life expectancy of a child with HS increased, so is the risk of development of other medical conditions. To our knowledge, there have been only two papers published in the English medical literature describing syringomyelia in patients with mucopolysaccharidosis type II (Hunter syndrome)[ 14 ] and type VI (Maroteaux–lamy syndrome).[ 10 ] There have been no reports on the diagnosis and management of a Chiari I malformation (CM-I) and syringomyelia in a patient with HS. In this manuscript, we present a case of a 6-year-old child with HS who was diagnosed with CM-I and a cervicothoracic syrinx during a preoperative magnetic resonance imaging (MRI) for the surgical management of his thoracolumbar kyphosis.

CASE REPORT

The patient is a 6-year-old male who was referred to a pediatric clinic for an incidentally found CM-I and cervicothoracic syrinx [ Figure 1 ] identified during a preoperative workup prior to the surgical management of a progressive thoracolumbar kyphosis [ Figure 2 ]. The child has been experiencing daily headaches, but denied dysphagia, neck pain, or numbness or weakness in the upper extremities. His family also noted difficulty with hand coordination and strength when compared to his peers. Born via caesarian section at 41 weeks with a birth weight of 8 pounds and 12 ounces, he was diagnosed with HS and underwent a bone marrow transplant at the age of 14 months.

Figure 1

Preoperative MRI findings. (a) MRI brain, T1WI sagittal view. Demonstrates cerebellar ectopia, measuring approximately 5.9 mm with crowding within the foramen magnum. (b) MRI brain, T2WI coronal view. Demonstrates prominent retrocerebellar cystic space. The differential diagnosis includes major cisterna magna versus an arachnoid cyst. (c) MRI cervicothoracic spine, T2WI sagittal view. Demonstrates 8 mm syrinx from C₅ to T_1-2. (d) MRI cervicothoracic spine, T2WI axial view at the level of C_6-7

Figure 2

Spinal Imaging. (a) MRI thoracolumbar spine, sagittal view. (b) CT thoracolumbar spine, sagittal view. Both demonstrate severe gibbus deformity centered at L1 causing moderate to severe bony spinal canal stenosis

On physical examination, the patient was noted to be alert and oriented with clear speech and normal cranial nerve function. Muscle strength was 5/5 in bilateral biceps, triceps, and deltoids, 4+/5 in hand grip and finger abduction. Deep tendon reflexes were grade 2/4 in the upper and lower extremities with a negative Hoffman's sign bilaterally, no ankle clonus, and a downgoing Babinski test bilaterally. The patient was unable to perform single-leg stance.

On August 4, 2015 the patient was taken to the operating room where he underwent a successful suboccipital craniectomy measuring 3 × 3 cm, C₁ laminectomy, intradural exploration with coagulation of cerebellar tonsils, lysis of arachnoid adhesions, resection of thick posterior arachnoid membrane, and duraplasty measuring 3 × 3 cm utilizing Dura-Guard™ (Baxter Healthcare Corporation, Mountain Home, Arizona) and DuraSeal™ (Medtronic, Minneapolis, Minnesota). Intraoperatively, he was noted to have numerous arachnoid adhesions, an arachnoid cyst, and cerebellar tonsillar herniation to the level of C₁ was confirmed. Postoperative course was unremarkable, and he was ultimately discharged home on postoperative day 3.

At his first 2-week postoperative follow-up, his mother reported more stability with his gait and improved balance. The patient returned to school. The patient's physical examination was unchanged from his preoperative exam except that he was now able to perform a single-leg stance. At his 3-month follow-up visit, his parents reported that he continued to improve. His daily headaches had resolved, and the MRI of the cervicothoracic spine revealed improvement in the size of the syrinx measuring 3.5 mm at its widest point [ Figure 3 ].

Figure 3

3-month postoperative MRI. (a) MRI cervicothoracic spine, T2 WI sagittal view. Demonstrates improvement in syrinx from C₅ to T_1-2. (b) MRI cervicothoracic spine, T2 WI axial view at the level of C_6-7

Six months after suboccipital craniectomy, the patient underwent an uncomplicated anterior release and posterior spinal fusion with correction of his thoracolumbar kyphosis. During the most recent 3-month follow-up visit, the patient was found to have complete resolution of his gibbus deformity and no changes with his neurologic exam. The MRI of the cervical and thoracic spine revealed a stable syrinx. This case report was approved by the University of Missouri Health Sciences Institutional Review Board, and an informed consent was obtained from the patient's parents.

DISCUSSION

In 1891, Hans Chiari documented three cases of congenital defects of the rhombencephalon, classified as type I, II, and III.[ 6 ] The most common type is CM-1, which is present in 0.56–1% of the population.[ 16 ] The radiologic diagnosis of CM-I is best made on cranial midsagittal MRI studies, with cerebellar tonsil herniation of at least 3 mm below the basion-opisthion line suggesting the condition [ Table 1 ].[ 3 11 15 ] The symptoms of CM-I include head, neck, and back pain, cape pain (shoulders), nonradicular limb pain, weakness, paresthesias, vestibular symptoms, diplopia, tinnitus, hearing loss, syncope, slurred speech, dysphagia, urinary incontinence, and sleep disturbance.[ 16 ] A syrinx is present in 30–70% of cases of CM-I.[ 15 ]

Table 1

Diagnostic quick reference for Chiari I malformation and variants. This table is reproduced with the permission of the authors and the Neurologic Clinics

MPSI is an autosomal recessive lysosomal storage disease caused by mutation in the IDUA gene located on chromosome 4p16.3,[ 12 ] resulting in deficient or absent activity of the IDUA, which catalyzes the degradation of the glycosaminoglycans (i.e., dermatan and heparan sulfates).[ 25 ] These molecules can be found in free form in the extracellular matrix or as part of the structure of different types of proteoglycans, with important functions both in the structure of tissues and intercellular communication. Intralysosomal accumulation of these substrates results in pathological processes that produce a progressive dysfunction resulting in multiorgan deterioration that includes hepatosplenomegaly, dysostosis multiplex, short stature, coarse facial features, corneal clouding, joint contractures, umbilical hernias, failure to thrive, intellectual disability, and developmental delay.[ 5 12 ] The extensive storage of these glycosaminoglycans is also known to cause meningeal thickening.[ 4 ] Intraoperatively, our patient was noted to have thickened arachnoid membrane, which was biopsied and sent for pathological assessment. The sample did not reveal any intracellular storage of Luxol Fast Blue or Periodic Acid-Schiff positive contents, which neither supports nor refutes the clinical diagnosis of mucopolysaccharidosis.

Historically, MPSI has been divided into three clinical subtypes – Hurler (severe), Scheie (mild/attenuated), and Hurler–Scheie (intermediate).[ 1 ] This classification is based on clinical factors such as the age of onset, the rate of functional deterioration, and the range of affected organs (i.e., CNS involvement).[ 1 ] HS is the most severe phenotype in the spectrum of MPSI, with a prevalence of approximately 0.69 cases per 100,000 births.[ 2 ] Diagnosis of MPSI is based on IDUA enzyme analysis in leukocytes or dried blood spots followed by molecular confirmation of the IDUA gene mutations in individuals with low enzyme activity.[ 12 ]

HS progresses rapidly from 6 to 24 months resulting in significant multiorgan dysfunction.[ 5 ] Historically, the natural history of HS involved death before the age of 10 due to respiratory complications or cardiomyopathy.[ 17 ] Because new therapies such as allogeneic hematopoietic stem cell transplantation became a viable treatment option, reversal of organomegaly, preservation of neurocognitive development, and improved hearing, vision, and cardiopulmonary function in most transplanted patients have been observed.[ 1 8 9 13 18 20 21 ] To our knowledge, there have been only two papers published in the English language medical literature describing the diagnosis and treatment of syringomyelia in mucopolysaccharidosis patients. No one has reported this diagnosis in a patient with HS.

Manara et al.,[ 14 ] reported a case of CM-I and holocord syringomyelia in a patient who was diagnosed with Hunter syndrome at the age of 18 months. Patient was ultimately treated with enzyme replacement therapy with idursulfase. A brain MRI revealed enlarged cisterna magna along with cerebellar tonsils ectopia consistent with CM-I. MRI of the cervical spine failed to reveal a syringomyelia, whereas a repeat MRI at the age of 5 years revealed a focal thin syrinx. The child only complained of upper limbs numbness and loss of sphincter control without any other neurological deficits. A follow-up MRI 1 year later showed a holocord syrinx extending from the cervicomedullary junction to the conus medullaris. The child underwent posterior fossa decompression (PFD) for CM-I. At 7-months follow-up preoperative symptoms had resolved, whereass the MRI demonstrated significant decreased in size of the syrinx.

Hite et al.,[ 10 ] reported the case of a 6-month-old boy who initially presented for evaluation of hepatosplenomegaly and increased head circumference. He was diagnosed with mucopolysaccharidosis type VI (Maroteaux–lamy syndrome) and treated with allogeneic bone marrow transplantation at the age of 14 months. Pretransplant spinal MRI was essentially normal, however, by 4 years of age a follow-up MRI revealed a holocord syringomyelia from C2 to L1. The syrinx remained stable on serial MRIs and the patient continued to have no focal motor or sensory abnormalities. Thus, no neurosurgical intervention was performed.

In 2003, Zafeiriou et al.,[ 26 ] summarized typical brain and spine MRI findings in patients with mucopolysaccharidosis. It was noted that the most prominent brain features identified in almost all types of mucopolysaccharidosis were white and gray matter changes, ventriculomegaly and hydrocephalus, cortical atrophy, and enlargement of the perivascular spaces. Spinal MRIs usually revealed canal stenosis and cord compression with spinal cord signal changes [ Table 2 ].[ 26 ] Looking specifically at the posterior fossa, mega cisterna magna was the most common radiologic finding. Ultimately, the correlation between imaging findings and the disease severity remains unclear. Intraoperatively, in our patient, the posterior fossa thickened membrane versus arachnoid cyst appeared to be causing compression on the surrounding tissue, which may have played a role in the tonsillar ectopia.

Table 2

Overview of the most frequent brain and spinal MRI abnormalities identified in MPS according to disease type. This table is reproduced with the permission of the authors and the American Journal of Neuroradiology

Tandon et al.,[ 22 ] published a case series among 12 patients with HS with a mean of 4.5 years follow-up after undergoing bone marrow transplantation. High lumbar kyphosis was noted in 10 patients, which was associated with thoracic scoliosis in one, whereas isolated thoracic scoliosis was seen in another. One patient did not have any significant problems in the thoracic or lumbar spine but had odontoid hypoplasia, which was also seen in three other children. Four of the 8 patients in whom MRI of the cervical spine had been performed had abnormal soft tissue around the tip of the odontoid. Neurological problems were only seen in two patients. In one it was caused by cord compression in the lower dorsal spine 9.5 years after posterior spinal fusion for progressive kyphosis, and in the other by angular kyphosis with thecal indentation in the high thoracic spine associated with symptoms of spinal claudication.

PFD has long been performed to relieve compression and restore normal CSF pathways at the craniocervical junction.[ 24 ] A survey on surgical treatment of CM-I with syringomyelia conducted by the American Society of Pediatric Neurosurgeons showed that 85% of the respondents perform PFD as first-line treatment, whereas less than 3% offer syrinx drainage as first-line therapy.[ 7 19 ] In addition, routine practice consisted of bony decompression alone for 7%, decompression with duraplasty in 36%, and additional tonsil reduction for 27%.[ 7 ] Xie et al.[ 24 ] examined 87 patients aged 5–18 years who had undergone PFD. They noted 72.4% improvement of symptoms at final follow-up. In 90.8% of the cases, significant syrinx resolution was also noted. Wu et al.[ 23 ] reported that typically the syrinx resolved within 6 months after PFD. In their retrospective review of patients with CM-I who had undergone PFD, Chotai et al.[ 7 ] noted that 87% of the patients indicated they would choose to undergo the surgery again.

CONCLUSION

MPSI is an autosomal recessive lysosomal storage disorder causing a chronic, progressive multiorgan disease by deficient or absent activity of the α-L-iduronidase enzyme, which catalyzes the degradation of glycosaminoglycans.[ 25 ] Bone marrow transplant and enzyme replacement therapy has led to an increased life expectancy for this once fatal disease. Patients with HS are now at an increased risk of developing other medical conditions associated with their disease, including progressive TL kyphosis, symptomatic carpal tunnel syndrome, angular deformity of the lower limbs, and hip dysplasia that may require surgical treatment. Diagnosing and properly managing a CM-I and syrinx in this patient population is necessary to avoid neurologic complications and spinal cord injury that could occur from anesthesia and surgical management of HS patients. Though these three reports represent a small case series, given the fact that all three patients developed a syrinx on serial imaging, and two of the three demonstrating neurologic abnormalities, we would suggest that patients with mucopolysaccharidosis require routine follow-up for clinical assessments with spinal imaging as indicated by history and physical examination.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant. 2008. 14: 485-98

2. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005. 28: 1011-7

3. Barkovich AJ, Wippold FJ, Sherman JL, Citrin CM. Significance of cerebellar tonsillar position on MR. AJNR Am J Neuroradiol. 1986. 7: 795-9

4. Boor R, Miebach E, Bruhl K, Beck M. Abnormal somatosensory evoked potentials indicate compressive cervical myelopathy in mucopolysaccharidoses. Neuropediatrics. 2000. 31: 122-7

5. Campos D, Monaga M. Mucopolysaccharidosis type I: Current knowledge on its pathophysiological mechanisms. Metab Brain Dis. 2012. 27: 121-9

6. Chiari H. Concerning alterations in the cerebellum resulting from cerebral hydrocephalus. 1891. Pediatr Neurosci. 1987. 13: 3-8

7. Chotai S, Kshettry VR, Lamki T, Ammirati M. Surgical outcomes using wide suboccipital decompression for adult Chiari I malformation with and without syringomyelia. Clin Neurol Neurosurg. 2014. 120: 129-35

8. Coletti HY, Aldenhoven M, Yelin K, Poe MD, Kurtzberg J, Escolar ML. Long-term functional outcomes of children with hurler syndrome treated with unrelated umbilical cord blood transplantation. JIMD Rep. 2015. 20: 77-86

9. Guffon N, Souillet G, Maire I, Straczek J, Guibaud P. Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr. 1998. 133: 119-25

10. Hite SH, Krivit W, Haines SJ, Whitley CB. Syringomyelia in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): Imaging findings following bone marrow transplantation. Pediatr Radiol. 1997. 27: 736-8

11. Jayarao M, Sohl K, Tanaka T. Chiari malformation I and autism spectrum disorder: An underrecognized coexistence. J Neurosurg Pediatr. 2015. 15: 96-100

12. Johnson BA, Dajnoki A, Bodamer OA. Diagnosing lysosomal storage disorders: Mucopolysaccharidosis type i. Curr Protoc Hum Genet. 2015. 84: 11-8

13. Malm G, Gustafsson B, Berglund G, Lindstrom M, Naess K, Borgstrom B. Outcome in six children with mucopolysaccharidosis type IH, Hurler syndrome, after haematopoietic stem cell transplantation (HSCT). Acta Paediatr. 2008. 97: 1108-12

14. Manara R, Concolino D, Rampazzo A, Zanetti A, Tomanin R, Faggin R. Chiari 1 malformation and holocord syringomyelia in hunter syndrome. JIMD Rep. 2014. 12: 31-5

15. McVige JW, Leonardo J. Imaging of Chiari type I malformation and syringohydromyelia. Neurol Clin. 2014. 32: 95-126

16. McVige JW, Leonardo J. Neuroimaging and the clinical manifestations of Chiari Malformation Type I (CMI). Curr Pain Headache Rep. 2015. 19: 18-

17. Moore D, Connock MJ, Wraith E, Lavery C. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. Orphanet J Rare Dis. 2008. 3: 24-

18. Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996. 87: 4894-902

19. Rocque BG, George TM, Kestle J, Iskandar BJ. Treatment practices for Chiari malformation type I with syringomyelia: Results of a survey of the American Society of Pediatric Neurosurgeons. J Neurosurg Pediatr. 2011. 8: 430-7

20. Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis. 1995. 18: 413-29

21. Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003. 31: 1105-17

22. Tandon V, Williamson JB, Cowie RA, Wraith JE. Spinal problems in mucopolysaccharidosis I (Hurler syndrome). J Bone Joint Surg Br. 1996. 78: 938-44

23. Wu T, Zhu Z, Jiang J, Zheng X, Sun X, Qian B. Syrinx resolution after posterior fossa decompression in patients with scoliosis secondary to Chiari malformation type I. Eur Spine J. 2012. 21: 1143-50

24. Xie D, Qiu Y, Sha S, Liu Z, Jiang L, Yan H. Syrinx resolution is correlated with the upward shifting of cerebellar tonsil following posterior fossa decompression in pediatric patients with Chiari malformation type I. Eur Spine J. 2015. 24: 155-61

25. Yang JS, Min HK, Oh HJ, Woo HI, Lee SY, Kim JW. A simple and rapid method based on liquid chromatography-tandem mass spectrometry for the measurement of alpha-L-iduronidase activity in dried blood spots: An application to mucopolysaccharidosis I (Hurler) screening. Ann Lab Med. 2015. 35: 41-9

26. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidoses: A review. AJNR Am J Neuroradiol. 2013. 34: 5-13

Abstract

Background:Recent studies suggest that the behavior and biology of WHO grade I pilocytic astrocytomas (PAs) in adults is different than that associated with grade I PAs in children.

Methods:We evaluated Ki-67 labeling, BRAF abnormalities, isocitrate dehydrogenase R132 immunoreactivity phosphorylation (activation) of p44/42 mitogen activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) in formalin-fixed tissue from 21 adult (18 years or older, mean age 37 years) and 10 children (mean age 9.4 years) WHO grade I PAs.

Results:The mean Ki-67 labeling was 4.8% in adults and 3.8% in children. There was no significant difference between Ki-67 labeling in children and adults or either subgroups of adults. No differences were found in phospho p44/42MAPK in adult subgroups (18–33 years and 34 and older) compared to children. Activation/phosphorylation of mTOR was biphasic in adults being significantly lower than children in young adults but significantly higher than children in older adults (age 34 and older).

Conclusions:Identifying mTOR phosphorylation/activation may represent a difference in biology and a new marker to guide chemotherapy with recently approved mTOR inhibitors.

Keywords: mTOR, pilocytic astrocytoma, p44/42MAPK

INTRODUCTION

A recent study suggests that the recurrence rate for pilocytic astrocytomas (PA) in adults may be significantly higher than that in children. Progression after gross total resection was found to be approximately 40% in adults compared to relatively infrequent in children.[ 22 ] The molecular differences promoting recurrence likely involve growth regulatory kinase cascades,[ 2 4 13 ] however, this has not been extensively evaluated in adult PAs.

Activation of the p44/42 mitogen activated protein kinase (MAPK) has been implicated in several neoplasias[ 5 13 14 ] and is thought to be important in the pathogenesis of PAs in children.[ 2 10 ] Activation of the MAPK pathway appears to be, in some cases, by activation of upstream BRAF by the BRAF tandem duplication KIAA 1549 fusion or a mutation at BRAF V600E.[ 2 10 11 ] These result in the activation of the MAPK kinase (Raf-1)–MAP kinase/ERK kinase (MEK-1)-p44/42 MAPK cascade. BRAF activation also results in the activation of mammalian target of rapamycin (mTOR) by the phosphoinositide 3 kinase (PI3K)-protein kinase PKB/Akt–mTOR pathways in part by activation through the p44/42MAPK kinase.[ 7 ] Activation of the RAF1-MEK1 p44/42MAPK and PI3K-Akt-mTOR and other kinase cascades that promote cell proliferation and inhibit apoptosis[ 15 16 20 21 ] have been studied along with many types of gliomas, but have not been extensively evaluated in adult PAs.

MATERIALS AND METHODS

Pilocytic astrocytoma tissue

Thirty-one formalin-fixed paraffin embedded World Health Organization (WHO) grade I PAs from 21 adults (mean age 37 years, adults range 18–70, 10 females and 11 males) and 10 children, mean age 9.4 years (9 females and 1 male), were identified in the University of Rochester Medical Center archives and consultations with Institutional Review Board approval from 2008 to 2015 and reviewed following WHO criteria and recent findings.[ 3 4 ] In adult cases, the distribution of cases based on age shows a distinct clustering of cases in young and those in older adults. Consequently, adult cases were grouped as those 18 to 33 and those older than 33. Characteristics are listed in Table 1 .

Table 1

Pilocytic astrocytomas characteristics and findings

Immunohistochemistry for phospho-p44/42MAPK and phospho- mTOR in pilocytic astrocytomas

Each case was analyzed with a polyclonal antibody to phospho p44/42 MAPK (Thr 202/Tyr 204, 1:400) and human phospho-mTOR (Ser 2448, 1:100 Cell Signaling, Beverly MA.) and MAC4 universal HRP-polymer (Biocare) with diaminobenzidene (DAB) chromagen and hematoxylin counterstain (Biocare), as described previously.[ 9 ] For antigen retrieval, tissue sections were incubated in a thermoresistant chamber with X Reveal Decloaker (Biocare Medical, Concord CA) at 120–123°C and pressure of 20–24 psi, according to manufacturer's specifications. Immunoreactivity in tumor cells (excluding blood vessels) was assessed by two of us as “0” for no distinct immunoreactivity, “1+” if 1–30% of cells were immunoreactive, “2+” if 30–50%, and “3+” if greater than 50% of cells were positive. Scores were analyzed by two-way t-tests comparing cumulative scores between young and adults, young and adult subgroups, and between 18 and 33 versus patients older than 33 years of age.

RESULTS

Comparison of pathological features of pilocytic astrocytomas in adults and children

The mean Ki-67 labeling index was 4.8% in adults and 3.8% in children. The Ki-67 labeling was not significantly different in either the 18–33 or 34 and older adults compared to children, and was not statistically different between the subgroups in adults. Neither adults nor children showed IDHR132 immunoreactivity. None of the 6 adults analyzed had a BRAFv600E mutation but one showed the BRAF-KIAA fusion. Two of the 4 tumors in children had BRAF mutations [ Table 1 ].

Phospho-p44/42MAPK and phospho-mTOR immunoreactivity in pilocytic astrocytomas

As summarized in Table 1 the mean immunoreactivity for phospho p44/42 MAPK was 1.1 ± 0.93 for children, 0.8 ± 1.03 SD for 18–33-year olds and 1.11 for 34–70-year olds. This was not statistically different comparing younger and older adults and children.

Phospho-mTOR immunoreactivity had a mean of 1.37 ± 1.18 SD in children (< 18 years of age, 0.33 ± 0.487 in young adults (18–33) and 1.36 ± 1.28 in adults 34 or greater years of age. Phospho-mTOR was biphasic in adults being significantly lower than children in young adults (P = 0.05) but significantly higher than children in older adults (age 34–70 years) (P = 0.05) [ Figure 1 ].

Figure 1

Phospho-MAPK 44/42 (a) phospho-mTOR (b), immunohistochemical control (c) in adult pilocytic astrocytoma (case 21) (Hematoxylin counterstain. Diaminobenzidine chromagen, original magnification ×400)

DISCUSSION

The BRAF v600E mutation was found in only 1 of the 6 cases analyzed, which is consistent with previous reports that BRAF v600E mutations are rare in adults.[ 2 4 ] Similarly, BRAF fusion appears less common in adult PAs.[ 4 6 ]

Two studies suggest that the MEK-1-p44/42 MAPK pathway is involved in the pathogenesis of childhood PAs.[ 2 10 ] Our findings suggest that p44/42 MAPK phosphorylation/activation occurs in many Pas, however, this is not significantly different between adult and childhood WHO grade I PAs. In contrast, in children, this activation appears associated with anaplastic progression.[ 18 ] In addition, activation of p44/42 MAPK also influences oncogene-induced senescence in Pas.[ 8 17 ] The role of this pathway in tumor behavior warrants additional review after longer follow-up.

The PI3K- PKB/Akt-mTOR pathway influences several functions central to neoplasia including cell proliferation and metabolism.[ 1 21 24 ] mTOR is a serine/threonine kinase present in two compositionally distinct complexes with different functions. The mTOR complex 1 (mTORC1) contains PRAS40, and is activated by numerous extracellular growth factors and cellular mitogens.[ 23 ] Activation of mTORC1 phosphorylates S6 kinase stimulating a number of growth-related functions including protein synthesis and cell proliferation. In contrast, mTORC2 is associated with cell metabolism and cytoskeletal organization. mTORC1 is strongly activated by rapamycin.[ 24 ] The effectiveness and side effect profiles of various mTOR inhibitors depends on their relative inhibition of the more growth regulatory mTORC1 compared to mTORC2.[ 1 21 ]

The PI3K- PKB/Akt-mTOR pathway is also activated in many WHO grade I adult PAs, and is significantly higher in older adults compared to children. This raises the possibility that activation of this pathway may participate in the pathogenesis of PAs in the older population. Activation of mTOR is also increased in anaplastic PAs.[ 18 ] Consequently, drugs inhibiting mTOR activation may represent a viable chemotherapy for recurrent PAs in this population. Nonetheless, identifying the optimal therapy may require considerable study because several recently developed rapamycin analogues show different activities for mTORC1 and mTORC2.[ 1 ] Rapamycin (sirolimus) is a highly effective inhibitor of mTORC1 and associated components of the PI3K-PKB/Akt-mTOR pathway. Nonetheless, it has limited effectiveness in tuberous sclerosis, except possibly in some angiomyolipomas. This may reflect secondary activation of mTORC2 and Akt.[ 1 ] Everolimus has been approved for the treatment of tuberous sclerosis subependymal giant cell astrocytomas, neuroendocrine carcinomas of the pancreas, and advanced renal carcinomas.[ 1 12 ] More recently developed orally available analogues such as temsirolimus is currently approved for other malignancies such as mantle cell lymphoma and renal carcinoma.[ 1 ] Because of the secondary activation of other pathways, use of combination therapy with other kinase inhibitors may be more effective.[ 1 ]

Phosphorylation of p44/42MAPK and mTOR have been found to be less stable with cold ischemia after surgical removal than some other phosphoproteins.[ 23 ] Nonetheless, our tissues are rapidly placed in formalin (typically in less than 30 minutes). Moreover, in our recent studies on meningiomas, phospho p44/42 MAPK was consistently found in almost 10% of the cases by immunohistochemistry and western blot.[ 9 ]

In summary, phosphorylation/activation of mTOR appears increased, particularly in PAs in adults 34 years of age and older. Identifying mTOR phosphorylation/activation likely represents a new marker to guide chemotherapy because several rapamycin analogues that inhibit mTOR activation are now in clinical trials or FDA approved.[ 1 12 19 ]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: A new generation of mTOR inhibitors. Nature. 2011. 10: 868-80

2. Brokinkel B, Peetz-Dienhart S, Ligges S, Brentrup A, Stummer W, Paulus W. A comparative analysis of MAPK pathway hallmark alterations in pilocytic astrocytomas: Age related and mutually exclusive. Neuropathol Appl Neurobiol. 2015. 41: 258-61

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