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 »  Looking Back; Le...
 » Introduction
 »  Review: Lessons ...
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 »  ”biopsy in...
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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 20-36

Changing paradigms in the surgical management of brainstem gliomas. Lessons learnt from Prof Nagpal's paper published in 1983

1 Department of Neurosurgery, Institute of Neurosciences, SRM Institutes for Medical Sciences, Vadapalani, Chennai, Tamil Nadu, India
2 Department of Neurosurgery, Adyar Cancer Institute, Chennai, Tamil Nadu, India
3 Department of Neurophysiology, Institute of Neurosciences, SRM Institutes for Medical Sciences, Vadapalani, Chennai, Tamil Nadu, India

Date of Web Publication7-Mar-2019

Correspondence Address:
Dr. V R Roopesh Kumar
Department of Neurosurgery, Institute of Neurosciences, SRM Institutes for Medical Sciences, Vadapalani, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.253617

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How to cite this article:
Ratha V, Sundar I V, Sampath N, Kumar V R. Changing paradigms in the surgical management of brainstem gliomas. Lessons learnt from Prof Nagpal's paper published in 1983. Neurol India 2019;67:20-36

How to cite this URL:
Ratha V, Sundar I V, Sampath N, Kumar V R. Changing paradigms in the surgical management of brainstem gliomas. Lessons learnt from Prof Nagpal's paper published in 1983. Neurol India [serial online] 2019 [cited 2022 May 26];67:20-36. Available from: https://www.neurologyindia.com/text.asp?2019/67/1/20/253617

In these days when science is clearly in the saddle and when our knowledge of disease is advancing at a breathless pace, we are apt to forget that not all can ride and that he also serves who waits and who applies what the horseman discovers.

Harvey Cushing (1869-1939)

We are at present in the ”Golden era of Neurosurgery”! The last 2 decades have seen huge strides taken in the field of neurosciences, neuropathology and neuroimaging, drastically altering the way we have been managing and understanding many neurological diseases. The technological innovations have helped us in conquering the neuroanatomy and there isn't any corridor left in a human skull which is inaccessible to the modern neurosurgeon. As Dr. Cushing rightly reminded us, it is imperative for all neurosurgeons to take up the saddle and report on what is discovered; and those who choose to wait, learn and serve, should read and learn from the past, as often as they can.

There is one region, however, which has continued to flummox neurosurgeons with its intricate neurophysiology and neuroanatomy, and that is the 'brainstem'. In the last 100 years, we have come a long way in this journey focused on the treatment of brainstem lesions. Today, the brain stem has emerged from being an absolutely inaccessible region to becoming one of the last frontiers in the brain getting conquered by neurosurgeons.

 » Looking Back; Learning from the Past Top

”If you don't know history, then you don't know anything. You are a leaf that doesn't know it is part of a tree.”

Michael Crichton

If anything, history has taught us that for every success, a brutal journey has to be endured. Nothing describes it better than the tryst of neurosurgeons with brainstem gliomas since their initial discovery.

In the 1960s, the brainstem was still the forbidden region for surgery, and the mortality rate of operation on brainstem tumors was nearly 100%. In 1969, Maston [1] stated that ”regardless of specific histology, brainstem gliomas must be classified as malignant tumors since their location itself renders them inoperable.”

The earliest written report of a brainstem lesion was the autopsy report by Dr. Charles Mills in 1881.[2] Surgical resection of lesions were not even contemplated until 1909, when Dr. Weisenburg [3] performed a decompressive resection of a suspected cerebellar lesion on a 46-year old patient who later succumbed and a postmortem examination revealed an extensive tumor of the cerebellum, medulla, pons, and cerebral peduncle. A year later, in 1910, Dr. Zenner [4] reported one of the earliest operative interventions for a suspected cerebellar tumor in a pediatric patient, which on autopsy proved to be a large tumor of the pons.

By the turn of the twentieth century, Dr. Harvey Cushing had recognized the clinical challenge of resecting brainstem tumors especially in the pediatric age group, where diagnosing the lesion itself was a formidable task. He commented that, ”Comparatively little is known of the functions and the relations of the midbrain and its nuclei to the medulla oblongata and the cord…it has become customary to neglect somewhat the brainstem and upper cord, and to pay too much attention to the parts above this.” Dr. Cushing's first surgical encounter with a pediatric brainstem glioma in 1910 at the John Hopkins University, was disastrous with the patient succumbing in 2 days.[5]

The next 4 decades did not change much in terms of the surgical outcome. In 1939, this prompted Bailey et al., to describe the treatment of brainstem gliomas as ”a pessimistic chapter” in the history of neurosurgery.[6] Later, Dr. Matson in fact, was so assured of the bad outcome of surgery for brainstem glioma (BSG) that he stated that ”..exploration for confirmation of diagnosis should be avoided if possible, since such surgery is useless.”[1]

The turnaround came when in 1968, when Dr. Pool [7] became the first neurosurgeon to successfully resect brainstem gliomas and reported a long-term survival of up to 22 years. Three years later, in 1971, Lassiter et al., operated on 34 patients harbouring a BSG, of whom 8 patients survived for a period ranging from 3 months to 9 years.[8] He advocated in his paper that BSG should be explored in the hope of finding cystic lesions, where a resection may provide a good outcome.

The advent of the microscope and the computed tomographic (CT) scan in the 1980s brought a new promise to this field. Hoffman et al.,[9] reported the existence of a group of benign brainstem gliomas with distinct clinical and pathological manifestations, which originate at the fourth ventricle floor, arising from the dorsal part of brainstem and grow into the fourth ventricle through the ependyma. These tumors were amenable to surgical resection with a good survival outcome. These findings reported by Hoffman et al., initiated a paradigm shift in the traditional thought process of neurosurgeons across the globe.[9]

In this chaos related to the understanding of the ideal management strategy for BSGs, one seminal paper from the Indian subcontinent got buried in the dissonance. Dr. RD Nagpal in 1983, published an epoch- making paper,[10] which along with the landmark paper by Hoffman et al.,[9] three years earlier, dared to challenge the traditional notions on surgical resections in BSG. Dr. Nagpal elucidated the intricate subgrouping of BSGs and indicated the subgroups that showed an extremely beneficial effect from surgical resection. It was a pioneering work on BSG with an in-depth analysis of the pathophysiology and surgical techniques, which reverberates even in today's era of advanced imaging techniques.[10]

By the late 1980s, this pioneering work inspired several neurosurgeons to replicate the results successfully [9],[11],[12] and paved the path to the introduction of the modern classification systems to identify BSGs that could be successfully treated with surgery.

 » Introduction Top

BSGs account for approximately 10–20% of all childhood central nervous system (CNS) tumors. An estimated 350–400 pediatric cases (3–4 per 100,000 pediatric population) were diagnosed yearly in the United States of America (USA) from 2007 to 2011.[13],[14],[15] It can present at any age, but the usual age at presentation is 6 – 7 years and there is no gender predilection.[16] The BSGs are less common and have a less aggressive course in adults.[16] [Figure 1] depicts a brief summary of characteristics of BSGs in adults and children.
Figure 1: A brief summary of characteristics of BSGs in adults and children is presented

Click here to view

Over the past 2 decades, the management of BSG has seen a tremendous progress especially with the advancements in microsurgical techniques, sophisticated imaging technology, pathological classification and the clinical applicability of intra-operative neurophysiological monitoring (IONM).[17],[18] Neuro-navigation and intraoperative imaging have also positively influenced the surgical oucome.[17],[18] We now know that BSGs are a heterogeneous group of tumors and the development of molecular genetics and molecular imaging has further promoted the progress of individualized and precise diagnosis and treatment in BSGs.

The hidden gem

In the seminal article, Dr. R D Nagpal attempted to visualize the ideal management of BSG in an entirely unique way. He deviated from the accepted norm and bravely tread in a direction, very few prior to him had attempted. He stated in his paper, ”We decided to deviate from the widely accepted policy of 'after making anatomical diagnosis of a brainstem tumor, the patient should be treated with radiotherapy' and instead operate on every one of these patients …. and excise a benign lesion as completely as possible.”[10]

The evidence prior to this landmark paper on BSG was vehemently against surgical resection. In his era, the conventional practice was to offer radiotherapy directly once an anatomical diagnosis of brainstem lesion was made. Surgery for these tumors were avoided because of fear of brainstem swelling, irreparable neurologic damage, inability to obtain adequate tissue, and death. It was a bold decision by him to publish this paper, backed by his own experience of sound understanding of glioma surgery, and fueled by an inordinate will to find a solution for this enigmatic pathology. His own clinical experience as a leading neurosurgeon in a developing country, taught him two essential lessons: (1). Radiotherapy for benign and inflammatory brain stem lesions is catastrophic, and it is, therefore, imperative to rule out a benign pathology prior to administering radiotherapy in such patients; and, (2). As the histology of BSGs and brain gliomas is similar, occurrences of cystic and exophytic BSGs gives us the opportunity for resection of these tumors, and thus improve survival in our patients, as was evident in gliomas. With these two principles as the basis of his paper, Dr Nagpal provided a thorough and comprehensive clinicopathological evaluation of BSGs and a strategy for their surgical management for his era of neurosurgeons. The in-depth insight related to the natural course of the disease and its management provided in that article, is still relevant today. He reported on 20 operated cases out of a total of 36 patients with an anatomical diagnosis of brainstem masses. Majority of his patients (almost 67%) were in the 1st or 2nd decades of life.[10]

In Dr. RD Nagpal's series, clinical localization, aided by the conventional and invasive imaging techniques were the only way to establish the diagnosis of BS lesions. He was handicapped by the absence of a CT scan machine at his institute in planning a proper neurosurgical approach. The outcome of complex surgery is quite often dependent on the availability of latest technology. But this did not deter Prof. Nagpal, whose surgical approaches were more “exploratory” than “planned” but backed by sound clinical and surgical skills.

His greatest triumph in this series was in being able to avoid conventional radiotherapy as the initial mode of treatment. He also advocated for surgical resection as the only treatment for benign, radioresistant lesions. He provided evidence that resection of cystic BSG often helps in increasing the length and quality of life of the patients harboring these lesions.

However, despite all the limitations that the diagnostic and surgical armamentarium imposed upon him, none of his patients worsened as a “consequence of surgery”. These amazing results initiated the role of surgical intervention in BSG.

 » Review: Lessons Learnt Top

Broadly, the evolution of neurosurgery for brainstem lesions can be summarized as ”imagination to visualization”.

[18] This ability (or lack of) to diagnose brainstem lesions can be used to subdivide the evolution of neurosurgery into 4 eras as described in the [Figure 2]. The journey which started from being completely blind while attempting to visualize brainstem lesions has reached a point where we are integrating molecular pathology to neuroimaging and providing a molecular vision of BSGs [Figure 3]. The major part of the 20th century was devoid of satisfactory visualization utilizing the imaging technology and this spilled over into a poor surgical outcome for BSGs. This dogma was so strongly entrenched in neurosurgical principles that even after improvement in neuroimaging, the reluctance to provide surgical resection persisted. It is only in the 21st century, that major strides have resulted in a better outcome for BS lesions. Imaging genomics, imaging proteomics, and imaging metabolomics represent the new branch in science that link currently used imaging modalities to predict and correlate genomic, proteomic, and metabolic profiles in gliomas.[19]
Figure 2: The evolution of neurosurgery can be subdivided into 4 eras

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Figure 3: A: An autopsy specimen of BSG; B: Plain lateral radiograph of the skull showing the perfomance of a stereotactic biopsy to obtain a histological sample; C: Sagittal contrast MRI of the brain showing the well-enhancing exophytic BSG emnable to surgical resection

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Although Dr. Nagpal's study belonged to the “CT and magnification era” of neurosurgery, the existing set up of the developing world hindered this. The first accessible CT scan in Mumbai was established only in 1981!

 » Localization: Clinical Features to Visualization Top

Probably, the most unchanged part through the eons in the clinical management of brainstem is the clinical evaluation and anatomical localization. In his paper, Dr. RD Nagpal summarized the clinical features in a table and noted that the commonest single symptom was gait disturbance (in 25 patients) followed by headache, oculomotor dysfunction, lower cranial nerve palsies (in 13 patients each) followed by slurred speech and motor weakness (in 11 patients each). The most common signs were gait ataxia and a positive bilateral Babinski's sign (21 patients each) followed by unilateral 7th nerve palsy (19 patients), and lower cranial nerve palsy (15 patients). Most of the patients were in the first and second decades and had an almost equal sex ratio of 1.25:1 (male: female). The time interval between the symptom onset and presentation varied from 15 days to 10 months.

Comparing with the world literature at that time, Golden et al.,[20] in 1972, correlated the clinical features of 13 cases of brainstem glioma and found that all of them had disorders of ocular motility followed by hemiparesis and other cranial nerve palsies. Albright et al.,[21] in 1983, found that cranial nerve palsies at the time of diagnosis were associated with an increased mortality. Later, Walker et al., in 1999[22] elaborated that the symptoms at presentation correlated to the level of the lesion and the direction of growth. The ready availability of imaging modalities then made it easy to confirm or refute such a suspicion. Chandy and Rajshekhar [16] in their 1999 analysis, comparing pediatric and adult BSG, found no significant differences in the clinical features. A recent review by Eisele et al.,[23] in 2016, that included 12 publications on adult brainstem gliomas published from 1998 to 2015, reported cranial nerve dysfunction as the most common presenting feature, followed by gait disturbances and long tract signs.

In summary, apart from a poor performance score, the radiological features, the pathological grade, extremes of age, and a short symptom duration [less than 3 months] have also been associated with a poor prognosis.

 » Visualization: from Picture to Proton (Mri) Top

One of the striking points which Dr. Nagpal made in his paper was in the first paragraph itself. He comments, ”The conventionally accepted and widely practiced therapy for brainstem occupying lesions has been in controlling raised intracranial pressure followed by radiotherapy. This was based on the premise that most if not all brain stem masses are gliomas and thus not surgically resectable.”

With the increasing acceptability of CT scan, the blind regions of brain became more visible and our understanding of brainstem lesions improved. Dr. Nagpal had the liberty of performing a CT imaging in only 5 patients but he used it to understand and correlate the intra-operative and pathological findings with the CT scan images. Unfortunately, the basic resolution of the CT scan images at that time was poor, thus presenting a heterogenous and variable imaging, and was of limited use in making a pathological diagnosis.

Out of the 5 patients, 3 cases were operated and 2 were presumptively given radiotherapy due to the difficult location of the tumor. All the 3 operated cases showed an intense contrast enhancement, of which one was a tuberculous abscess. The one mortality was attributed to the extensive brainstem edema noted on CT scan of the brain. Four out of the 5 cases were doing well on a 1-year follow up. He also noted the change in enhancement pattern on follow-up scan of the one case who underwent radiation. He pointed out ”With a CT scan, it is possible to say whether the lesion is intra or extra-axial. Prior to CT scan, one could only know from imaging if brainstem was swollen or not.”

The imaging technology has immensely influenced the way we have approached the BSG. From the era of imagination, where clinical features were the sole parameter to localize BSG, we moved to the indirect invasive way of visualization by using pneumoencephalography, ventriculography and cerebral angiography. Although the localization improved, it did not correlate with the histopathological diagnosis, guide the treatment, and monitor the effects of treatment, except for providing the indirect signs of a space occupying lesion. It all changed with the improvement in CT/MR images and their interpretations. An ideal imaging modality should be able to anatomically localize, qualitatively diagnose and dynamically monitor the disease evolution.

The knowledge gap was answered largely by 1985 by Stroink et al.,[24] wherein he classified the brainstem tumor into four types based on CT findings of the lesions and the intraoperative findings [Table 1]. It was successful in defining the growth pattern into the 'exogenous' and 'endogenous' types and the latter into 'diffuse' and 'focal' types. This was an immense improvement from the clinical localization alone. Due to the low resolution of soft tissues, low ability to reflect tumor information and bone artifacts of the posterior fossa, however, it did not gain much momentum in BSG (as predicted by Dr. Nagpal). The arrival of MRI provided high resolution images of the soft tissues, a three-dimensional reconstruction at any angle for a precise localization, an imaging study that was devoid of radioactivity, an imaging sequence diversification, and no bone artifacts, which were extremely helpful for delineating BSGs.
Table 1: History of Classification systems in Brainstem Gliomas

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Epstein et al., utilized the MRI to provide a landmark classification for BSGs in 1985. He divided these lesions into the exophytic, intrinsic, and disseminated types.[24] He was able to establish the surgical outcome depending on the location and growth pattern of BSGs. The new MRI based visual classification was a triumph of technology over pathology. He demonstrated that cervicomedullary tumors are benign and grow from the upper cervical spinal cord but the pyramidal decussation, decussation of the lemniscus and the pia mater limit its growth and directs it into the IVth ventricle, thereby making it amenable to resection. Its prognosis, therefore, mimicked that of low grade intramedullary tumors of the spinal cord and it was concluded from the study that it has to be treated like an intramedullary low-grade tumor.[25] Similarly, the dorsal exophytic variety of the tumor was categorized as one kind of focal benign tumor with its epicenter in the medulla oblongata but its growth being limited by the surrounding fibers, thus changing the growth direction into the fourth ventricle through the ependyma,[26] thereby making it surgically resectable. This concept that the prognosis of BSG is not just dependent on histopathology but also on its location and growth pattern, revolutionized the role of surgery in BSG.[26] However, the diffuse intrinsic pontine glioma (DIPG) continued to perplex neurosurgeons with its highest incidence among the brainstem gliomas, its shortest survival time, and its highest difficulty in responding to therapy. A proper imaging alone has been enough to start a non-surgical mode of intervention.[27]

The classification systems continued to be refined and improved over the next decade. A brief history of classifications is outlined in [Table 1].

Barkovich et al., in 1990[28] further refined the classification system by including different parameters, such as growth patterns, the location of the original site from where the tumor originated, and the characteristics of the tumor itself [Table 1]. Later in 2000, Choux et al.,[29] used both a CT scan and an MRI to group brainstem tumors into four types. [Table 1]. In 2009, Mehta et al.,[30] proposed a modification in the classification by including the subcategory of 'intrinsic' tumors with a paucity of neurological signs, as a distinct subgroup of brainstem tumors (expanding variety), which is amenable to resection, and is an entity distinct from diffuse brainstem gliomas, which are unresectable. This expanded the role of surgery in some of the subset of tumors that were initially classified as 'diffuse,' if they fulfilled other criteria of the expanding variety.

Thus, the various classification systems in BSG have shaped our approach towards management of BSG, especially by categorizing the tumor into either a 'focal' or 'diffuse' growth pattern. As this understanding developed, the more complex schemes further subclassified these lesions based upon their locations within the brainstem (midbrain, pons, or medulla), the contrast enhancement pattern, the presence or absence of exophytic growth in relation to the brainstem, and the presence of hydrocephalus or hemorrhage. These essential details have helped in ascertaining tumor behavior (i.e., the World Health Organization [WHO] grade) and have provided a guideline for the surgical versus non-surgical management for these lesions.

Has MRI answered all our questions?

MRI, although being the gold standard for diagnosing BSG, still has some limitations especially with respect to: a) the qualitative diagnosis: The current MRI standards still find it difficult to reliably differentiate between low grade and high grade lesions, and neoplastic from non-neoplastic lesions.[31],[32] The conventional MRI imaging is also unable to accurately differentiate the subgroup of DIPG that have a variable prognosis; and, b) the dynamic monitoring of the treatment effect: The MRI imaging is still unable to quantify and predict the response to radiotherapy and chemotherapy, especially in differentiating pseudo-progression from tumor recurrence and radiation-induced necrosis.[33]

The future lies in amalgamating molecular imaging with the imaging features of the conventional MRI, to address some of these unanswered questions.

 » Surgical Management: the Janus View Top

The surgical management of brainstem gliomas has undergone significant changes since the paper by Dr. RD Nagpal, aided primarily by the parallel growth in neuroimaging, operating microscopes and better anesthetic drugs. The complexity in the accurate visualization of these lesions, and the intricacies of brainstem anatomy and physiology had initially convinced the erstwhile neurosurgeons that there is no role of surgical management in BSG except for reducing raised intracranial pressure. For many decades, this philosophy dictated the use of radiation therapy as the first mode of treatment.

Dr. Nagpal questioned the legitimacy of this philosophy.[10] Despite being able to use a CT scan to diagnose the tumor in only 5 patients in his study, the imaging still guided him to plan his surgical approach according to the location of the tumor (a subtemporal transtentorial approach in 3 cases and a standard, posterior, midline, suboccipital approach to the brainstem in 17 of them).

Due to being partially limited by the drawbacks of the existing imaging conventional modality, he eloquently explained the significance of surgery in BSG as being “exploratory” prior to taking a decision to subject the patient to either surgery or direct radiotherapy. Autopsy was performed wherever possible, especially in those who did not undergo surgery and a post-mortem histopathological diagnosis was made in these patients. In the result section, he noted that 16 of the 36 patients had died, among whom 12 had an astrocytoma.

A similar study in 1979 by Riegel et al.,[34] described 26 patients who underwent a biopsy after an initial CT scan of the brain, and reported no mortality. The morbidity was largely related to an increased incidence of cranial nerve deficits. Subsequently, Stroink et al.,[24] in 1986, in a landmark paper on the classification of brainstem gliomas based on CT findings, helped in creating a consensus among the neurosurgeons that the focal variety, the dorsal exophytic variety and the cervicomedullary BSGs immensely benefited by surgery, and the diffuse ones did not. But the controversy regarding subjecting the patient suffering from a BSG to an initial biopsy prior to starting radiation therapy versus administering direct radiation therapy (especially in the diffuse pontine glioma variant of the tumor) continues to generate debate in the neurosurgical and radiation oncology field.

 » ”biopsy in BSG”: Where Do We Stand? Top

Brainstem gliomas are regarded as a group of heterogeneous tumors with a varying biological behavior and a differing potential for growth. The role of surgery started with biopsy and evolved to resection. Conventionally, an open anterolateral approach was the main corridor for biopsy. The lateral suboccipital corridor is mainly suited for laterally placed lesion in the cerebellar peduncle or the brainstem.[34],[35]

Stereotactic biopsy of the brainstem lesions was first described in 1978 by Gleason et al.[36] Since then, stereotactic biopsies have been completely integrated in the diagnostic and management armamentarium of several intracranial lesions and have been found to be essentially helpful in differentiating various non-neoplastic pathologies which mimic their neoplastic counterparts on radiology. With the advent of MRI in the late 1980s, the classification system in BSG were based more on radiological than histological parameters. This resulted in a decline in interest in obtaining a histological diagnosis in brainstem lesions as it avoided an invasive procedure in an anatomically complex region. This fact was evident from the review of Albright et al., who concluded that an MRI should replace biopsies as the diagnostic procedure of choice due to the high complication rate (around 9%) found in the latter procedure.[37] Furthermore, considering the fact that a biopsy of one region was not always a representative of the overall pathology, the efficacy of stereotactic biopsy in establishing the diagnosis was questioned. Moreover, the histological diagnosis did not alter the therapy administered or the outcome, especially in diffuse intrinsic pontine gliomas (DIPGs).

However, by the early 2000s, many authors demonstrated the MRI-based diagnosis to be erroneous in 10-20% of the cases.[38] Further, with regard to establishing the tumor grade in the classification, it was noted that the accuracy of MRI brain in correctly assessing the grade of the lesion was correct in 35% of low grade gliomas and in 27% of high grade gliomas.[39] Selvapandian et al., also confirmed the importance of grading of a brainstem glioma in establishing its prognosis in adult patients, while this parameter is not so much effective in prognosting the outcome in children.[16]

A review of the current literature indicates that the procedure of stereotactic biopsy has not been found to be associated with an increased risk, and often achieves a satisfactory diagnostic yield of tumor tissue for establishing its diagnosis. Samadani et al.,[40] in a meta-analysis of 13 studies in which a stereotactic biopsy for a brainstem lesion had been performed, reported transient and permanent neurological deficits in 4 and 1% patients, respectively, with a 0.3% mortality. A diagnostic yield of 94% was reported after the first biopsy. The yield increased to 96% after the second biopsy. These authors reported that around 40% tumors were detected to be having a non-neoplastic pathology on biopsy, encouraging them to conclude that, ”Empiric treatment of brain-stem lesions is not prudent because there is a wide spectrum of diverse pathology in this location. Stereotactic biopsy is a safe and effective method for determining histopathology.”[40]

In developing countries, where chronic inflammatory lesions like tuberculosis and cysticercosis are more prevalent, a high index of suspicion for a nonmalignant lesion with an atypical clinical or radiological presentation is imperative.[39] Selvapandian et al.,[16] also emphasized the role of biopsy in their comparative analysis between pediatric and adult BSG. They demonstrated that tumor grade was a significant factor in predicting survival in adults. Pediatric DIPG differ considerably from adult DIPG in terms of prognosis and outcome and unfortunately our understanding of the difference between both these entities is limited due to a lack of biopsy samples that have determined the immune and molecular biology in both subsets of the tumor. The emphasis on molecular pathology in the recent times, with the presence of findings like 1p19q loss and, O6-methylguanin-DNA-methyltransferase (MGMT) positive status of the tumor, has correlated with the outcome and response to newer chemotherapeutic agents. Also, in future, the genetic profiles of the tumor are expected to play a role in influencing treatment of these tumors. As Leach et al.,[41] concluded, ”However, with an increasing knowledge of tumor biology and genetics, there is the potential for specific treatments tailored for individual tumors based on their biological or genetic characteristics. The progress of such science in the first instance requires biopsy samples to identify the tumors that may respond to such treatments.”

The next decade should see steps in improvising the locoregional delivery of newer biological agents and immunotherapeutic strategies.[42] Based on the literature, stereotactic biopsy of DIPG is as safe and diagnostic as supratentorial biopsy; and, the amount of tissue obtained allows for a molecular biological analysis, including whole genome sequencing. The field opens up the prospect for characterization of biological markers that permit the treatment of newly diagnosed DIPG in children as a part of next-generation clinical trials with targeted therapy.

Role of surgical resection in BSG

The brainstem, contains a rich concentration of nuclei and fibers in a small sectional area. Most of the focal upper midbrain and tectal tumors and cervicomedullary tumors have a very slow growth rate potential with a non-progressive indolent course and patients harboring these tumors often have a favorable survival rate after undergoing surgery. The concept of the main safe entry zones (SEZ) in the brainstem has been a pivotal factor in reducing morbidity during excision of any lesion that does not surface at the pial or ependymal surface of the brainstem. These zones represent entry points and trajectories where eloquent structures and perforators are sparse and a neurotomy would cause the least possible damage.[43] The discovery of these safe entry zones has revolutionized the role of surgery in pure brain-stem lesions. Before the usage of intraoperative neuromonitoring, the ideal corridor for BSGs was always through the area where the lesion was closest to the surface of brainstem or through an accompanying cyst, if present. The various surgical corridors used for brain-stem lesions are outlined in [Table 2]. The case illustrations are depicted in [Figure 4] and [Figure 5].
Table 2: Surgical approaches to the brainstem according to lesion location

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Figure 4: Sagittal MRI with contrast enhanced image showing (a and c) the preoperative images of two exophytic midline tumors. (b and d) The respective postoperative images showing total excision using the midline suboccipital craniectomy

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Figure 5: (a) Preoparative image of a middle cerebellar peduncle brainstem glioma (b) Total excision by a retromastoid suboccipital approach. (c) A midbrain glioma at the level of collicular plate. (d) Postoperative image showing total excision

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After Mehta et al.,[30] reviewed the cases of intrinsic BSGs from 1998 to 2007 and classified them further into the expanding variety, infiltrating variety and ventrally located tumors, he also demonstrated a good outcome of even the expansile subtype. Sinha et al.,[44] later in 2014, followed with their retrospective review of 58 patients and concluded that patients with well-delineated posteriorly, posterolaterally and ventrolaterally located tumors with slow progression and relative preservation of the motor power benefit maximally by resection. Most of these tumors are amenable to radical resection, and the surgeon's experience and modern surgical facilities help in achieving excellent surgical results.

However, when the lesions does not reach the pial or ependymal surface of the brainstem, it is essential to have a fundamental understanding of the concept of safe entry zones (SEZ). SEZ are landmarks on the brainstem that represent small regions between vital neural structures and take advantage of the sparseness of perforators in these areas.[43],[45] Kyoshima et al., in 1993,[45] they described two SEZs: (1) the “suprafacial triangle,” bordered medially by the medial longitudinal fascicle (MLF), caudally by the facial nerve (FN) and laterally by the cerebellar peduncle; and, (2) the “infrafacial triangle,” bordered medially by the MLF, caudally by the striae medullares, and laterally by the FN. Following this landmark paper, various authors performed dissections on the brainstem in cadavers to study the microsurgical neuroanatomy of neural structures of the brainstem and outlined various SEZ for brainstem surgery [43] [Table 3]. However, it is essential to understand that when the lesions are large, these SEZ can get distorted due to the pathology itself and the external landmarks may not be reliable.[43] An algorithmic approach to the management in BSG is shown in [Figure 6].
Table 3: Accessible safe entry zones by surgical approach

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Figure 6: An algorithmic approach to the management in BSG; ETV: Endoscopic third ventriculosotmy; HCP: Hydrocephalus

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In summary, surgery for brainstem gliomas started with a biopsy to obtain a tissue diagnosis, evolved to maximal excision of exophytic tumors, and then included certain groups of intrinsic tumors for maximal resection to prolong survival. Although advances in imaging technology are questioning the need for a tissue diagnosis in some types of brainstem lesions, the advent of molecular studies in addition to histopathological grading has again placed emphasis on the need for a tissue diagnosis.

 » Where are We Headed? Top

The rise of intraoperative neurophysiological monitoring (IONM): Journey from anatomical to functional safe entry zone

Following the emergence and refinement in IONM, the shift in identifying the ideal BS corridor has occurred from anatomy to physiology and from mapping to monitoring. After the advent of intraoperative neurophysiological monitoring (IONM), the success rate for achieving safe resection has increased by many folds. SEZ, although a useful guide, becomes of less practical value when pathology distorts the anatomical landmarks.[46]

The techniques employed in IONM for brainstem lesions can be classified into 3 broad categories: 1) Mapping: To differentiate neural structures from the lesion; 2) Monitoring: To provide real-time feedback of functional integrity of the nervous tracts; and, 3) Developing techniques for testing the brainstem reflexes.

Mapping is done to localize the cranial nerve motor nuclei, cranial nerves and corticospinal tract using a monopolar probe and is used when anatomical landmarks fail to aid in identifying the neural structures due to compromised anatomy produced by the lesion. Monitoring involves a range of techniques like sensory evoked potentials (SEPs), brainstem auditory evoked potentials (BAEPs), motor evoked potentials (MEPs), corticobulbar motor evoked potentials (CoMEPs) and free running electromyography (fEMG). The various parameters monitored and mapped via IONM are outlined in [Table 4].
Table 4: Various IONM modalities and parameters monitored

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The conventional approach of IONM in brainstem lesions originated with the use of somatosensory-evoked potentials (SEPs) and brainstem auditory-evoked potentials (BAEPs). However, Deletis demonstrated that these two methods are suitable for evaluating functioning in less than 20% of brainstem areas.[47] This resulted in establishment of motor evoked potentials (MEPs) for evaluating the functional integrity of motor pathways passing through the brainstem. MEPs have rapidly became the most essential IONM modality in brainstem surgeries with a high sensitivity and specificity for predicting postoperative neurological motor function.[48],[49],[50] Recently, corticobulbar motor evoked potentials (CoMEPs) are being used to monitor the corticobulbar pathways and cranial motor nerves (VIIth, IXth, Xth, XIIth).[48],[51]

Lately, the utilization of free-run EMG (fEMG) for monitoring the spontaneous muscle activity occurring during the non-electrically stimulated phase, has opened up a new avenue in predicting the neurological deficits during intra-operative surgical interventions related to nerve irritation, traction and injury. Extrapolating these findings, Prell et al.,[52] classified the EMG patterns based on the characteristics of the waveforms obtained, of which, “A” train was the only pattern that was indicative of an incipient postoperative paresis.

However, we have yet to find a way to assess brainstem reflexes during surgery. This is primarily due to our inability to monitor any of the brainstem reflexes under anaesthesia. Monitoring brainstem reflexes is the next exciting new frontier in IONM. Deletis et al.,[47] have been able to describe a method to elicit the R1 component of blink reflex by applying a constant current stimulus over the supraorbital nerve, but these techniques are yet to be developed and standardized for intra-operative use.

Thus, the use of multi-modal IONM techniques like fEMG and MEP, along with mapping of the corticospinal tract and the mapping of the VII, IX-X and XII cranial nerve motor nuclei on the floor of the fourth ventricle, can be used to evaluate the functional integrity of these pathways during surgery and identify “safe entry-zones (SEZ), “ especially when the normal anatomy is distorted by a tumor. These mapping techniques permit the recognition of anatomical landmarks such as the facial colliculus, and the hypoglossal and glossopharyngeal triangles on the floor of the fourth ventricle, and aid in recognizing specific patterns of output of motor cranial nuclei. There has been a gradual shift in the concept of locating SEZ purely by anatomical landmarks to a combined localization utilizing functional-anatomical landmarks with the aid of IONM and navigation.

 » Navigation Guided Ionm Top

IONM, especially the transcranial (Tc)-MEP monitoring, is effective for corticospinal tract protection and has changed how we have approached intrinsic brainstem lesions. A lack of consensus regarding the accepted warning criterion has hampered a consistent maximal safe resection. When both neurosurgeons and electrophysiologists work in synchrony to preserve motor functions, the results are always better.

Li et al., in 2018, have demonstrated that the novel technique of integrating the neuronavigation protocol with IONM (corticospinal tract mapping) has the potential to detect the relationship between the corticospinal tract and the resection point (as well as the specific location of the corticospinal tract within the operative field).[53] Neuronavigation combined with IONM provides anatomical as well functional guidance for selecting the SEZ and achieves better preservation of motor function in surgery for brainstem tumors.

Resurgence in endoscopy

The use of flexible endoscope was limited to only biopsy of ventral, dorsal (quadrigeminal plate), and diffuse brain-stem tumors Although an effective and a safe procedure that also simultaneously treats obstructive hydrocephalus secondary to the tumors, it could not be used for resection of a BSG.[54]

In 2018, Fernandez et al., used the endonasal endoscopic transclival approach for resection of a pontine glioma.[55] They utilized tractography to assess the ideal ventral approach and were able to resect the exophytic component of the pontine glioma without causing any major neurological disturbances. This has opened up the possibility of using endonasal endoscopic assistance as a potential alternative for ventral BSGs.

The advancement of neuroimaging and molecular imaging

In the recent 10 years, molecular pathology has gradually replaced histopathology as the gold standard for guiding the personal diagnosis and treatment of gliomas. However, the diagnosis by molecular pathology only reflects the information of the selected location, but not the whole tumor. Often a repeated sample collection may be required, thus leading to difficulties in assessing the molecular pathology and in dynamic monitoring of changes during the tumor treatment. In contrast, tumor imaging can reflect the entire information of the tumor and can also dynamically monitor the changes during the treatment process. It is necessary to combine these two disciplines if one want to fully utilize their advantages. Imaging genomics, imaging proteomics, and imaging metabolomics represent new branches in science that link the currently used imaging modalities to predict and correlate genomic, proteomic, and metabolic profiles in gliomas. The magnetic resonance spectroscopic measurement of tumor-associated choline and N-acetyl aspartate levels may help to distinguish high-grade from low-grade brainstem gliomas.[56] Other new imaging techniques that are used in non-tissue-based diagnoses for brainstem tumors include the rapid diffusion MRI, thallium single-photon emission computed tomography (SPECT), and positron emission tomography (PET). With the development of diagnostic modalities, significant advances have been made in the classification of brainstem tumors.[37],[38],[56]

 » Summary Top

From the “no man's land” to the “safe entry zone”, the surgical management of brainstem gliomas has seen a lot of tectonic shifts. Dr. Nagpal's landmark paper was an eye opener and many of his concepts were anachronistic to his era and still reverberate even after 45 years. Surgery in the brainstem has remained as challenging as ever; however, the last 2 decades have seen tremendous strides. Especially with the emergence of functional (IONM) and anatomical visualization (MRI and molecular Imaging), the modern neurosurgeon is more aware of the intricate neural structures while operating in this region. This provides him an edge, never experienced by the earlier neurosurgeons. Although, we have made tremendous strides in last 5 decades, there is more to be done. As Cushing had once said,

I would like to see the day when somebody would be appointed surgeon somewhere who had no hands, for the operative part is the least part of the work.”

 » Take Home Message Top

Brainstem gliomas are a heterogenous group of neoplasms with adults faring better than children. Magnetic resonance imaging is the gold-standard and tractography combined with navigation is essential for surgical planning. Surgical intervention is essential for ruling out non-neoplastic etiologies of brainstem lesions and also for categorizing their molecular pathology. Stereotactic/navigation-guided biopsy is a safe and reliable option and should be employed whenever radiological diagnosis is in doubt. Intraoperative neuromonitoring along with neuronavigation should be employed to identify the functional and anatomical safe entry zones in brainstem surgeries. Dorsally exophytic, cervico-medullary and focal cystic tumors benefit immensely from radial resection. Molecular pathology and imaging are the key features in understanding and predicting the prognosis of intrinsic brain-stem gliomas, like the diffuse intrinsic pontine gliomas.

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[Additional file 1]

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2], [Table 3], [Table 4]


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