Clinical Presentation and Outcome of Patients With Optic Pathway Glioma

Accepted Manuscript Title: Clinical Presentation and Outcome of Patients with Optic Pathway Glioma Author: Viviane Robert-Boire, Lorena Rosca, Yvan Samson, Luis H Ospina, Sébastien Perreault PII: DOI: Reference:

S0887-8994(17)30386-7 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.019 PNU 9189

To appear in:

Pediatric Neurology

Received date: Revised date: Accepted date:

20-4-2017 29-6-2017 30-6-2017

Please cite this article as: Viviane Robert-Boire, Lorena Rosca, Yvan Samson, Luis H Ospina, Sébastien Perreault, Clinical Presentation and Outcome of Patients with Optic Pathway Glioma, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.019. 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.

Clinical presentation and outcome of patients with optic pathway glioma Viviane Robert-Boirea, Lorena Roscaa, Yvan Samsonb, Luis H Ospinac, Sébastien Perreaulta a

Department of pediatrics, Division of Child Neurology, CHU Sainte-Justine, Montreal, QC, Canada b Department of pediatrics, Division of hemato-oncology, CHU Sainte-Justine, Montreal, QC, Canada c Department of ophthalmology, CHU Sainte-Justine, Montreal, QC, Canada Viviane Robert-Boire: [email protected] Lorena Rosca: [email protected] Yvan Samson: [email protected] Luis H Ospina: [email protected] Sébastien Perreault: [email protected] Corresponding author: Sébastien Perreault CHU Sainte-Justine 3175 Chemin de la Côte-Sainte-Catherine, Montreal, QC H3T 1C5 Canada [email protected] Word count (excluding abstract, references, tables and figures): 2170 Complete title: Clinical presentation and outcome of patients with optic pathway glioma Running title: Clinical presentation of OPG

Page 1 of 25

ABSTRACT Background: Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study is to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. Methods: We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation and outcome were collected. Results: Forty patients were retrieved. Of those, 23 patients had sporadic tumors (57.5 %) and 17 had NF1 related tumors (42.5 %). Among the children with NF1, there was a significant overrepresentation of females (82.3 %) (P=0.02), while among the children without NF1, there were slightly more males (56.5 %) than females (43.5 %). The presence of nystagmus was strongly associated with sporadic OPGs. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis and optic nerve atrophy. Of 40 patients, 5 died of OPG complications (12.5 %) and all had sporadic tumors. Conclusion: Our study is one of the largest cohorts of OPGs with detailed description of clinical presentation at diagnosis and progression. We observed a significant difference between sporadic and NF1 OPGs in terms of demographics, clinical presentation and outcome.

KEYWORDS NF1; neurofibromatosis; optic pathway glioma; pilocytic astrocytoma; pediatric tumor; clinical presentation

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INTRODUCTION Optic pathway gliomas (OPGs) are low-grade tumors with unpredictable clinical outcome that mainly affect children under 6 years old1. Histologically, OPGs are primarily pilocytic astrocytomas (World Health Organization (WHO) grade I)2. The most significant risk factor for OPG is neurofibromatosis type 1 (NF1). NF1 gene codes for the neurofibromin protein, a tumor suppressor 3,4. Approximately 15 to 20 % of children with NF1 will develop an OPG1,5. Conversely, children without neurofibromatosis may also develop sporadic OPGs. The molecular pathogenesis of sporadic OPGs is yet to be understood but the most common genetic alteration in sporadic tumors is a duplication of the proto-oncogene BRAF6,7. Despite the fact that OPGs are low-grade neoplasms, patients with OPGs may show a variety of symptoms and signs at diagnosis, particularly decreased visual acuity, proptosis, strabismus, nystagmus, headaches, seizures and precocious puberty8,9. Some authors suggest that sporadic OPGs are associated with a greater risk of visual loss than OPGs related to NF110-12. In this study, we retrospectively reviewed clinical presentation and outcome of children diagnosed with OPG at our institution over the course of 15 years.

METHODS A retrospective study was conducted at CHU Sainte-Justine from January 1st, 2000, through December 31st, 2015. Patients were included if they had a diagnosis of OPG. Patients were excluded if the follow-up was less than 1 month.

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The age at diagnosis, gender, NF1 status, tumor location, signs and symptoms at diagnosis, duration of follow-up, treatment modality, tumor response to treatment, symptomatic progression and complications were reported. Tumor location was defined as the most posteriorly involved structure: pre-chiasmatic, chiasmatic or post-chiasmatic. The tumor was considered bilateral when both optic nerves were affected or when the chiasma was predominantly involved, and unilateral when only one optic nerve was affected. Progression on MRI was defined as an increase of 20% in the longest diameter or apparition of new areas of abnormalities. In preverbal patients, visual acuity was tested with Teller Acuity CardsTM, while in verbal patients, visual acuity was analyzed with Snellen or Allen Acuity CardsTM. Visual decline was defined as category deterioration in the WHO Categories of Childhood Visual Impairment scale13. If visual decline was seen in one eye, despite visual stability of the other eye, it was considered that visual acuity loss occurred. Statistical analyses were performed using Fisher’s exact test, chi-square analysis, and unpaired t-test.

Survival was calculated by the Kaplan-Meier made curves and

comparisons using the log-rank (Mantel Cox) test. SPSS Statistics, version 24.0 (IBM, Armonk, NY) was used for all analyses. The log-rank test was used to determine the statistical significance of progression and survival differences between patients’ subgroups. P-values less than 0.05 were considered significant.

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RESULTS Patients’ characteristics A total of 40 patients with OPG were included in our retrospective study (Table 1). Seventeen patients were diagnosed with NF1 and 23 had sporadic OPG. While the distribution of females and males was balanced among patients without NF1, there were significantly more females with NF1 and OPG (14 females vs 3 males, P=0.02). Among the 40 patients, 11 (27.5 %) had strictly prechiasmatic involvement which was more common in patient with NF1 (47.1% vs 13.0 %, P=0.04).

Signs and symptoms at diagnosis Most patients (65.0%) were symptomatic prior to diagnosis (Table 2). The most common symptom was headache (32.5 %), followed by squinting (25.0 %) and decreased vision (22.5 %). Patients and their families also reported nausea (12.5 %), dizziness (7.5 %), convulsions (7.5 %) or developmental regression (5.0 %). Among the 40 patients, 6 were asymptomatic at diagnosis (15.0 %) and showed no ophthalmological findings. Of those, 5 patients with NF1 were diagnosed when a routine MRI was requested. One sporadic OPG was an incidental finding and the patient remained asymptomatic. As expected, patients without neurofibromatosis were more likely to be symptomatic (91.3 %) than the patients with neurofibromatosis (29.4 %) (P <0.01). Squinting was the only symptom that was more likely to be reported by patients with sporadic tumors than patients with neurofibromatosis (P <0.01).

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The majority of patients had clinical findings on physical examination at diagnosis (85.0 %) (Table 2). The most common signs were decreased visual acuity (47.5 %), followed by optic atrophy (42.5 %) and nystagmus (32.5 %). No patient showed precocious puberty prior to the diagnosis of OPG. Nystagmus was the only sign that was strongly related to sporadic tumors (P <0.01). Of the 13 patients with nystagmus, 9 had spasmus nutans, while 4 had nystagmus retractorius associated with Parinaud’s syndrome. Eye movement deficit was found in 9 patients. Four of them had 6th nerve palsy secondary to increased intracranial pressure, 3 had vertical gaze palsy associated with Parinaud’s syndrome and 2 had restrictive eye movement deficit related to a retro-ocular glioma. Proptosis was more likely to occur in patients with prechiasmatic involvement (P=0.01) whereas nystagmus was exclusively found in tumors with chiasmatic or postchiasmatic involvement (P=0.02). The other clinical findings did not correlate with age at diagnosis or tumor location. All patients with headache had other symptoms and/or signs. The most common symptom of the patients with headache was nausea found in 5 patients, followed by dizziness in 3 patients, convulsions in 2 patients and developmental regression in one patient. On physical examination, the most common signs were visual acuity deficit and papilloedema, both found in 5 patients with headache complaints.

Clinical presentation at progression A total of 31 patients (77.5 %) had tumor progression on MRI. Six (19.3%) had stable vision, whereas the remaining showed radiological and visual deterioration.

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The most common sign of progression was vision acuity loss, found in 20 patients (50.0 %). Of those, 12 patients (60.0 %) reported decreased vision prior to the ophthalmological exam. The most common signs and symptoms at progression by NF1 status are detailed in supplementary Table 1.

Visual outcome Children who developed progressive vision loss were younger than those who did not develop it (median = 2.4 years versus 4.6 years), but the difference did not reach statistical significance (supplementary Table 2). Moreover, gender, NF1 status and tumor location were not related to visual outcome. However, tumor extension was associated with visual outcome; 90 % of patients with progressive vision loss had bilateral OPG compared to 10 % with unilateral OPG (P <0.01). The most common sign at diagnosis of patients with poor visual outcome was visual acuity deficit, found in 55.0 % of patients. Hydrocephalus at diagnosis was found in 8 patients and was correlated with poor outcome with progressive vision loss (P=0.04). Two signs were associated with visual acuity loss during follow-up: progressive visual field deficit found in 11 patients (55.0 %) (P=0.01) and optic nerve atrophy noticed in 13 patients (65.0 %) (P <0.01). It should be noted that 6 patients with visual acuity deterioration were asymptomatic at diagnosis. Three of them showed no clinical findings on ophthalmological examination at diagnosis. Their age at diagnosis was 1.0, 2.9 and 3.7 years old. Visual loss was demonstrated 6, 17 and 32 months after diagnosis. One patient had a strictly unilateral prechiasmatic involvement, whereas one had a bilateral chiasmatic OPG and one had

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bilateral involvement of the optic nerves, chiasm and optic tracts. The patient with unilateral prechiasmatic OPG became eventually blind in her affected eye despite treatment. Loss of visual acuity was preceded by optic nerve atrophy in 2 of the 3 patients. In the remaining patient, the first visual acuity loss was noted with concomitant optic nerve atrophy onset.

Treatment Most patients from our cohort received treatment for their OPG, whereas 8 (21.1 %) were strictly observed (Supplementary Table 3). Of these, two patients were asymptomatic (25.0 %), while the remaining 6 were symptomatic at diagnosis (75.0 %), but showed no clinical progression during the period of follow-up. Mortality The overall survival (OS) rate was 87.5 % for all patients. There was a statistical difference between the survival rate of NF1 patients (100 %) and patients with sporadic tumors (78.3 %) (P =0.02). Five patients (12.5 %), 4 boys and 1 girl, died from tumor progression. Their median age at diagnosis was 0.7 years (range: 0.4-2.6 years). All patients had a bilateral sporadic OPG; 3 had chiasmatic involvement and 2 had post-chiasmatic involvement. At diagnosis, all 5 patients had eye movement deficit, nystagmus and hydrocephalus. Prior to their death, 4 of them had been treated; all received chemotherapy and one received radiotherapy. The death was attributable to intracranial hemorrhage in 2 patients and to tumor growth/hydrocephalus in 3 patients. The median duration between diagnosis and death was 5 months (range: 1-116 months).

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Sporadic tumor, eye movement deficit, nystagmus, convulsions and hydrocephalus at diagnosis were associated with a worse survival (Figure 1). The OS did not vary in regard to age, gender and tumor location or laterality.

DISCUSSION Our study is one of the largest cohorts of OPGs with detailed description of clinical presentation at diagnosis and progression. We were able to correlate our observations to tumor location, NF1 status and outcome. In terms of demographics, our study is representative of previous reports. Within our cohort, 42.5 % had NF1 and 57.5 % had sporadic tumors. It is generally accepted that patients with NF1 account for approximately 33 to 60 % of patients with OPGs and the remaining 40 to 66 % have sporadic OPGs 10,14-24. Interestingly, gender distribution varied significantly between the patients with or without NF1 (P = 0.02). Among the children with NF1, the majority were female (82.3 %), while among the children without NF1, there were slightly more males (56.5 %) than females (43.5 %). While some studies have reported a more balanced distribution between males and females, others have also reported that more females with neurofibromatosis develop OPGs 1,12,25-29. The physiopathological mechanism responsible for this discrepancy is yet to be determined, but might be related to epigenetic phenomenon. Within our study population, pre-chiasmatic OPGs were more commonly found in neurofibromatosis patients, whereas there was no statistical difference in chiasmatic and postchiasmatic OPGs. It has been recognized that OPG related to NF1 are more

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frequently prechiasmatic, whereas sporadic OPGs involve the chiasmatic and postchiasmatic region9,11,23,30. As expected, all patients with sporadic OPGs, except one, had new symptoms or signs at diagnosis. The most common symptom was headache, found in 9 patients, which is often not specific in children. However, headache was associated with other symptoms and signs suggestive of an intracranial lesion in all patients. In our study, nystagmus was characteristic of sporadic tumors. Nystagmus might be observed more often in non-NF1 population since the chiasmatic region is typically affected in case of spasmus nutans and large chiasmatic lesions are susceptible to induce hydrocephalus and Parinaud’s syndrome. Wan et al., who only evaluated children with sporadic OPGs, listed nystagmus as the most common sign (27 %), followed by visual acuity loss (25 %)31. In our study, a relatively high number of children with NF1 were symptomatic (65.0 %). This can be explained by the fact that we have decreased the use of routine MRI in search of OPG in asymptomatic NF1 patients. This clinical practice is supported by several studies which suggested there is no benefit to identify asymptomatic OPGs in patients with NF1

32,33

. Five patients with NF1 were asymptomatic at time of diagnosis. Three of

those 5 patients eventually had visual deterioration and were treated between 6 months and almost 3 years after diagnosis. There is no evidence that an early detection and initiation of treatment would have changed the outcome. Worst visual outcomes have been reported in patients with sporadic OPG others found no correlation

12,22,34

10,16,30

, while

. In our study, children with and without

neurofibromatosis were as likely to have progression, either symptomatic or on MRI. As

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Kaufman and Doroftei stated, the relationship between OPG aggressiveness and sporadic tumors may be biased8. The asymptomatic patients with sporadic OPGs are only diagnosed by incidental finding, whereas asymptomatic patients with NF1 linked to OPG are diagnosed by neuroimaging screening. Therefore, the asymptomatic patients without neurofibromatosis will be screened out, altering the results towards more aggressive tumors for patients with sporadic tumor. Furthermore, in some studies, risk factors for visual deficit included younger age at presentation27,31,34, optic nerve atrophy at presentation31,34 and postchiasmatic involvement16,31,34,35. A total of 5 patients died during the time of follow-up. All of them had sporadic tumors, with chiasmatic or postchiasmatic involvement and hydrocephalus which is consistent with other studies

16,24

. It should be noted that mortality was only observed in young

infants.

CONCLUSION Our study described clinical presentation and outcome of patients with OPGs. We observed significant difference between patients with sporadic OPGs when compared to OPGs associated with NF1. The majority of NF1 OPGs were more frequently found in females, involved more often the prechiasmatic region and had a better outcome. Nystagmus was exclusively found in tumors involving the chiasmatic region and in patients with sporadic tumors. Poor visual outcome was related to tumors affecting both optic pathways, hydrocephalus at diagnosis, progressive visual field deficit and optic nerve atrophy. Eye movement deficit, nystagmus, convulsions and hydrocephalus at diagnosis were associated with a higher rate of mortality.

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ACKNOWLEDGEMENTS We would like to acknowledge the work of Linda Hershon, Research Nurse at CHU Saint-Justine, for her logistic support. REFERENCES 1.

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Wright, J.E., McNab, A.A. & McDonalrd, W.I. Optic nerve glioma and the management of optic nerve tumours in the young. British Journal of Opthalmology 73, 967-974 (1989).

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FIGURE 1. Comparison of overall survival between the type of tumor or clinical manifestations at diagnosis A: In children with or without NF1 (Log Rank = 0.05). B: In children with or without nystagmus (Log Rank <0.01). C: In children with or without eye movement deficit (Log Rank <0.01). D: In children with or without hydrocephalus (Log Rank <0.01).

Time

(months) since diagnosis

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TABLE 1. Demographics of children with OPG Number of patients (%) Total

NF1 +

n = 40 (%)

n = 17 (%)

n = 23 (%)

3.5

3.5

3.4

Range (years)

0.4-14.2

1.0-9.1

0.4-14.2

≤ 2 years

14 (35.0)

6 (35.3)

8 (34.8)

2-5 years

12 (30.0)

7 (41.2)

5 (21.7)

≥ 5 years

14 (35.0)

4 (23.5)

10 (43.5)

6.8

9.1

5.7

0.1-15.8

0.1-15.8

0.1-14.3

Female

24 (60.0)

14 (82.3)*

10 (43.5)

Male

16 (40.0)

3 (17.6)

13 (56.5)

Prechiasmatic

11 (27.5)

8 (47.1)**

3 (13.0)

Chiasmatic

19 (47.5)

5 (29.4)

14 (60.9)

Postchiasmatic

10 (25.0)

4 (23.5)

6 (26.1)

Variable

Sporadic

Age at diagnosis Median age (years)

Follow-up Median duration (years) Range (years)

Gender

Tumor location

Page 17 of 25

*Statistically significant P = 0.02, ** P = 0.04

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TABLE 2. Symptoms complain and clinical signs at diagnosis Number of patients (%) Total

NF1 +

Sporadic

n = 40 (%)

n = 17 (%)

n = 23 (%)

No clinical complain

14 (35.0)

12 (70.6)

2 (8.70)

Symptomatic

26 (65.0)

5 (29.4)

21 (91.3)*

Decreased vision

9 (22.5)

3 (17.6)

6 (26.1)

Headache

13 (32.5)

4 (23.5)

9 (39.1)

Convulsions

3 (7.50)

-

3 (13.0)

Nausea

5 (12.5)

2 (11.7)

3 (13.0)

Dizziness

3 (7.50)

1 (5.88)

2 (8.70)

Squinting

10 (25.0)

-

10 (43.5)**

Developmental regression

2 (5.00)

-

2 (8.70)

No clinical sign

6 (15.0)

5 (29.4)

1 (4.4)

With clinical findings

34 (85.0)

12 (70.6)

22 (95.7)

Ophthalmological findings

33 (82.5)

11 (64.7)

22 (95.7)***

Proptosis

7 (17.5)

4 (23.5)

3 (13.0)

Visual acuity deficit

19 (47.5)

5 (29.4)

14 (60.9)

Visual field deficit

7 (17.5)

1 (5.9)

6 (26.1)

Eye movement deficit

9 (22.5)

2 (11.8)

7 (30.4)

SYMPTOMS COMPLAIN

CLINICAL SIGNS

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Nystagmus

13 (32.5)

-

13 (56.5)****

Strabismus

10 (25.0)

2 (11.8)

8 (34.8)

Optic atrophy

17 (42.5)

7 (41.2)

10 (43.5)

Papilloedema

10 (25.0)

5 (29.4)

5 (21.7)

Hydrocephalus

10 (25.0)

2 (11.8)

8 (34.8)

2 (5.0)

1 (5.9)

1 (4.4)

Growth retardation

*Statistically significant P <0.01, ** P <0.01, *** P 0.03, **** P <0.01

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SUPPLEMENTARY TABLE 1. Clinical manifestation at progression of OPG Number of patients (%) Total

NF1 +

Sporadic

n = 40 (%)

n = 17 (%)

n = 23 (%)

No progression

8 (20.0)

3 (17.6)

5 (21.7)

Progression

32 (80.0)

14 (82.4)

18 (78.3)

On MRI

31 (77.5)

13 (76.5)

18 (78.3)

Signs and symptoms

25 (62.5)

11 (64.7)

14 (60.9)

Vision acuity loss

20 (50.0)

8 (47.1)

12 (52.2)

Optic atrophy

14 (35.0)

7 (41.2)

7 (30.4)

Visual field loss

13 (32.5)

5 (29.4)

8 (34.8)

Precocious puberty

6 (15.0)

1 (5.90)

5 (21.7)

Proptosis

6 (12.5)

5 (29.4)

1 (4.30)

Papilloedema

3 (7.50)

3 (17.6)

3 (13.0)

Hydrocephalus

3 (7.50)

2 (11.8)

1 (4.3)

Developmental regression

3 (13.0)

-

3 (13.0)

Progression

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SUPPLEMENTARY TABLE 2. Visual outcome after diagnosis of OPG Number of patients (%) Progressive visual acuity Stable visual acuity loss Criteria

n = 18 (%)

n = 20 (%)

Age at diagnosis 2.39 (0.42-14.17)

4.60 (0.40-9.32)

Female

10 (50.0)

12 (66.7)

Male

10 (50.0)

6 (33.3)

NF1+

8 (40.0)

8 (44.4)

Sporadic

12 (60.0)

10 (55.6)

13 (65.0)

16 (88.9)

7 (35.0)

2 (11.1)

Unilateral

2 (10.0)

10 (55.6)

Bilateral

18 (90.0)*

8 (44.4)

Median (years) Gender

Tumor location No postchiasmatic involvement Postchiasmatic involvement Tumor laterality

Presentation at diagnosis

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Asymptomatic

6 (30.0)

8(44.4)

Proptosis

4 (20.0)

3 (16.7)

Visual acuity deficit

11 (55.0)

7 (38.9)

Visual field deficit

6 (30.0)

1 (5.6)

Eye movement deficit

6 (30.0)

1 (5.6)

Nystagmus

8 (40.0)

4 (22.2)

Strabismus

4 (20.0)

4 (22.2)

Optic atrophy

8(40.0)

9 (50.0)

Papilloedema

5 (25.0)

3 (16.7)

Hydrocephalus

8 (40.0)**

1 (5.6)

Proptosis

4 (20.0)

1 (5.6)

Visual field deficit

11 (55.0)***

2 (11.1)

Eye movement deficit

1 (5.00)

-

Optic atrophy

13 (65.0)****

1 (5.6)

Papilloedema

2 (10.0)

-

Hydrocephalus

3 (15.0)

-

Progressive symptoms

Statistically significant *P <0.01, ** P=0.04, *** P=0.01, **** P<0.01

Page 23 of 25

SUPPLEMENTARY TABLE 3. Treatment Modalities Number of patients (%) Total

NF1 +

Sporadic

n = 38 (%)

n = 16 (%)

n = 22 (%)

No treatment

8 (21.1)

4 (25.0)

4 (18.2)

Chemotherapy

24 (63.2)

11 (68.8)

13 (59.1)

Radiotherapy

7 (18.4)

3 (18.8)

4 (18.2)

Surgery

20 (52.6)

3 (18.8)

17 (77.3)

Biopsy only

5 (25.0)

-

5 (29.4)

Resection/Debulking

15 (75.0)

3 (18.8)

12 (70.6)

Treatment

Page 24 of 25

Figure 1.

Page 25 of 25