INTRAMEDULLARY TUMOR OF SPINAL CORD

Intramedullary spinal cord tumor is the rare condition demanding high index of suspicion in diagnosis and high yield surgical expertise to produce good outcome.

1. SURESH BISHOKARMA, MS MCH RESIDENT, NEUROSURGERY NINAS INTRAMEDUALLARY TUMOR

2. INTRAMEDULLARY Ependymoma Astrocytoma Hemangioblastoma EXTRADURAL Degenerative: Synovial cyst, Disc Infection/abscess INTRADURAL EXTRAMEDULLARY Nerve sheath tumor: Schwannoma, neurofibroma Meningioma Myxopapillary ependymoma ,Lipoma/Dermoid/Epidermoid Spinal Lesion

3. Primary Spinal tumor Location

4. EXTRADURAL IDEM INTRAMEDULLARY Spinal cord tumor

5. 2 % to 4% of all the central nervous system neoplasms 20–25 % of all intra spinal tumors. Intramedullary tumor

6. TUMOR TYPE EPIDEMIOLOGY Astrocytoma 60% to 70% of IMSCTs Ependymoma 30% to 40% of IMSCTs Myxopapillary ependymoma NF-1 association Subependymoma Ependymoma Anaplastic ependymoma Intramedullary Haemangioblastoma 2% to 15% of IMSCTs VHL association Metastases ( Lungs 40-60%, Breast 14%) 1-1.5% Epidemiology Ependymomas are common in adults than children, alike astrocytoma.

7. SYMPTOMS Back pain Diffuse or radicular Upper or lower extremity numbness Gait Imbalance Urinary incontinence Nocturnal back pain Hand incoordination Burning dysaesthesias Sudden paraparesis or quadraparesis SIGNS Spasticity Hyperreflexia Upward Babinski sign Objective bilateral weakness Sensory level Positive Hoffman’s sign SYMPTOMS AND SIGNS

8. Intramedullary vs extramedullary

9. D/D IMSCT Tumor: Intradural extramedullary spinal tumours Epidural spinal tumours Degenerative: Myelopathy due to degenerative disease, Disc Vascular Cord infarct Vascular lesions such as spinal arteriovenous malformations and Dural arterio -venous fistulae I nflammatory processes Multiple sclerosis, Transverse myelitis Sarcoid Syringomyelia Vit B12 def NPH If the patient is relatively stable and the MRI is equivocal, repeat imaging after one month should show decreased oedema and mass effect in acute auto-immune lesions.

10. Plain Film Increased inter pedicular distance, pedicle thinning (occasional erosion), scalloping of vertebral bodies, scoliosis Myelogram + CT Widened spinal cord , dye block MRI T1- iso or ↓ signal lesion ± cysts, most gadolinium enhancing, edema , T2 - ↑ signal edema Angiogram May be useful in distinguishing hemangioblastoma from AVM CSF may show extremely elevated protein levels and / xanthochromia MODALITY FEATURES

11. 40-60% in adults, 30% in children Most common intrinsic cord tumour . Arises from ependymal cells of central canal Male predilection Mean age - 35-40 years Occur anywhere, m/c in conus medullaris Slow growing Ependymoma

12. Histologically, ependymomas can be classified into 4 types: myxopapillary ependymoma (WHO Grade I ), Subependymoma (WHO Grade I), Ependymoma (WHO Grade II), Anaplastic ependymoma (WHO Grade III). Most WHO grade II. Compress rather than infiltrate cord ( c.f Astrocytoma infiltrate) Tend to expand the cord symmetrically and focally ( c.f astrocytomas more diffuse and eccentrically located) Rarely change growth characteristics and metastasize Ependymoma

13. C entrally located, well circumscribed, and non infiltrative L ocalized enlargement of the spinal cord on T1- and T2-weighted images. T1: hypo- or isointense ( Myxopapillary Hyper) T2: Hyperintense Usually enhance more homogeneously than astrocytomas with sharply defined poles and are capped superiorly by a cyst , inferior cyst is less common. All types appear to show heterogeneous enhancement with contrast, and cyst formation and syrinx are common especially at the cervical level IMAGING Ependymoma

14. In most cases, ependymomas have an easily identied plane of dissection, and thus GTR is the primary form of treatment. There are several studies showing that the extent of resection is a strong predictor of overall survival, with 90%–100% of patients showing improvement following complete resection. Surgery Guidetti B, Mercuri S, Vagnozzi R: Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. J Neurosurg 54: 323–330, 1981 Ependymoma

15. GTR is not achieved in most patients due to most ependymomas being located in areas that, if resected, would decrease neurological function. GTR in cases of myxopapillary ependymomas has been controversial, but a recent study found that GTR is associated with lower overall recurrence compared with subtotal resection (STR )*, but also states that there is no evidence whether GTR contributes to better functional outcome in patients. Ependymoma Feldman WB, Clark AJ, Safaee M, Ames CP, Parsa AT: Tumor control after surgery for spinal myxopapillary ependymomas : distinct outcomes in adults versus children: a systematic review. J Neurosurg Spine 19: 471–476, 2013

16. While adjuvant radiotherapy is not recommended for completely resected tumors, it has been traditionally used following STR, recurrent tumors, or when surgery cannot be performed. The benefit of radiotherapy has also been contested, with some studies reporting a 5-year survival rate of 70% for patients receiving adjuvant irradiation compared with 20% for patients treated with surgery alone. More recent studies suggest that radiotherapy is not associated with lower overall recurrence regardless of the extent of resection. * Radiotherapy for Ependymoma Ependymoma Abul-Kasim K, Thurnher MM, McKeever P, Sundgren PC: Intradural spinal tumors: current classification and MRI features. Neuroradiology 50:301–314, 2008

17. In the 2002 study by Chamberlain , the topoisomerase-2 inhibitor etoposide was well tolerated and had a partial response in 2 of 10 treated patients (20 %). Chemotherapy Ependymoma Chamberlain MC: Salvage chemotherapy for recurrent spinal cord ependymona . Cancer 95: 997–1002, 2002

18. 1/3 of spinal cord gliomas. MC IMSC Tumour in children. Holo cord involvement common in children Usually grey tumor, more infiltrative , often poor plane Astrocytoma

19. Raco et al.54 found 48 % to be WHO Grade II 31 % to be WHO Grade I 21% to be WHO Grade III to IV. Epidemiology Raco A, Esposito V, Lenzi J, Piccirilli M, Del ni R, Cantore G: Long-term follow-up of intramedullary spinal cord tu - mors : a series of 202 cases. Neurosurgery 56: 972–981, 2005

20. 2 histologies D iffuse fibrillary and P ilocytic (low grade) On MRI diffuse fibrillary usually seen as a non-enhancing diffuse cord thickening while pilocytic are usually focal, intensely enhancing and associated with a large cyst which can span many spinal levels

21. Ependymoma vs Astrocytoma

22. U sually hypo- or isointense on T1-weighted images and hyperintense on T2-weighted images, their asymmetry and slightly off-center location may help distinguish them from other tumor types . Similar to ependymomas , astrocytomas show heterogeneous enhancement with contrast IMAGING Astrocytoma

23. Astrocytomas typically lack a clear plane of dissection and demonstrate a much more infiltrative nature than ependymomas  Incomplete resection and poor prognosis In current practice, attempting GTR is not recommended H owever , partial resection or STR can be attempted. This increases the likelihood of recurrence as microscopic remnants of the tumor may remain. Surgical aspect Astrocytoma

24. Recurrence is high with infiltrative astrocytoma (47.6%) ( c.f Ependymoma 7.3%. ( Karikari et al 2011) If recurrence of astrocytoma does occur, radiotherapy is the next course of treatment. Recurrence risk Karikari IO, Nimjee SM, Hodges TR, Cutrell E, Hughes BD, Powers CJ, et al: Impact of tumor histology on resectability and neurological outcome in primary intramedullary spinal cord tumors: a single-center experience with 102 patients. Neurosurgery 68:188–197, 2011 Astrocytoma

25. This is especially true when surgery and radiotherapy have been unsuccessful. Studies of chemotherapeutic agents for astrocytomas are very limited, and further studies are warranted. Some studies have suggested a possible therapeutic value for the DNA-alkylating drug temozolomide . Chamberlain et al . * showed that temozolomide treatment led to 27% progression-free survival at 2 years with a median survival of 23 months. As temozolomide has shown some efficacy in treating intracranial astrocytomas , such as glioblastoma, it has been used in treating astrocytomas within the spinal cord as well. Toxicity: constipation , fatigue, neutropenia, lymphopenia, and thrombocytopenia in several patients. Chemotherapy Astrocytoma Chamberlain MC: Temozolomide for recurrent low-grade spinal cord gliomas in adults. Cancer 113:1019–1024, 2008

26. B enign tumors; WHO grade I M esenchymal origin that originate from the vascular system within the spinal cord. Hemangioblastomas most commonly present in the posterior fossa(83 %); however, approximately 13% are found within the spinal cord. 1-7 % of spinal cord neoplasms. Cell of origin – unknown ( vasculature that nourishes the spinal cord can lead to the rare development of intramedullary tumor. Hemangioblastoma

27. Most solitary; Multiple – R/o VHL (approximately 1/3) : gene mutation results in the enhanced transcription of several genes, including vascular endothelial growth factor ( VEGF) Intramedullary hemangioblastomas tend to develop in the dorsal portion = progressive sensory deficits (Particularly proprioception). Associated syrinx common 10-15% along nerve roots Occasionally exophytic Diffuse cord expansion Highly vascular Rarely may be a source of hematomyelia or SAH Hemangioblastoma

28. Cervical intramedullary hemangioblastoma Hypervascularity along with tumor enhancement

29. On imaging may be solid mass or nodule & cyst MRI - T1: Variable, most common isointense T2: Hyperintense May see flow voids Intense enhancement May have surrounding edema Cyst formation common Cord appears enlarged when tumor is present, while inflammatory lesions result in normal or minimal increase in cord size. D/D Tuberculoma Dural AV fistula with edema Demylination Transverse myelitis Syrinx Multiple sclerosis Hemangioblastoma

30. R esection is the primary treatment for intramedullary hemangioblastomas . Hemangioblastomas typically exhibit a clear dissection plane that allows for GTR. Tortuous arteries and varicosities often seen emerging from solid component. Shouldnot be internally debulked before removal but circumferentially removed. Due to the vascularity of the lesion , resection does pose a risk of intraoperative bleeding. Preoperative embolization and temporary artery occlusion. Sun HI 2014. World Neurosurg Surgical aspect Sun HI, Özduman K, Usseli MI, Özgen S, Pamir MN: Sporadic spinal hemangioblastomas can be effectively treated by microsurgery alone. World Neurosurg 82: 836–847, 2014 Hemangioblastoma

31. The use of radiotherapy in the treatment of hemangioblastomas is very limited, while chemotherapy has been studied even less. Antiangiogenic therapy using the VEGF receptor-2 inhibitor SU5416 was shown to be somewhat effective in patients with VHL disease. In contrast, the use of the monoclonal antibody bevacizumab to inhibit the VEGF receptor was shown to be ineffective, resulting in increased tumor invasiveness following antiangiogenic therapy. Variable response with VEGF inhibitor Chemoradiotherapy Hemangioblastoma

32. Although intramedullary metastases are considered rare, they affect 0.4% of all patients with cancer and represent 1%–3% of intramedullary tumors. They are most commonly derived from primary tumors found in the lung (49%), breast (15%), and lymphoma (9 %). The prognosis of paatients diagnosed with intramedullary metastases is generally very poor, and thus prompt diagnosis and treatment are often crucial for survival. Recent studies have shown a median survival time of 4 months with 0 patients achieving complete remission. Resection may be attempted , but the lack of a clear plane of dissection often prevents achievement of GTR. Intramedullary metastases

33. Use of chemotherapy in the treatment of intramedullary metastases in the literature, which show mixed results of efficacy. C omplete response following the administration of the epidermal growth factor receptor (EGFR) inhibitor gefitinib following radiotherapy and other chemotherapeutic agents. Hata et al. 2013 Chemotherapy in metastases Hata Y, Takai Y, Takahashi H, Takagi K, Isobe K, Hasegawa C, et al: Complete response of 7 years’ duration after chemoradiotherapy followed by gefitinib in a patient with intramedullary spinal cord metastasis from lung adenocarcinoma. J Thorac Dis 5: E65–E67, 2013

34. GENERAL MANAGEMENT ASPECTS OF IMSCTs

35. 1907: the first successful resection of an intramedullary spinal cord tumor was performed by A nton Von Eiselsberg in Vienna, 1907 1911: Elsberg and Beer : current surgical concepts for intramedullary tumors Two staged surgery: The first stage involved a surgical myelotomy with an unclosed durotomy , followed a week later by the second stage in which, due to the unclosed durotomy , the tumor would, by this point, be partially extruded from the spinal cord, thus facilitating resection 1950s: Greenwood : Microsurgical resection: Didn ’ t gain popurality in conservative era. 1980: Resurgence of intramedullary tumor resection. History

36. Surgical resection remains the mainstay of treatment of IMSCTs. Opening of the spinal cord in order to access the spinal tumor is commonly done through a longitudinal, midline incision: avoid transection of the white matter tracts of the dorsal columns and avoid disturbing motor and cerebellar long tracts found laterally and ventrally in the spinal cord . Spinal cord is sensitive to decreased perfusion, and hypotension should be avoided. Perform myelotomy at the thinnest area between the tumor and spinal cord. Incision: midline/ eccentric lesions: dorsal root entry zone . Exophytic component initial area of approach Immediate biopsy taken for histological examination Resection initiated at midportion rather than poles. (least voluminous/Dangerous) Hemangioblastoma shouldnot be internally debulked before removal but circumferentially removed. Debulk exophytic part prior to parenchymal tumor. Monitoring spinal cord function using intraoperative electrophysiology. PRINCIPLE OF SURGERY

37. Ascertain the histological diagnosis. Apply the most effective oncologic treatment. Prevent long-term neurologic dysfunction. Indication for Surgical Removal

38. C urrent evidence-based recommendations for the treatment of IMSCTs

39. P roposed management strategy for IMSCTs Tobin MK, Geraghty JR, Engelhard HH, Linninger AA, Mehta AI: Intramedullary spinal cord tumors: a review of current and future treatment strategies. Neurosurg Focus 39:E14, 2015

40. Laminectomy approach Midline durotomy separate from arachnoid to avoid precipitous CSF egress and decompression of epidural veins and bleeding Arachnoid opening Midline myelotomy to tumor Intraoperative U/S useful for delineating poles, localizing myelotomy , defining cysts (which are generally not excised) Dorsal Root entry zone approach Surgical options

41. Neurological outcome – Gross total (>95%) or subtotal resection (80-95%) does not significantly affect the long-term outcome – Partial resection (<80%) fared significantly worse Oncological outcome E ven with gross total resections, some residual microscopic fragments always remain in the resection bed. T his residual tissue may remain dormant or involute over time. R esection that exceeds 80-90% removal is as good as 98- 100% removal in terms of long-term progression-free survival. Outcome for astrocytoma

42. Grade is most important predictor of long term survival : 5yrsurvival : WHO I : 98 mth WHO II : 68 mth WHO III : 15 mth All astrocytomas:50-60% Low grade :80% High grade : 0-15% Long term survival • Astrocytoma

43. Tumor grade only independent variable predictive of outcome – 5 yrs survival : Well differentiated : 97% Poor or intermediately differentiated :71 % Overall 5 year survival 70-90% 10 year survival 70 % Total resection :85-90 % Subtotal :80 % Biopsy : 25 % Ependymomas

44. Intraoperative Neurophysiological Monitoring

45. Somatosensory evoked potentials (SEPs) technology slow, prone to artifact, and often difficult to interpret. SEPs reflect the functional integrity of sensory pathways, information for the more relevant motor pathways , only indirect. Intramedullary surgery carries clear risk for selective damage to the motor tract, not necessarily reflected by changes in SEPs. Deterioration or loss of SEPs during the myelotomy at intramedullary operations is common and also does not correlate to the motor outcome. Due to signal averaging, a time delay occurs and the identification of injury can lag behind the progress of the surgery. Somatosensory evoked potentials (SEPs)

46. D wave Muscle MEPs Motor evoked potentials

47. D-wave parameter monitored is the peak-to-peak amplitude. A decrease >50% of the baseline value – a/w a long-term motor deficit. D WAVE 1950: Merton and Morton's Description of transcranial electrical motor cortex stimulation, gives rise to a recordable travelling wave, the D-wave. High clinical correlation, does not require averaging , near real-time feedback, and a pattern of reversibility that allows corrective action D-waves are recorded as traveling waves directly from the spinal cord with an electrode inserted into spinal epidural space by the surgeon after laminectomy

48. E licited with ' multipulse technique’ CMAPs recorded with needle electrodes from target muscles in all four extremities ( thenar , anterior tibialis, and abductor hallucis ) Real-time feedback is possible here as well. Muscle MEPs are recorded in an alternating fashion with D-waves P arameter monitored is the presence or absence of muscle MEPs (all-or-none concept ) M otor deficit occur only when the muscle response is lost Muscle MEPs

49. D-waves are elicited with single electrical stimuli, and muscle MEPs with fast trains of stimuli . For the D-wave the monitoring parameter is its peak-to-peak amplitude. Muscle MEPs during spinal cord surgery follow an all-or-none pattern: their presence indicates intact motor control, their loss (when combined with preserved D-wave) indicates temporary motor deficit Principles of intraoperative MEP monitoring for surgery

50. Halogenated volatile anesthetics are avoided - interfere with SSEPs Short-acting muscle relaxants are given only for intubation Low levels of muscle relaxants are used to minimize spontaneous muscle activity but permit MEP and detect elicited EMG activity The spinal cord is sensitive to decreased perfusion, and an arterial line is needed to ensure that dips in blood pressure are detected and corrected as quickly as possible Anesthetic prerequisite

51. D-wave amplitude reflects no. of fast-conducting fibers in the corticospinal tract. If 50% of these fibers are damaged by the procedure, the amplitude will decrease to 50% of its baseline value. In general, D-wave amplitude decrease is a/w loss of some muscle MEPs In any event, preservation of D-wave >50% cutoff value is predictive of long-term preservation (or recovery) of voluntary motor control in the lower extremities . Sudden decrease in D-wave amplitude, often coinciding with sudden loss of muscle MEPs, is considered a result of vascular mechanism rather than direct physical tissue manipulation Combined Interpretation of D-Wave and Muscle MEPs

52. With loss of muscle MEPs and preserved D-wave amplitude, a temporary motor deficit is expected postop. In this situation it is still safe to complete resection, or to pause and wait for recordings to improve again, which they often do. This situation is the window of reversible change, which allows for a change in surgical strategy before irreversible injury has occurred

53. Prognosis of IM tumor Tobin MK, Geraghty JR, Engelhard HH, Linninger AA, Mehta AI: Intramedullary spinal cord tumors: a review of current and future treatment strategies. Neurosurg Focus 39:E14, 2015

54. The most important predictor for tumour recurrence and survival is pathology. Malignant astrocytomas of the spinal cord have an overall recurrence rate of greater than 95%, with outcome unaffected by extent of surgery. Complete resection of ependymomas and haemangioblastomas , however, carry a very favourable outcome, with recurrence rates less than 10% over a ten year period. Extent of resection does not necessarily correlate with progression-free survival in low grade astrocytomas , however, a growing body of evidence suggests that an increased extent of resection is beneficial to overall neurological outcome in this group of patients Surgeons are commonly less aggressive with resections, if intraoperative histology during the case indicates a diagnosis of astrocytoma and are conversely more aggressive for ependymomas and hemangioblastomas . Predictors of recurrence

55. The presence of preoperative scolio - sis, syrinx, long-standing neurological deficit, or cervicothoracic junction location has been correlated with the development of post-opera- tive spinal deformities that can be functionally limiting. U se of osteoplastic lamino - plasty or preemptive internal spinal fixation with fusion in children Currently, outcome-modifying treatments for malignant astrocytomas of the spinal cord do not exist. Patients are empirically treated with postoperative radiation with or without chemotherapy with universally poor results. Aggressive resection, including cordotomy , has not yielded any benefit to outcome and most die of complications of paralysis or progres - sion of disease. Predictors of post op deformities

56. Thank you  TAKE HOME MESSAGE NATIONAL INSTITUTE OF NEUROLOGICAL AND ALLIED SCIENCES, BANSBARI, KATHMANDU Intrinsic tumors of the spinal cord occur infrequently. In adults, ependymomas occur more frequently, but in children low grade astrocytomas are by far the most common. The onset is usually gradual. Segmental pain is common. Interruption of the decussating fibres of the lateral spinothalamic tract causes loss of pain and temperature sensation at the level of the involved segments. lower motor neuron weakness of the corresponding muscle groups; upper motor neuron weakness below the level of the lesion . The sensory deficit spreads downwards bilaterally, the sacral region being the last to become involved . Surgical resection remains the mainstay of treatment of IMSCTs. Astrocytomas typically lack a clear plane of dissection and demonstrate a much more in ltrative nature than ependymomas . For this reason, GTR is often not achieved, and astrocytomas are associated with a poorer prognosis Hemangioblastoma shouldnot be internally debulked before removal but circumferentially removed. Preoperative embolisation or temporary arterial occlusion may minimise intraoperative bleeding. Radiotherapy is the next course of treatment if recurred, chemotherapy is less promising in IMSCTs. Monitoring spinal cord function using intraoperative electrophysiology.