Thankamma Ajithkumar
Case history
A 33-year-old woman presented with nausea and a tingling sensation over her left hand for 2 weeks, and one episode of grand mal seizure. She had a CT scan followed by MRI of the brain (Fig. 25.1). A CT scan of the chest, abdomen, and pelvis and blood tests were unremarkable. Her ECOG performance status was 1.
Fig. 25.1
Questions
1. What do the scans in Fig. 25.1 show?
2. Outline your initial management.
Answers
1. What do the scans in Fig. 25.1 show?
T1-weighted MRI shows an irregular hypo-intense mass in the right temporoparietal region, which enhances peripherally on administration of gadolinium. The FLAIR (fluid-attenuated inversion recovery) image shows a hyper-intense lesion representing the tumour and surrounding oedema. There is minimal pressure effect on the anterior horn of the right lateral ventricle. The appearance is suggestive of an aggressive intrinsic brain tumour, and since it is a single lesion with normal staging investigations it is most likely to be a high-grade glioma.
2. Outline your initial management.
The initial management includes general medical measures and referral to a MDT meeting for discussion of primary surgical management. Steroid and antiepileptic drugs (AEDs) are important in the initial management of patients with suspected brain tumours. Steroids help to reduce the intracranial pressure and reverse symptoms. Steroids are started at the maximum dose likely to reverse symptoms and rapidly titrated against the patient’s symptoms. The usual agent used is dexamethasone 2–16mg daily. The temptation to treat seizures with a steroid, except as a short-term expedient, should be avoided.
All patients with brain tumour-associated seizure should be treated with AEDs. However, there is no established role for the prophylactic use of AEDs in patients with brain tumours.
Long-acting carbamazepine is probably the best initial drug, starting at 100mg twice daily and increasing after 2 weeks to 200mg twice daily if necessary, after the estimation of blood levels of the drug. Lamotrigine and sodium valproate are effective alternatives in patients who tolerate carbamazepine poorly. Phenytoin has the convenience of once daily administration, with a starting dose of 200mg followed by a blood level assessment 7–10 days later. If seizures continue to be a problem after optimal monotherapy, levetiracetam 250mg twice daily is added, and the dose increased according to response and tolerance to a maximum of 1.5g twice daily.
Many AEDs are enzyme inducers and hence non-enzyme inducing (or weak enzyme inducing) drugs are preferred for patients with brain tumours in whom chemotherapy or biological therapies are considered (see Table 25.1).
Pain management is according to the WHO analgesic ladder. Depression, a common problem in patients with brain tumours, needs to be appropriately managed.
Table 25.1 Recommended AEDs for brain tumour-associated seizures
|
Type of seizure |
Recommended AED |
|
Infrequent, focal |
Lamotrigine 25mg once daily for 2 weeks and then increased to 50mg once daily. Increase by a maximum 100mg every 1–2 weeks. As monotherapy the maximum dose is 100–200 mg daily |
|
OR |
|
|
Levetiracetam 250mg once daily and increased after 1–2 weeks to 250mg twice daily; further increase in steps of 250mg twice daily every 2 weeks to a maximum of 1.5g twice daily AND clobazam 10–20mg once daily if needed |
|
|
Frequent, focal (at least once daily) Generalized |
Levetiracetam 500mg twice daily increasing to 1000mg twice daily within a week And clobazam 10–20mg once daily |
|
Generalized, presenting as severe clusters or status epilepticus |
Treat as status epilepticus and once stabilized convert to levetiracetam or lamotrigine |
She was started on levetiracetam 250mg twice daily and dexamethasone 8mg daily. She underwent an ‘awake’ craniotomy and excision of the tumour. The histopathology showed an anaplastic oligodendroglioma with frequent mitoses and microvascular proliferation, but without necrosis or microcalcification. The MIB-1 index was 50%.
Questions
3. What is the advantage of an ‘awake’ craniotomy?
4. What is the significance of the MIB-1 index?
5. What further management would you recommend?
6. What are the prognostic factors and what is the estimated prognosis?
Answers
3. What is the advantage of an ‘awake’ craniotomy?
Surgical techniques for brain tumours are constantly evolving. Patients with a suspected brain tumour will usually have an intraoperative frozen section or smear prior to attempting a full resection. Studies suggest that there is a correlation between the extent of resection and median survival in high-grade gliomas. Gross tumour resection (no post-operative contrast enhancement) results in a better median survival than subtotal resection (post-operative nodular enhancement) in both anaplastic astrocytoma (58 versus 34 months) and glioblastoma (13 versus 8 months). Therefore a complete or maximal surgical resection with minimal injury to neighbouring critical structures is the aim of surgery. Cortical mapping during ‘awake’ craniotomy is useful in the resection of tumours inside, or adjacent to, functional brain areas. Intraoperative stimulation of cortical and subcortical areas and related tracts allows one to identify and mark active areas, and facilitates sparing of functional areas during resection. In ‘awake’ craniotomy, the initial craniotomy and preliminary stimulation are done with the patient asleep. After arousal, sedative/hypnotic anaesthesia allows the patient to respond to motor and language commands but still provides subsequent amnesia.
4. What is the significance of the MIB-1 index?
The MIB-1 index (a marker of proliferation) is a predictor of survival in astrocytic tumours. In diffuse astrocytoma (grade 2), the MIB-1 index is usually less than 4% (mean 2.5%). The MIB-1 index of anaplastic astrocytoma (grade 3) is in the range of 5–10% and that of glioblastoma (GBM; grade 4) in the range of 15–20%. The survival of grade III tumours with a MIB-1 index of >15–20% is similar to that of glioblastoma.
5. What further management would you recommend?
The current standard treatment for glioblastoma is concomitant chemoradiotherapy followed by adjuvant temozolomide. A phase III trial has shown that the addition of concomitant and adjuvant temozolomide to radical radiotherapy in patients with glioblastoma improves survival compared with radiotherapy alone (a 5-year survival 10% versus 2% and median survival of 14.6 versus 12.1 months). A subset analysis has shown that patients with methylguanine methyl transferase (MGMT) methylated tumours have the best survival advantage with the addition of temozolomide to radiotherapy (median survival 23 versus 15 months). However, the role of concomitant chemoradiation in grade 3 tumours is yet to be proved, and the standard post-operative treatment in grade 3 tumours is radiotherapy alone.
It has been recognized that the presence of necrosis in oligodendroglial tumours is associated with a poor prognosis and therefore ‘anaplastic oligodendrogliomas with necrosis’ are classified as glioblastoma. There might be a subset of patients with anaplastic oligodendroglioma without necrosis but with a high MIB-1 index (>15%) with an outcome equivalent to glioblastoma. Some authorities recommend treatment of these tumours similarly to glioblastoma with concomitant/adjuvant temozolomide.
Thus, in view of the high MIB-1 index, this patient is recommended to have radical radiotherapy with concomitant/adjuvant temozolomide.
6. What are the prognostic factors and what is the estimated prognosis?
The median survival of anaplastic oligodendroglioma after radical treatment is 4.5 years. The presence of necrosis is associated with a poorer median survival (35 months), whilst the presence of the 1p/19q code deletion is associated with a better median survival (8.5 years with deletion and 3.7 years with no deletion). Other good prognostic factors include isocitrate dehydrogenase (IDH1) mutation and MGMT methylation.
The median survival of patients with typical anaplastic oligodendroglioma is 4.5 years; however, in the presence of a very high MIB-1 index it is likely that the prognosis may be similar to glioblastoma (12–16 months).
The patient completed radical radiotherapy and six courses of adjuvant temozolomide. A repeat MRI scan showed no evidence of contrast enhancement to suggest recurrent disease.
Five months later she presented with pain radiating to the right leg and an abnormal sensation in the right leg but without impaired mobility. The gadolinium-enhanced MRI scan is shown in Fig. 25.2.
Fig. 25.2
Questions
7. What does the MRI scan in Fig. 25.2 show?
8. What is your immediate management?
Answers
7. What does the MRI scan in Fig. 25.2 show?
MRI shows a contrast-enhancing intradural mass at the thoracic level (the mass measures 2.3cm and is at the level of T4). There are two other nodules, one at the level of T5/6 and another at the level of L1. There is some subtle linear contrast enhancement of the cord surface. Other images show cord compression and cord oedema. This appearance is consistent with drop metastases with leptomeningeal disease.
Symptomatic leptomeningeal or intramedullary metastasis can occur in up to 2% of patients with high-grade gliomas. It is common in infratentorial tumours. The mechanisms of dissemination include spread by invasion of the choroid plexus, through subpial, perivascular, and subarachnoid spaces, and via the cerebrospinal fluid. The common sites of drop metastases are the lower thoracic and lumbosacral regions. The clinical features include radicular pain and sensory and motor deficits suggesting cord compression or cauda equina syndrome. Surgical decompression is not an option for the majority of patients due to the diffuse nature of the disease; however, it may be useful in selected patients with a discrete mass causing cord compression and to achieve better pain control. Radiotherapy is useful in relieving pain temporarily, but seldom improves the neurological deficit. There is no proven role for systemic and/or intrathecal chemotherapy. Prognosis is poor with a median survival of 2–4 months.
8. What is your immediate management?
High-dose dexamethasone (16mg daily) and neurosurgical review for decompression of the thoracic lesion is the initial management. If surgery is not appropriate, emergency radiotherapy is indicated.
The patient underwent decompressive surgery. The pathology was consistent with a primary neuroectodermal tumour, suggesting an aggressive transformation of oligodendroglioma. Although she received thoracic spinal radiotherapy to a dose of 20Gy in five fractions her mobility continued to deteriorate. A MRI scan done 2 months later is shown in Fig. 25.3.
Fig. 25.3
Questions
9. What does the MRI scan in Fig. 25.3 show?
10. What is your management?
Answers
9. What does the MRI scan in Fig. 25.3 show?
The MRI shows progressive leptomeningeal/intradural contrast-enhancing disease involving the whole of area of the spinal canal.
10. What is your management?
She has rapidly progressive disease, and her treatment is essentially symptomatic and palliative. The patient died 4 weeks after the last scan.
Further reading
Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of malignant glioma: role of neuropathology. Journal of Neurooncology 2008; 89: 287–311.
Burnet NG, Lynch AG, Jefferies SJ, et al. High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiotherapy Oncology 2007: 85: 371–378.
Ricard D, Idbaih A, Ducray F, et al. Primary brain tumours in adults. The Lancet 2012; 26: 1984–1996.
Scoccianti S, Detti B, Meattini I, et al. Symptomatic leptomeningeal and intramedullary metastases from intracranial glioblastoma multiforme: a case report. Tumori 2008; 94: 877–881.
Thankamma Ajithkumar
Case history
A 33-year-old woman presented with nausea and a tingling sensation over her left hand for 2 weeks, and one episode of grand mal seizure. She had a CT scan followed by MRI of the brain (Fig. 25.1). A CT scan of the chest, abdomen, and pelvis and blood tests were unremarkable. Her ECOG performance status was 1.
Fig. 25.1
Questions
1. What do the scans in Fig. 25.1 show?
2. Outline your initial management.
Answers
1. What do the scans in Fig. 25.1 show?
T1-weighted MRI shows an irregular hypo-intense mass in the right temporoparietal region, which enhances peripherally on administration of gadolinium. The FLAIR (fluid-attenuated inversion recovery) image shows a hyper-intense lesion representing the tumour and surrounding oedema. There is minimal pressure effect on the anterior horn of the right lateral ventricle. The appearance is suggestive of an aggressive intrinsic brain tumour, and since it is a single lesion with normal staging investigations it is most likely to be a high-grade glioma.
2. Outline your initial management.
The initial management includes general medical measures and referral to a MDT meeting for discussion of primary surgical management. Steroid and antiepileptic drugs (AEDs) are important in the initial management of patients with suspected brain tumours. Steroids help to reduce the intracranial pressure and reverse symptoms. Steroids are started at the maximum dose likely to reverse symptoms and rapidly titrated against the patient’s symptoms. The usual agent used is dexamethasone 2–16mg daily. The temptation to treat seizures with a steroid, except as a short-term expedient, should be avoided.
All patients with brain tumour-associated seizure should be treated with AEDs. However, there is no established role for the prophylactic use of AEDs in patients with brain tumours.
Long-acting carbamazepine is probably the best initial drug, starting at 100mg twice daily and increasing after 2 weeks to 200mg twice daily if necessary, after the estimation of blood levels of the drug. Lamotrigine and sodium valproate are effective alternatives in patients who tolerate carbamazepine poorly. Phenytoin has the convenience of once daily administration, with a starting dose of 200mg followed by a blood level assessment 7–10 days later. If seizures continue to be a problem after optimal monotherapy, levetiracetam 250mg twice daily is added, and the dose increased according to response and tolerance to a maximum of 1.5g twice daily.
Many AEDs are enzyme inducers and hence non-enzyme inducing (or weak enzyme inducing) drugs are preferred for patients with brain tumours in whom chemotherapy or biological therapies are considered (see Table 25.1).
Pain management is according to the WHO analgesic ladder. Depression, a common problem in patients with brain tumours, needs to be appropriately managed.
Table 25.1 Recommended AEDs for brain tumour-associated seizures
|
Type of seizure |
Recommended AED |
|
Infrequent, focal |
Lamotrigine 25mg once daily for 2 weeks and then increased to 50mg once daily. Increase by a maximum 100mg every 1–2 weeks. As monotherapy the maximum dose is 100–200 mg daily |
|
OR |
|
|
Levetiracetam 250mg once daily and increased after 1–2 weeks to 250mg twice daily; further increase in steps of 250mg twice daily every 2 weeks to a maximum of 1.5g twice daily AND clobazam 10–20mg once daily if needed |
|
|
Frequent, focal (at least once daily) Generalized |
Levetiracetam 500mg twice daily increasing to 1000mg twice daily within a week And clobazam 10–20mg once daily |
|
Generalized, presenting as severe clusters or status epilepticus |
Treat as status epilepticus and once stabilized convert to levetiracetam or lamotrigine |
She was started on levetiracetam 250mg twice daily and dexamethasone 8mg daily. She underwent an ‘awake’ craniotomy and excision of the tumour. The histopathology showed an anaplastic oligodendroglioma with frequent mitoses and microvascular proliferation, but without necrosis or microcalcification. The MIB-1 index was 50%.
Questions
3. What is the advantage of an ‘awake’ craniotomy?
4. What is the significance of the MIB-1 index?
5. What further management would you recommend?
6. What are the prognostic factors and what is the estimated prognosis?
Answers
3. What is the advantage of an ‘awake’ craniotomy?
Surgical techniques for brain tumours are constantly evolving. Patients with a suspected brain tumour will usually have an intraoperative frozen section or smear prior to attempting a full resection. Studies suggest that there is a correlation between the extent of resection and median survival in high-grade gliomas. Gross tumour resection (no post-operative contrast enhancement) results in a better median survival than subtotal resection (post-operative nodular enhancement) in both anaplastic astrocytoma (58 versus 34 months) and glioblastoma (13 versus 8 months). Therefore a complete or maximal surgical resection with minimal injury to neighbouring critical structures is the aim of surgery. Cortical mapping during ‘awake’ craniotomy is useful in the resection of tumours inside, or adjacent to, functional brain areas. Intraoperative stimulation of cortical and subcortical areas and related tracts allows one to identify and mark active areas, and facilitates sparing of functional areas during resection. In ‘awake’ craniotomy, the initial craniotomy and preliminary stimulation are done with the patient asleep. After arousal, sedative/hypnotic anaesthesia allows the patient to respond to motor and language commands but still provides subsequent amnesia.
4. What is the significance of the MIB-1 index?
The MIB-1 index (a marker of proliferation) is a predictor of survival in astrocytic tumours. In diffuse astrocytoma (grade 2), the MIB-1 index is usually less than 4% (mean 2.5%). The MIB-1 index of anaplastic astrocytoma (grade 3) is in the range of 5–10% and that of glioblastoma (GBM; grade 4) in the range of 15–20%. The survival of grade III tumours with a MIB-1 index of >15–20% is similar to that of glioblastoma.
5. What further management would you recommend?
The current standard treatment for glioblastoma is concomitant chemoradiotherapy followed by adjuvant temozolomide. A phase III trial has shown that the addition of concomitant and adjuvant temozolomide to radical radiotherapy in patients with glioblastoma improves survival compared with radiotherapy alone (a 5-year survival 10% versus 2% and median survival of 14.6 versus 12.1 months). A subset analysis has shown that patients with methylguanine methyl transferase (MGMT) methylated tumours have the best survival advantage with the addition of temozolomide to radiotherapy (median survival 23 versus 15 months). However, the role of concomitant chemoradiation in grade 3 tumours is yet to be proved, and the standard post-operative treatment in grade 3 tumours is radiotherapy alone.
It has been recognized that the presence of necrosis in oligodendroglial tumours is associated with a poor prognosis and therefore ‘anaplastic oligodendrogliomas with necrosis’ are classified as glioblastoma. There might be a subset of patients with anaplastic oligodendroglioma without necrosis but with a high MIB-1 index (>15%) with an outcome equivalent to glioblastoma. Some authorities recommend treatment of these tumours similarly to glioblastoma with concomitant/adjuvant temozolomide.
Thus, in view of the high MIB-1 index, this patient is recommended to have radical radiotherapy with concomitant/adjuvant temozolomide.
6. What are the prognostic factors and what is the estimated prognosis?
The median survival of anaplastic oligodendroglioma after radical treatment is 4.5 years. The presence of necrosis is associated with a poorer median survival (35 months), whilst the presence of the 1p/19q code deletion is associated with a better median survival (8.5 years with deletion and 3.7 years with no deletion). Other good prognostic factors include isocitrate dehydrogenase (IDH1) mutation and MGMT methylation.
The median survival of patients with typical anaplastic oligodendroglioma is 4.5 years; however, in the presence of a very high MIB-1 index it is likely that the prognosis may be similar to glioblastoma (12–16 months).
The patient completed radical radiotherapy and six courses of adjuvant temozolomide. A repeat MRI scan showed no evidence of contrast enhancement to suggest recurrent disease.
Five months later she presented with pain radiating to the right leg and an abnormal sensation in the right leg but without impaired mobility. The gadolinium-enhanced MRI scan is shown in Fig. 25.2.
Fig. 25.2
Questions
7. What does the MRI scan in Fig. 25.2 show?
8. What is your immediate management?
Answers
7. What does the MRI scan in Fig. 25.2 show?
MRI shows a contrast-enhancing intradural mass at the thoracic level (the mass measures 2.3cm and is at the level of T4). There are two other nodules, one at the level of T5/6 and another at the level of L1. There is some subtle linear contrast enhancement of the cord surface. Other images show cord compression and cord oedema. This appearance is consistent with drop metastases with leptomeningeal disease.
Symptomatic leptomeningeal or intramedullary metastasis can occur in up to 2% of patients with high-grade gliomas. It is common in infratentorial tumours. The mechanisms of dissemination include spread by invasion of the choroid plexus, through subpial, perivascular, and subarachnoid spaces, and via the cerebrospinal fluid. The common sites of drop metastases are the lower thoracic and lumbosacral regions. The clinical features include radicular pain and sensory and motor deficits suggesting cord compression or cauda equina syndrome. Surgical decompression is not an option for the majority of patients due to the diffuse nature of the disease; however, it may be useful in selected patients with a discrete mass causing cord compression and to achieve better pain control. Radiotherapy is useful in relieving pain temporarily, but seldom improves the neurological deficit. There is no proven role for systemic and/or intrathecal chemotherapy. Prognosis is poor with a median survival of 2–4 months.
8. What is your immediate management?
High-dose dexamethasone (16mg daily) and neurosurgical review for decompression of the thoracic lesion is the initial management. If surgery is not appropriate, emergency radiotherapy is indicated.
The patient underwent decompressive surgery. The pathology was consistent with a primary neuroectodermal tumour, suggesting an aggressive transformation of oligodendroglioma. Although she received thoracic spinal radiotherapy to a dose of 20Gy in five fractions her mobility continued to deteriorate. A MRI scan done 2 months later is shown in Fig. 25.3.
Fig. 25.3
Questions
9. What does the MRI scan in Fig. 25.3 show?
10. What is your management?
Answers
9. What does the MRI scan in Fig. 25.3 show?
The MRI shows progressive leptomeningeal/intradural contrast-enhancing disease involving the whole of area of the spinal canal.
10. What is your management?
She has rapidly progressive disease, and her treatment is essentially symptomatic and palliative. The patient died 4 weeks after the last scan.
Further reading
Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of malignant glioma: role of neuropathology. Journal of Neurooncology 2008; 89: 287–311.
Burnet NG, Lynch AG, Jefferies SJ, et al. High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiotherapy Oncology 2007: 85: 371–378.
Ricard D, Idbaih A, Ducray F, et al. Primary brain tumours in adults. The Lancet 2012; 26: 1984–1996.
Scoccianti S, Detti B, Meattini I, et al. Symptomatic leptomeningeal and intramedullary metastases from intracranial glioblastoma multiforme: a case report. Tumori 2008; 94: 877–881.