Perioperative Risk Assessment of Patients with Gliomatosis Cerebri

Accepted Manuscript Perioperative risk assessment of patients with gliomatosis cerebri Nir Shimony, MD, Ben Shofty, MD, Zvi Ram, MD, Rachel Grossman, MD PII:

S1878-8750(16)31158-5

DOI:

10.1016/j.wneu.2016.11.014

Reference:

WNEU 4824

To appear in:

World Neurosurgery

Received Date: 3 September 2016 Revised Date:

31 October 2016

Accepted Date: 1 November 2016

Please cite this article as: Shimony N, Shofty B, Ram Z, Grossman R, Perioperative risk assessment of patients with gliomatosis cerebri, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.11.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1

gliomatosis cerebri

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Perioperative risk assessment of patients with

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Nir Shimony MD, Ben Shofty MD, Zvi Ram MD, and Rachel Grossman MD

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Department of Neurosurgery, Tel Aviv Medical Center, affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Corresponding author:

Rachel Grossman, M.D.

Department of Neurosurgery

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Tel-Aviv Medical Center

6 Weizmann St., Tel Aviv 6423906, Israel E-mail: [email protected] Telephone: +972-3-6974273

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Fax: +972-3-6974860

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Running title: Perioperative risk assessment of gliomatosis cerebri patients Key words: gliomatosis, ICP, surgery, complications Disclosure statement: The authors have nothing to disclose.

ACCEPTED MANUSCRIPT 2 Abstract Background: Gliomatosis-cerebri (GC) is a rare diffusely infiltrating malignant glial neoplasm. Presenting symptoms may include seizures, neurological deficits, and not infrequently,

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symptoms related to increased intra-cranial pressure(ICP). Surgical intervention, including brain biopsy may induce worsening of these neurological symptoms. We reviewed our database to identify prognostic and risk factors for peri-operative deterioration specifically associated with

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elevated ICP.

Methods: Between 2006-2014 seventy-eight patients were treated for GC. Ten patients required

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peri-operative emergent treatment for elevated intracranial pressure (ICP). The clinical course and outcome of these 10 patients(study group) were characterized and compared to the remaining 68 patients.

Results: The study group patients developed life-threatening symptoms of increased ICP and

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required urgent decompressive-craniectomy (n=5 urgent DC after biopsy, n=2 urgent DC on admission) or aggressive medical therapy(n=3). Demographic and clinical variables were similar in both groups. In patients with severe symptoms of increased ICP, the enhancing tumor volume

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was significantly greater than in asymptomatic patients. In addition, radiological evidence of obliteration of the basal cisterns and herniation was more common in symptomatic patients. The

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proliferation index in the biopsied tumors was also significantly higher in patients with symptomatic ICP elevation.

Conclusions: Clinical symptoms and radiological appearance suggestive of elevated ICP at presentation, as well as volume of contrast enhancement and high Ki67 proliferation index may predict the need for aggressive rapid treatment to control ICP in a small, but significant subset of

ACCEPTED MANUSCRIPT 3 patients with GC. Further studies are needed to clarify the biological basis for the unusually clinical course in these tumors. Introduction

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Gliomatosis cerebri (GC) is a rare diffusely infiltrating malignant glial neoplasm that involves at least three cerebral lobes1,2. According to the new WHO classification, it is no longer a distinct entity but a growth pattern 3 . Clinical symptoms and radiological features are non-specific, and

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patients are often misdiagnosed with other neurological diseases, such as CNS inflammatory conditions, vasculopathies or leukoencephalopathies4. Magnetic resonance imaging (MRI)

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typically demonstrates diffuse and contiguous infiltration of the white matter, appearing as isointense on T1-weighted sequences and as hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences 1, sometimes accompanied by focal enhancement. Because of the infiltrative nature of the disease, meaningful resection is impossible. Patients with

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GC who present with clinical and radiological signs of elevated ICP may quickly deteriorate even after minimal interventions, such as a biopsy, due to a small hemorrhage, increased edema, or a seizure. Identifying patients at risk of ICP-related deterioration and the precautionary

population.

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measures needed to prevent and manage such complications should be determined in this patient

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We retrospectively reviewed the demographic, clinical, radiological and histopathological

data of 78 consecutive GC patients treated in our institution between 2006 and 2014. Ten patients required intensive treatment to control symptoms of increased ICP and were studied in detail in an attempt to characterize this high-risk group of patients and to optimize future management schemes of such patients.

ACCEPTED MANUSCRIPT 4 Methods Patient Population A total of 78 adult patients (age >18 years) underwent brain biopsy for a presumed

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newly-diagnosed GC between 2006 and 2014. The diagnosis of GC was established by a typical appearance on MRI in addition to a neuropathological diagnostic criteria in all patients based on the World Health Organization (WHO) classification system 1,2. Clinical, radiographic, operative

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and outcome data were collected from inpatient and outpatient medical records. These included age, Karnofsky Performance Status (KPS) score, sites of tumor infiltration (frontal, temporal,

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insular, parietal, occipital, midline, and posterior-fossa) and tumor volumes. Other signs of elevated ICP were determined clinically and included in addition to headache also nausea, vomiting and decrease in consciousness. Three-dimensional volumetric measurements of preoperative magnetic resonance imaging (MRI) studies were performed retrospectively. Manual

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segmentation was performed with region-of-interest analysis to measure tumor volumes (cm3) using FLAIR abnormality and contrast-enhancing volume on T1-weighted MRI. Involvement of medial structures such as thalamus, basal ganglia and brainstem, including occlusion of basal

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cisterns or radiologic signs of subfalcine, uncal, central or tonsillar herniation, was documented. Postoperative mortality and surgery-related complications were recorded if they occurred within

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30 days after surgery. The study was approved by the local ethics committee, Patient consent was not required in this retrospective analysis.

Statistical Analysis

Demographic and clinical data including age, KPS score on admission, tumor volume, and pathological diagnosis, were compared with the 2-tailed t-test. The patients’ gender distribution

ACCEPTED MANUSCRIPT 5 was analyzed with the Chi-squared test. Neurological presentation, MRI parameters and pathological diagnoses were analyzed using the Fisher exact test in relation to perioperative morbidity. All values were expressed as either median or mean ± standard deviation (SD) with

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statistical significance being defined as a p value ≤ 0.05. Comparison of patient outcome among groups was by Kaplan-Meier plots. Finally, the likelihood of severe perioperative morbidity

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according to different statistical combinations was calculated by multi variant analysis.

Results

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The mean clinical follow-up duration for the entire cohort was 22 months (range 2–115 months), and no patient was lost to follow-up. Fifty-four patients (67.5%) eventually died during the study period, resulting in a median overall survival of 12.8 months. Sixty-eight patients (control group) did not required peri-operative intensive treatment for elevated ICP (mean age 52.6 ± 14.8

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years), and their characteristics were compared to 10 patients (study group) who required emergent treatment for elevated ICP at presentation or after the biopsy, (mean age 53.4 ± 13.5 years, p=0.99) (Table 1). There was a slight female predominance in the study group (80% vs.

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48.5%, p-=0.09). There was no significant different in median KPS at presentation between both groups (70 vs. 80 for the controls, p=0.92). The most common presenting symptom in the control

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group was seizures (52.9%), whereas headaches were more common among the study patients (30.9% vs.100%, respectively, p<0.0001), as well as other signs of elevated ICP, such as nausea and vomiting (26.5% vs. 100%, p<0.0001).

Radiological Characteristics and Volumetric Analysis

ACCEPTED MANUSCRIPT 6 The most common lesion location in both groups was the frontal lobe, followed by the temporal, parietal and occipital lobes. The mean number of involved lobes in each group was 3.3. Four patients from the control group had involvement of the posterior-fossa and none in the study

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group. Significantly more patients from the study group had involvement of midline structures, such as the thalamus and basal ganglia, compared to the controls (60% vs. 11.8%, p=0.002) (Table 1). Five of the study patients (50%) had a midline shift of more than 5 mm at presentation

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compared to three (4.4%) controls (p=0.0002). Occlusion of the basal cisterns was significantly more prevalent among the study patients compared to the controls (70% vs. 19.1%, p=0.002).

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Moreover, brain herniation was more common among the study patients compared to controls: Seven study patients (70%) had subfalcine herniation compared to 7 (10.3%) controls (p<0.0001). Three study patients (30%) had central herniation compared to two (2.9%) controls (p=0.014). Four study patients (40%) had uncal herniation compared to seven (7.3%) controls

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(p=0.02). One patient (10%) had tonsillar herniation compared to two (2.9%) controls (p=0.4). The mean tumor volumes on admission, as measured by the presence of a FLAIR abnormality and by contrast-enhancing tissue as seen on T1-weighted MRI, were larger for the study patients

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compared to the controls (mean FLAIR volume abnormality of 152.8cm3 vs. 145.6cm3, p=0.2, and mean volume of enhancement on T1Gd of 29.8cm3 vs. 7.6cm3, p<0.0001) (Table 1).

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Surgery-associated sequelae

Ten study patients required urgent peri-operative treatment for clinical signs of elevated ICP. Specifically, seven patients (70%) who presented with signs of elevated ICP required urgent decompressive hemicraniectomy and other three required aggressive medical treatment that consisted of hyperosmolar diuretics (mannitol, hypertonic saline), intubation with hyperventilation and deep sedation. In detail: Five study patients, who underwent a stereotactic

ACCEPTED MANUSCRIPT 7 brain biopsy, presented up to five days post-procedure with neurological deterioration related to an elevated ICP and required an urgent decompressive hemicraniectomy. Another two patients presented with symptoms of elevated ICP and radiological appearance of brain edema and mass

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effect, deteriorated rapidly after a seizure episode, before surgical procedure was taken, were operated at the same time for decompressive hemi-craniectomy and open biopsy. No patient had ICP monitor and no patient had hydrocephalus or needed an external ventricular drainage or a

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shunt. None of the patients in the current cohort underwent cranioplasty for bone flap

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replacement.

Pathology oncological treatment and survival

The most common pathological diagnosis in both groups was high-grade glioma (70 % study patients and 51.5 % controls, p=0.8), mainly anaplastic astrocytoma. The mean Ki67% was

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significantly higher among the study patients compared to controls (12.4% vs. 3.7%, respectively, p=0.012). Most of the patients had received oncologic therapy after pathological diagnosis was established unless their medical condition or their functional status did not allow

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it. Specifically, 58 patients (74.4%) received adjuvant oncological treatment. Fifty (73.5%) patients from the control group were treated with only radiation therapy and 5 (7.4%) patients

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from the control group were treated only with temozolomide. Most of the patients that were treated with adjuvant therapy were in the control group, whereas in the study group only three patient received combination of temozolomide and radiation therapy (Table 1). The overall median survival for the study and control patients were 3.1 and 14.7 months, respectively (p=0.46), (Figure21).

ACCEPTED MANUSCRIPT 8 Discussion The optimal treatment for GC has not been established. Its diffuse and infiltrative nature precludes any oncological-meaningful surgical resection and limits the effectiveness of therapy

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(1). In this report, we characterize a subgroup of GC patients who suffered from perioperative symptoms related to life-threatening increased ICP, in some precipitated by a biopsy of the

tumor. We identified several clinical and radiological parameters that may predict the occurrence

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of such condition and warrant precautionary preventive or therapeutic measures.

Presenting symptoms for patients with GC are usually subtle and nonspecific as the

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tumor characteristically grows slowly 5-13. The reported duration of symptoms before diagnosis and the occurrence of specific findings vary among different studies5,14, reflecting a wide disparity in the extent of tumor invasion and the histological characteristics. As for certain LGGs, neoplastic GC cells often invade normal brain tissue without disruption of the neuronal

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architecture 5,10,11,15,16. Such patients may have a more protracted and enigmatic presentation than other gliomas, which are more disruptive of the adjacent neuropil15,17. Most of the patients in our reported series had such an indolent clinical course.

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Our data indicate that special attention should be paid to selected patients who present with signs and symptoms of elevated ICP. Neurological symptoms, such as headaches, nausea

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and vomiting, were strongly associated with severe perioperative morbidity. No ICP monitors were used in this study because of the tendency in our center to use ICP monitor mostly in the setup of trauma but should be considered in future similar cases. Interestingly, seizures as a presenting symptom were associated with lower perioperative morbidity, perhaps due to earlier diagnosis and treatment and before the tumor grew into a significant life-threatening mass18-20.

ACCEPTED MANUSCRIPT 9 Several studies have suggested that GC involvement of specific brain structures may negatively affect outcome. Kaloshi et al.21 reported that the extent of gray matter involvement seems to correlate with poor prognosis, whereas Ware et al. reported improved survival in

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patients with involvement of the corpus callosum22. Based on our imaging data, neither the involvement of a particular cerebral lobe nor the number of involved lobes correlated with

perioperative morbidity. However, we did find that tumor involvement of midline structures,

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such as the thalamus and basal ganglia, correlated with perioperative morbidity. Patients who presented with a radiological appearance corresponding to occlusion of the basal cisterns, a

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midline shift of more than 5 mm, uncal, subfalcine or central herniation, but not tonsillar herniation, required additional treatment for lowering ICP by means of aggressive hyperosmolar infusion and even decompressive craniectomy. Interestingly, there was not much difference in the FLAIR-measured volume between the study and control groups. However, the mean contrast

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enhancing tumor volume as measured by T1Gd was more than three times higher in the study group compared to the controls. Notably, the study group had higher proliferation index as measured by Ki67. Taken all together, it seems that higher-grade component of the tumor as

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measured by the enhancing region in the MRI and high proliferation mitotic index induce more complicated clinical course that may require additional medical or surgical intervention for

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lowering the increased ICP. Importantly, despite the differences in MR imaging and pathological characteristics, there was no significant difference in pathological diagnosis between both groups, which may be related to sampling error during biopsy not providing the accurate pathological grade of the tumor. Several case reports have described the option of performing palliative surgery to decrease ICP in cases of life-threatening brain swelling or herniation in GC patients 23,24.

ACCEPTED MANUSCRIPT 10 Weinbergand et al.23, described the clinical course of three patients who underwent urgent posterior fossa decompression due to clinical and radiological signs of tonsillar herniation secondary to GC. Those authors could not identify any specific indications for surgery in this

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group of patients. Nevertheless, they recommended performing palliative decompression in patients whose symptoms correspond temporally to posterior fossa disease progression and

tonsillar herniation. In another case report25, Pérez-Bovet et al. described the clinical course of a

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48 year-old female who presented with lethargy and symptoms of high ICP secondary to GC. She underwent temporal lobectomy and survived 23 months after the procedure.

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Taken all together, the current data does not provide clear guidelines for treatment, but highlight the importance of identifying this unusual subset of patients who are at risk to develop ICP-related deterioration and may need precautionary measures. The current data perhaps support the idea that if decompressive craniectomy is performed earlier, before decompensation

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occurs, outcome may improve. Still, it is possible that a subset of patients presenting with imaging and pathological characteristics along with symptoms of increased ICP may have a

Conclusion

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worse clinical course and prognosis despite any medical or surgical intervention.

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Several clinical and radiological variables may predict the need for aggressive rapid treatment to control ICP among GC patients. Knowing these parameters may be useful for guiding decisionmaking in the management of this disease entity, optimize future management schemes to enable these patients to receive further oncologic treatment.

ACCEPTED MANUSCRIPT 11 References 1.

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pathology. 2007;17(3):304-307.

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ACCEPTED MANUSCRIPT 12 9.

Jennings MT, Frenchman M, Shehab T, et al. Gliomatosis cerebri presenting as intractable epilepsy during early childhood. Journal of child neurology. 1995;10(1):3745. Kim DG, Yang HJ, Park IA, et al. Gliomatosis cerebri: clinical features, treatment, and prognosis. Acta neurochirurgica. 1998;140(8):755-762.

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chemotherapy. Journal of neurosurgery. 1993;78(1):158-159. Vates GE, Chang S, Lamborn KR, Prados M, Berger MS. Gliomatosis cerebri: a review of 22 cases. Neurosurgery. 2003;53(2):261-271; discussion 271. Cohen AL, Colman H. Glioma biology and molecular markers. Cancer treatment and

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ACCEPTED MANUSCRIPT 13 18.

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Ware ML, Hirose Y, Scheithauer BW, et al. Genetic aberrations in gliomatosis cerebri. Neurosurgery. 2007;60(1):150-158; discussion 158.

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cerebri. Neuro-Chirurgie. 2013;59(2):85-88.

ACCEPTED MANUSCRIPT 14 Figure legends:

Figure 1. Kaplan-Meier survival curve for 78 patients diagnosed as having gliomatosis cerebri

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demonstrating a median overall survival of 3.1 months for the study patients compared to 14.7 months for the controls (p=0.46).

Figure 2. Representative MR FLAIR images, demonstrating the pre-operative imaging studies of

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35 years old female with gliomatosis cerebri involving the midline structures. This patient

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deteriorated after a needle biopsy and underwent an urgent decompressive craniectomy.

ACCEPTED MANUSCRIPT TABLE 1: Demographic and clinical characteristics of 78 patients with gliomatosis cerebri who did (study group) or did not (control group) have perioperative complications Control Group

10

68

53.4

52.6

Number of patients Age (yrs, mean)

8

KPS (median)

70

0.99

33

0.09

80

0.92

58 (85.3%)

0.3

58 (85.3%)

1

43 (63.2%)

0.5

1 (8.3%)

16 (23.5%)

0.4

0 (0%)

4 (5.9%)

1

6 (60%)

8 (11.8%)

0.002

2 (16.7%)

7 (10.3%)

0.1

16.7%

52.9%

0.03

100%

30.9%

<0.0001

Signs of elevated ICP (other)*

100%

26.5%

<0.0001

Motor deficit

16.7%

19%

1

Tumor location (n) Frontal lobe

10 (100%) 9(90%)

Parietal lobe

5 (50%)

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Temporal lobe

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Females (n)

p-value

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Study Group

Occipital lobe Posterior fossa Midline structures*

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Bilateral Presenting symptoms (n) Seizures*

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Headaches*

ACCEPTED MANUSCRIPT TABLE 2: Radiological and pathological characteristics of 78 patients with gliomatosis cerebri who did (study group) or did not (control group) have perioperative complications Study Group

Control Group

p-value

152.8

145.6

0.265

7.6 (33%)

0.<0.0001

33 (48.5%)

0.8

Mean FLAIR volume Mean contrast-enhancing volume (%patients)

29.8 (70%)

Pathological diagnosis, n 4 (33.3%)

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Low-grade (WHO II)

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Tumor volume, cm3

3 (25%)

33 (48.5%)

0.2

Oligodendroglioma

1 (8.3%)

0 (0%)

0.15

7(70%)

35 (51.5%)

0.8

5 (41.6%)

25 (36.8%)

0.75

3 (25%)

10 (14.7%)

0.4

12.4%

3.7%

0.012

7 (58.3%)

14 (20.6%)

0.01

0

50 (73.5%)

0.01

0

5 (7.4%)

0.4

3 (30%)

0

0.3

High-grade (WHO III + IV) Anaplastic astrocytoma GBM

Ki67 >5%*

Radiation Temozolomide

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Adjuvant Treatment

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Ki67

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Diffuse astrocytoma

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Radiation and temozolomide

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ACCEPTED MANUSCRIPT Highlights •

Subset of patients with GC who present with clinical and radiological signs of elevated ICP may quickly deteriorate even after minimal interventions

•

Several clinical and radiological variables may predict the need for aggressive rapid

•

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treatment to control ICP among these GC patients. Knowing these parameters may be useful for guiding decision-making in the

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management of this disease entity.

ACCEPTED MANUSCRIPT Abbreviation List: Gliomatosis cerebri=GC, Intracranial pressure=ICP Decompressive craniectomy=DC, Karnofsky score= KPS

Fluid-attenuated inversion recovery= FLAIR Intra cranial pressure=ICP Magnetic resonance imaging=MRI

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Anaplastic astrocytoma=AA

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Glioblastoma multiform=GBM