Acta Ophthalmologica 2015

Assessment and diagnosis of suspected glaucoma in patients with mucopolysaccharidosis Jane Ashworth,1 Maree Flaherty,2 Susanne Pitz3 and Azura Ramlee4 1

Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK 2 Department of Ophthalmology, The Children’s Hospital at Westmead, Sydney, NSW, Australia 3 Department of Ophthalmology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany 4 Department of Ophthalmology, Hospital Selayang, Kuala Lumpur, Malaysia

ABSTRACT. Purpose: The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders, characterized by the accumulation of glycosaminoglycans within multiple organ systems including the eye. This study aimed to determine the prevalence of glaucoma in patients with MPS, as well as the characteristics, diagnosis and management of patients with MPS and glaucoma. Methods: A multicentre retrospective case-note review was carried out by ophthalmologists from four tertiary referral centres to identify patients with MPS who had been treated for glaucoma. Clinical ophthalmological data were collected using standardized data collection forms. Results: Fourteen patients were identified (27 eyes) of 294 patients with MPS. The prevalence of glaucoma ranged from 2.1% to 12.5%. The median age at diagnosis of glaucoma was 8 years. Diagnostic evaluation of glaucoma was incomplete in many patients: intraocular pressure was documented in all eyes, but optic disc appearance was only assessed in 67%, central corneal thickness in 26%, visual fields in 19% and iridocorneal angle in 15%. Conclusions: Patients with MPS need regular assessment for possible glaucoma including during childhood. Multiple factors contribute to the challenges of assessment, diagnosis and monitoring of glaucoma in these patients. Key words: glaucoma – Hunter – Hurler – Hurler–Scheie – Maroteaux–Lamy – Morquio – mucopolysaccharidosis – prevalence – Scheie

Acta Ophthalmol. 2015: 93: e111–e117 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

doi: 10.1111/aos.12607

Introduction The mucopolysaccharidoses (MPS) are a group of rare inherited metabolic diseases, characterized by deficiencies of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). This leads to the accumulation of GAGs in lysosomes, resulting in progressive cellular damage and dysfunction of multiple tissues and organs. Clinical manifestations include

dysmorphic facial features, cardiovascular and respiratory problems, musculoskeletal and neurological problems and intellectual impairment (Muenzer 2011; Fahnehjelm et al. 2012a). Treatment such as enzyme replacement therapy (ERT), which is currently available for MPSI (Hurler), II (Hunter), IVa (Morquio) and VI (Maroteaux–Lamy), and haematopoietic stem cell transplantation (HSCT) for MPSI (Hurler) have been shown to

improve some systemic parameters and increase the life span of patients with MPS (Noh & Lee 2014). Ophthalmologic complications such as corneal clouding, retinopathy, glaucoma, optic nerve swelling and atrophy are caused by intra- and extracellular accumulation of GAGs in ocular tissues. Corneal clouding may be present from an early age in MPSI and VI (Ashworth et al. 2006; Ferrari et al. 2011; Summers & Ashworth 2011). Open-angle glaucoma may be caused by GAG deposits within the trabecular meshwork, causing outflow obstruction, while angle-closure glaucoma may result from changes in anterior segment morphology as a result of GAG accumulation (Ahmed et al. 2014). The current literature describes small numbers of MPS patients with glaucoma from single treatment centres with incomplete clinical details, including patients with MPS I (Quigley et al. 1975; Spellacy et al. 1980; Nowaczyk et al. 1988; Mullaney et al. 1996), MPS II (Kaiden et al. 1982), MPS IV (Cahane et al. 1990) and MPS VI (Cantor et al. 1989). This multicentre retrospective case review aimed to determine the prevalence, characteristics and management of suspected glaucoma in patients with MPS.

Methods A multicentre retrospective case review was carried out by ophthalmologists from four tertiary referral centres (Central Manchester NHS Foundation

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Trust, Manchester, United Kingdom; The Children’s Hospital at Westmead, Sydney, Australia; University Medical Centre, Mainz, Germany; and Hospital Selayang, Kuala Lumpur, Malaysia); the medical records of patients attending each hospital with a diagnosis of MPS were reviewed to identify all patients who were or had been treated for glaucoma, either medically or surgically. Data were collected using standardized data collection forms. In addition to demographic data and general clinical and treatment-related data regarding MPS, data regarding visual acuity (VA), intraocular pressure (IOP), optic disc appearance, iridocorneal angle, central corneal thickness (CCT), visual fields, other ocular findings (e.g. corneal clouding) and medical treatment for glaucoma were documented for each visit. The study adhered to the tenets of the Declaration of Helsinki, and written informed consent was obtained for all patients included in the study. If the date of diagnosis of glaucoma was not mentioned specifically in the data collection form, the date of first mentioning of ‘glaucoma’ at any reported visit report was used as the date of diagnosis. All variables were summarized using descriptive statistics, including mean, median and range (minimum and maximum values) for continuous variables, and numbers (N) and percentages for categorical variables.

Results Fourteen patients treated for glaucoma were identified (27 eyes), of a total of 294 patients with MPS. The prevalence varied between 2.1% and 12.5% according to the treatment centre (Table 1), with a mean prevalence of 6.8% (standard deviation 4.5). Seven of the 14 patients treated for glaucoma had MPS VI (Table 2). All reported visits took place between October 1997 and July 2012. The mean number of visits reported per patient was 5.5 (median: 5.0), and the mean time between the first and the last reported visit was 4 years (median: 3 years; range 0–13 years). Median age at MPS diagnosis and diagnosis of glaucoma was 2 and 8 years, respectively (Table 3). Eleven patients received ERT (Table 2); median age of starting ERT was 11 years (Table 3).

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Table 1. Prevalence of glaucoma by centre.

Country

Number of patients with MPS*

Number of eyes/ patients treated for glaucoma

Prevalence of glaucoma

United Kingdom Germany Australia Malaysia

95 150 25 24

4/2 13/7 4/2 5/3

2.1% 4.7% 8.0% 12.5%

* Only patients with MPS who underwent eye assessment in the respective centre were included.

Table 2. Patient characteristics. Number of patients treated for glaucoma in at least 1 eye (N = 14) MPS type: N (%) I (Hurler/Scheie syndrome) II (Hunter syndrome) III (Sanfilippo syndrome) IV A (Morquio A syndrome) VI (Maroteaux–Lamy syndrome) VII (Sly syndrome) IX (Natowicz syndrome) Enzyme replacement therapy: N (%) Yes No Unknown Haematopoietic stem cell transplantation: N (%) Yes No Unknown

4 2 0 1 7 0 0

(29%) (14%) (7%) (50%)

11 (79%) 2 (14%) 1 (7%) 0 10 (71%) 4 (29%)

Table 3. Age at diagnosis of mucopolysaccharidosis (MPS), at diagnosis of glaucoma, at start of enzyme replacement therapy (ERT) and at last reported visit for the 14 patients with MPS treated for glaucoma.

Pt (centre)

MPS type

Age at MPS diagnosis (yr)

Age at diagnosis of glaucoma (yr)

Age at ERT start (yr)

Age at last reported visit (yr)

1 (UK) 2 (Mal) 3 (UK) 4 (Aus) 5 (Mal) 6 (Ger) 7 (Mal) 8 (Ger) 9 (Ger) 10 (Ger) 11 (Ger) 12 (Ger) 13 (Ger) 14 (Aus) All

VI IV A I II I VI II VI VI VI VI I VI I Median Mean

1 2.5 2.3 20 0.5 12 5 12 5 5 2 – 1 1 2.5 5.3

6.2 7.8 6.5 20 1.4 – 7.5 35 3 28.4 – – 12.8 18.6 7.8 13.4

10.5 No ERT 2.3 44.6 3.0 16 No ERT 29 11 27 10 10 – – 10.8 15.9

17.7 11.0 8.2 47.4 3.8 20.3 7.5 37.6 13.0 30.0 16.3 20.7 14.0 18.6 17.0 19.0

Pt, patient; yr, year; –, data unknown. Centre: UK, United Kingdom; Mal, Malaysia; Ger, Germany; Aus, Australia.

Visual acuity was reduced (0.2 LogMAR or less) in all eyes treated for glaucoma. Visual acuity was significantly reduced to LogMAR 1.0

or less in 10 eyes of seven patients, and to light perception or less in six eyes of four patients (Table 4).

Acta Ophthalmologica 2015

Table 4. Characteristics of patients with mucopolysaccharidosis treated for glaucoma. Patients whose initials are in grey colour were treated (medically or surgically) for glaucoma before the first reported visit. Age is indicated at the first diagnosis of glaucoma. For corneal clouding and visual acuity (VA), values measured at diagnosis or at the first reported visit are indicated. For intraocular pressure (IOP), central corneal thickness (CCT), optic disc appearance and visual field assessment (VF), the maximum/worst measured value at any reported visit is indicated. In the column medical treatment, all treatments are listed that were prescribed at any reported visit.

Pt

Age (yr)

1

6.2

2

7.8

3

6.5

4

20

5

1.4

6



7

7.5

8

35

9

3

10

28.4

11



12



13

12.8

14

18.6

Eye

Corneal clouding

VA (LogMAR)

IOP (mmHg)

Optic disc Cup:disc ratio

CCT (lm)

VF

Iridocorneal angle

R L R L R

+++ +++ + + +

PL PL 0.6 (Sn) 0.6 (Sn) 0.475 (Lm)

91 89 31 30 60

(T)* (T)* (AT) (AT) (I)*,‡

0.7 0.7 0.4* 0.4* 0.6*

1090* 1099* 570* 596* 554*

– – – – –

N N – – A*

L

+

0.475 (Lm)

56 (I)*,‡

0.6*

560*



A*

R† L† R L R

+++ + + ++

no PL* 0.2 (Sn)* 0.8 (Cf) 0.8 (Cf) 0.4 (Sn)*

(I)* (I)* (I)* (I)* (AT)

1.0§ Normal 0.6 0.5 0.5

1097* 618* 591* 599* 610*

– A* – – –

L

++

0.5 (Sn)*

(AT)

0.5

610*

R L R

++

0.5 (Cf) 0.5 (Cf) 0.7 (Sn)

(I) (I) (AT)

0.6 0.2 Swollen

L R† L† R L

++ ++ ++ ++ ++

0.2 1.2 0.6 1.3 0.7

(AT) (AT) (AT) (P)* (AT)

R

++

0.5 (Sn)

L

++

0.3 (Sn)

R† L R L R L

+++ +++ +++ +++ +++

0.2 (Sn) PL 1.0 (Sn) 2.0 (Sn) PL PL

50 15 26 26 23 * 23 * 22 18 66 * 21 25 24 30 31 * 28 * 32 * 20 32 30 30 36 31

(Sn) (Sn) (Sn) (Sn) (Sn)

Diagnosis

Medical treatment

Surgery VPS VPS

– – – – –

BB, CAI, PGA BB, CAI, PGA BB, CAI BB, CAI AA, CAI, CA, PGA, comb, other AA, CAI, CA, PGA, comb, other PGA, comb, other PGA, comb, other CAI CAI AA, CAI, PGA





AA, CAI, PGA

543





PGA

636*

A



PGA, comb

Swollen N N N N

617* – – 667* 713*

A A A A A

– – – – –

PGA, comb None None CAI, comb CAI, comb

(AT)

N

736*





PGA, comb

(AT)

N

704*





PGA, comb

(AT) (AT) (P) (P)‡ (I) (I)

N N – – – –

520 566 – – 789 814

A – – – – –

– – – – – –

None PGA BB BB Unknown Unknown

PI

PI, Cr PI

TR/ MMC TR TR

KP

A = abnormal finding; N = normal finding; – = not assessed or impossible to assess (due to corneal clouding, non-co-operative patient, etc.) Corneal clouding: +: mild; ++: moderate; +++: severe. * Value measured while on medical treatment or after surgery for glaucoma. † All available measurements were taken after surgery for glaucoma or keratoplasty. ‡ Value measured after patient had not taken eyedrops for several days. § Value obtained from medical history, measured before the first reported visit. AT, applanation tonometry; AA, a-adrenergic receptor agonist; BB, b-adrenergic receptor antagonist; CA, cholinergic agonist; CAI, carbonic anhydrase inhibitor; CCT, central corneal thickness; Cf: Cardiff cards; comb, fixed combination b-adrenergic receptor antagonist/CAI; Cr, cyclocryotherapy; I, icare tonometry; KP, keratoplasty; Lm, LogMAR and card; NR, no response; P, palpation; PGA, prostaglandin analogue; PI, peripheral iridotomy/iridectomy; PL, perception of light; Sn, Snellen charts; T, tonopen; TR, trabeculotomy; TR/MMC, trabeculectomy with mitomycin C; VPS, ventriculoperitoneal shunt.

Intraocular pressure

IOP was measured in all eyes at the time of diagnosis. Applanation tonometry (including Goldmann tonometry, Perkins tonometry, tonopen) and icare tonometry (icareTA01i) were most commonly used (Table 4). Palpation was used to estimate IOP in the German

centre (three eyes of two patients; Table 4). IOP rose to high levels (greater than 30 mmHg) at some point during follow-up in 14 eyes of nine patients treated for glaucoma (Table 4). Three patients had undergone surgery before the first reported visit which may have

influenced their IOP readings (patients 4, 9 and 12). IOP varied significantly according to the technique used to measure it. In patients for whom icare tonometry was used, mean IOP at diagnosis was approximately 10 mmHg higher (32 mmHg; 95% CI: 23–42) than

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40

Mean IOP (mmHg)

35 30

31.4

30.5

25 20

20.4

18.5

15 10 5 0

Absent (N = 2)

Mild (N = 6)

Moderate (N = 10) Severe (N = 9)

Severity of corneal clouding Fig. 1. Mean intraocular pressure (IOP) in patients with mucopolysaccharidosis at the time of diagnosis of glaucoma according to the severity of corneal clouding (N = 27 eyes). If the diagnosis of glaucoma was made before the first reported visit, findings at the first reported visit were used. Error bars represent standard deviations.

in patients for whom applanation tonometry was used (23 mmHg; 95% CI: 20–25) (Mann–Whitney U-test: p = 0.0479). icare readings were higher than applanation tonometry for individual patients: patient 3 had icare readings of 56 mmHg (OS) and 38 mmHg (OD), while Goldmann applanation tonometry readings at the same visit were 27 mmHg (OS) and 26 mmHg (OD). Patient 11 had icare readings of 51 mmHg OD and 50 mmHg OS and applanation tonometry readings of 28 mmHg OD and 32 OS at the same visit. Optic disc appearance

Optic disc appearance was assessed in 18 eyes (67%) at the time of diagnosis of glaucoma. Evaluation of optic disc appearance became impossible at some time during follow-up in 15 of 27 eyes (56%) due to corneal clouding. The optic disc was cupped in 11 of the 23 eyes assessed at any reported visit (48%) (Table 4). Disc cupping was thought to be significant if there was a greater cup: disc ratio than had been previously documented (patient 1 and 3), or if the cup:disc ratio was asymmetrical (at least 0.2 difference) between the two eyes (patient 7). In patients 4 (left eye) and 9–12 (both eyes), the optic disc was described as normal without documentation of the cup:disc ratio.

and Pentacam in one patient (Table 4). As CCT was not measured simultaneously with IOP in all patients, we were not able to assess the correlation between IOP and CCT. Visual fields and iridocorneal angle

Visual field testing was only carried out for eight eyes (30%). The visual field was evaluated before diagnosis of glaucoma in only five eyes (19%), using either Goldmann visual field or standard automated perimetry with the Humphrey field analyser. All tests demonstrated visual field abnormalities. However, only one patient had documented progression of visual field loss (patient 4’s left eye had normal fields before diagnosis and marked peripheral constriction less than 10 degrees on Humphrey field analyser 13 years after glaucoma diagnosis). Five eyes had an increase in the mean deviation assessed by automated perimetry (patient 8 both eyes, patient 12 right eye, and patient 10 both eyes), and one patient had concentric reduction of peripheral field as assessed by Goldman field testing (patient 9 both eyes). Iridocorneal angle was only documented in four eyes (patients 1 and 3; 15%) (Table 4). Iridocorneal angle was normal in a boy with MPS VI and open-angle glaucoma (patient 1, assessed by anterior segment OCT) and abnormal in a girl with MPS I and CAG (patient 3, assessed by ultrasound biomicroscopy).

Central corneal thickness (CCT)

CCT was evaluated at at least one visit in 23 of 27 eyes (85%). Pachymetry was used to measure CCT in 11 patients, anterior segment OCT in two patients

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Other ocular findings

Corneal clouding was the most commonly reported ocular finding. It was

present at or before diagnosis in 25 of 27 eyes (93%), except for two eyes of two patients with MPS II (Table 4). Corneal clouding was moderate in 10 eyes (37%) and severe in nine eyes (33%). The severity of corneal clouding did not correlate with IOP at the time of diagnosis (Fig. 1), and there was no correlation between the severity of corneal clouding and CCT. Other reported ocular manifestations were strabismus (three patients), high hypermetropia (two patients), bullous/exposure keratopathy (two patients) and exotropia (two patients). Retinopathy was only documented in a single patient (patient 4). Medical and surgical treatment

In six of 21 eyes that received medical treatment (29%), initial therapy comprised more than one drop type. In 12 eyes, the type of medical treatment changed during follow-up. In total, 16 of 22 eyes (73%) received more than one type of medical treatment during their follow-up. The impact of medical treatment on IOP could be assessed in 12 eyes. In 7 eyes (58%), IOP was reduced after medical treatment. Two patients stopped treatment during follow-up. One of them was not compliant with treatment (Table 4, patient 13). A patient with MPS I (Table 4, patient 12) had undergone keratoplasty in the right eye 3 years prior to the first reported visit, following which IOP was reduced. Surgery (trabeculotomy, trabeculectomy with mitomycin C, peripheral iridotomy or keratoplasty) was performed in 7 eyes (26%) at a median age of 15 years (range: 3–33 years; N = 5) (Table 4). Both patients with CAG underwent peripheral iridotomy (PI) in at least one eye. Diagnostic evaluation of glaucoma

In 8 eyes (30%), neither optic disc cupping nor abnormal visual fields had been documented at any reported visit, and these eyes were only characterized by a highly elevated (≥30 mmHg) IOP and impaired VA. In seven of these eyes (patients 11, 12 OS, 13, 14), assessment of these parameters became impossible at some point during follow-up due to severe corneal clouding. In the majority of patients, it was not possible to distinguish between OHT and glaucoma from the evidence

Acta Ophthalmologica 2015

available (due to lack of documentation of progression of disc cupping and no visual field assessment in patients 2, 5 and 6; the documentation of ‘normal discs’ in patients 9 and 10; and ‘normal discs’ without visual field assessment in patients 11, 12 OS; no view of discs or visual field assessment in patients 13 and 14), and so, these patients could be considered to be glaucoma suspects (patients 2, 5, 6, 9, 10, 11, 12 OS, 13 and 14). Patients 1, 3, 4 OD and 7 OD could be classified as having glaucoma on the basis of raised IOP in addition to evidence of optic nerve damage (documented progression of disc cupping in patients 1 and 3; a high cup:disc ratio in patient 4 OD; asymmetrical disc cupping in patient 7).

Discussion This multicentre retrospective casenote review is the first case series to evaluate the assessment and diagnosis of glaucoma in patients with MPS and to determine its prevalence. Although several case reports have previously described glaucoma in patients with MPS I (Quigley et al. 1975; Lalive d’Epinay & Reme 1978; Spellacy et al. 1980; Nowaczyk et al. 1988; Girard et al. 1994; Mullaney et al. 1996; Sato et al. 2002; Lala-Gitteau et al. 2007), MPS II (Kaiden et al. 1982; Tchan et al. 2011), MPS IV (Cahane et al. 1990) or MPS VI (Cantor et al. 1989), the prevalence of glaucoma has never been specifically described in a multinational population comprising multiple MPS types. A single-centre retrospective study evaluated 50 MPS patients, finding only 1 MPS VI patient with glaucoma (Ashworth et al. 2006). One of 24 patients with MPSIVA from Taiwan (7%) had glaucoma (Lin et al. 2014). The estimated prevalence of glaucoma among patients with MPS in the current study is between 2.1% and 12.5%. Prevalence figures for open-angle glaucoma in the general population over 40 years of age has been estimated as 1.86% (Friedman et al. 2004) and for primary angleclosure glaucoma as 0.4% (Day et al. 2012), and the prevalence would be expected to be much lower in younger patients. However, our data may give an overestimation of the true prevalence in patients with MPS for several reasons. Only tertiary referral centres

who had treated at least 1 MPS patient with glaucoma contributed to this study. There may also be some bias in the MPS type seen at a particular centre, as six of seven patients treated at the German centre had MPS VI. As in the current literature, patients with MPS I, II, IV and VI were identified who had been treated for glaucoma (and not any patients with MPS III, MPS VII or IX). There was variation in prevalence of suspected glaucoma between different centres (12.5% in the Malaysian centre and 2.1% in the United Kingdom centre), and the centres with the lowest numbers of patients with MPS (Australia and Malaysia) had an apparently higher prevalence of glaucoma (8.0% and 12.5%). Only patients with MPS who were treated for glaucoma were included in this study, and so, this variation in prevalence may reflect differences in the threshold for starting treatment for glaucoma. Clinical guidelines for diagnosing and managing ocular manifestations in children with MPS (Fahnehjelm et al. 2012a,b) stipulate that assessments of IOP, optic nerve, visual field and iridocorneal angle are mandatory in all patients with MPS who are suspected to have glaucoma, while assessment of CCT can assist in the interpretation of IOP findings. However, in this study, optic disc appearance was only assessed in 67% of eyes suspected of having glaucoma, CCT in 26%, visual field in 19% and iridocorneal angle in 15%. None of the patients with MPS was reported to undergo all five evaluations. In four patients, there was insufficient clinical data to allow differentiation between OHT and glaucoma (patients 11, 12 OS, 13 and 14). There are multiple factors that hamper the assessment of glaucoma in patients with MPS. Corneal opacity was reported to hamper optic disc evaluation at some time during follow-up in 63% of eyes. Corneal clouding may also impair visualization of the drainage angle. Behavioural/intellectual impairment, physical disabilities and young age all effect the ability of patients with MPS to co-operate with the ophthalmic examination and visual field assessment and may limit the diagnostic evaluation (Ferrari et al. 2011). In addition, the presence of retinopathy causes constriction of

visual fields, particularly in patients with MPS I or II. Several factors may influence the reliability of IOP measurements in patients with MPS. Many patients with corneal clouding in MPS have thickened corneas, and it is well established that increased CCT can lead to falsely raised IOP readings (Friedman et al. 2004; Tonnu et al. 2005). A positive correlation has previously been demonstrated between IOP and CCT in patients with MPS I who had undergone HSCT (Connell et al. 2008), but not in patients with MPS II and MPS VI (Kottler et al. 2010). Corneal rigidity (hysteresis) has also been shown to influence IOP readings in patients with MPS (Fahnehjelm et al. 2012a,b), which may lead to difficulty in interpreting IOP measurements. The mean IOP in our patients at diagnosis measured with icare rebound tonometry was 10 mmHG higher than the mean IOP reading measured with (Goldmann) applanation tonometry, and two patients (patients 3 and 11) had a big difference in IOP readings using these techniques at the same visit. Previous studies in non-MPS patients with glaucoma or OHT have confirmed higher readings using rebound tonometry compared to applanation (Rehnman & Martin 2008; Martinezde-la-Casa et al. 2009; Flemmons et al. 2011; Gandhi et al. 2012; Vincent et al. 2012). IOP readings measured using icare tonometry in children with MPS should therefore be interpreted with caution and applanation tonometry used wherever possible. Difficulties in interpretation of IOP readings are also highlighted by the observed difference in IOP between grafted and nongrafted eyes within the same patient with MPS (patient 12). There are significant limitations of this retrospective case review. Although patients were included if they had or were currently being been treated for glaucoma, the criteria for treatment was not standardized, so that many patients were treated despite insufficient evidence to make a diagnosis of glaucoma (and who may be considered as glaucoma suspects). These limitations, however, reflect the difficulties faced by clinicians when assessing patients with MPS for glaucoma: variation in IOP depending on technique used, changes in CCT and corneal hysteresis which may affect

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IOP readings, difficulties in visualization of the angle and optic disc, unreliable visual fields due to poor co-operation and/or the presence of retinopathy. Glaucoma may be misdiagnosed if MPS is not considered as a cause of corneal clouding present in infancy or early childhood. In patient 9, the diagnosis of glaucoma was made prior to the diagnosis of MPS VI; trabeculotomy was carried out at 2 years of age, yet typical features of congenital glaucoma such as myopia, Haab’s striae and enlarged corneal diameters were not present, and optic discs and IOP were later assessed as normal. Patient 5 was treated for glaucoma at age 1 following the diagnosis of MPS; however, there was no documentation of corneal diameter or axial length or change in disc cupping which would have been helpful in evaluating the presence of glaucoma at this age. This study highlights the difficulties in diagnosing and monitoring glaucoma in patients with MPS and the importance of a thorough diagnostic evaluation of these patients by an experienced ophthalmologist who is familiar with the eye problems associated with MPS. Evaluation of IOP, CCT, optic disc appearance, visual fields and iridocorneal angle should be carried out whenever possible (Fahnehjelm et al. 2012a,b). Applanation tonometry is preferable to measure IOP. The ocular response analyser, where available, may be used to assess corneal hysteresis, leading to a more reliable measurement of IOP (Fahnehjelm et al. 2012a,b). Both ultrasound biomicroscopy and anterior segment OCT may be helpful to assess the anterior chamber angle (Ahmed et al. 2014), while the latter technique may also be applied to assess corneal thickness. In addition, posterior segment OCT or ultrasound of the optic nerve can be alternatives for ophthalmoscopy to assess optic disc appearance in patients with MPS. Additional tests may be helpful in the diagnosis of glaucoma, such as electroretinography in MPS I/II patients with a clinical suspicion of retinopathy (which may influence the results of visual field testing), and assessment of VEPs in patients with suspected optic nerve damage (Fahnehjelm et al. 2012a,b). It is hoped that the use of these techniques

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will help us to overcome some of the difficulties associated with the diagnosis of glaucoma in patients with MPS and to detect patients with glaucoma at an earlier stage, thereby reducing both over- and undertreatment. This study demonstrates that clinicians managing patients with MPS should ensure that they are regularly assessed for the presence of glaucoma, even in childhood. Visual outcomes are poor when a confirmed diagnosis of glaucoma is made, so ophthalmologists should exert caution when managing patients with MPS in whom they suspect glaucoma. A thorough diagnostic evaluation is important and early treatment when the IOP is considered to be genuinely raised, particularly when it is impossible to monitor the optic disc and visual field.

References Ahmed TY, Turnbull AM, Attridge NF, Biswas S, Lloyd IC, Au L & Ashworth JL (2014): Anterior segment OCT imaging in mucopolysaccharidoses type I, II, and VI. Eye 28: 327–336. Ashworth JL, Biswas S, Wraith E & Lloyd IC (2006): The ocular features of the mucopolysaccharidoses. Eye 20: 553–563. Cahane M, Treister G, Abraham FA & Melamed S (1990): Glaucoma in siblings with Morquio syndrome. Br J Ophthalmol 74: 382–383. Cantor LB, Disseler JA & Wilson FM (1989): Glaucoma in the Maroteaux-Lamy syndrome. Am J Ophthalmol 108: 426–430. Connell P, McCreery K, Doyle A, Darcy F, O’Meara A & Brosnahan D (2008): Central corneal thickness and its relationship to intraocular pressure in mucopolysaccararidoses-1 following bone marrow transplantation. J AAPOS 12: 7–10. Day AC, Baio G, Gazzard G, Bunce C, Azuara-Blanco A, Munoz B, Friedman DS & Foster PJ (2012): The prevalence of primary angle closure glaucoma in European derived populations: a systematic review. Br J Ophthalmol 96: 1162–1167. Fahnehjelm KT, Ashworth JL, Pitz S, Olsson M, T€ ornquist AL, Lindahl P & Summers CG (2012a): Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 90: 595–602. Fahnehjelm KT, Chen E & Winiarski J (2012b): Corneal hysteresis in mucopolysaccharidosis I and VI. Acta Ophthalmol 90: 445–448. Ferrari S, Ponzin D, Ashworth JL, Fahnehjelm KT, Summers CG, Harmatz PR & Scarpa M (2011): Diagnosis and management of ophthalmological features in

patients with mucopolysaccharidosis. Br J Ophthalmol 95: 613–619. Flemmons MS, Hsiao YC, Dzau J, Asrani S, Jones S & Freedman SF (2011): Icare rebound tonometry in children with known and suspected glaucoma. J AAPOS 15: 153–157. Friedman DS, Wolfs RC, O’Colmain BJ et al. (2004): Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 122: 532–538. Gandhi NG, Prakalapakorn SG, El-Dairi MA, Jones SK & Freedman SF (2012): Icare ONE rebound versus Goldmann applanation tonometry in children with known or suspected glaucoma. Am J Ophthalmol 154: 843–849. Girard B, Hoang-Xuan T, D’Hermies F, Savoldelli M, Bennouna M, Poenaru L, Maroteaux P & Pouliquen Y (1994): Mucopolysaccharidosis type I, Hurler-Scheie phenotype with ocular involvement. Clinical and ultrastructural study. J Fr Ophtalmol 17: 286–295. Kaiden JS, Schecter R, Bader BF et al. (1982): Angle closure in a patient with Hunter’s syndrome. J Ocul Ther Surg 1: 250–252. Kottler U, Demir D, Schmidtmann I, Beck M & Pitz S (2010): Central corneal thickness in mucopolysaccharidosis II and VI. Cornea 29: 260–262. Lala-Gitteau E, Majzoub S, Labarthe F, Blesson S & Pisella PJ (2007): Ophthalmologic signs in mucopolysaccharidoses: two case reports. J Fr Ophtalmol 30: 165– 169. Lalive d’Epinay S & Reme CE (1978): Congenital glaucoma in Hurler’s syndrome and in Lowe’s syndrome. Clinical and electron microscopy findings. Adv Ophthalmol 36: 80–89. Lin HY, Chuang CK, Chen MR et al. (2014): Natural history and clinical assessment of Taiwanese patients with mucopolysaccharidosis IVA. Orphanet J Rare Dis 9: 21. Martinez-de-la-Casa JM, Garcia-Feijoo J, Saenz-Frances F, Vizzeri G, FernandezVidal A, Mendez-Hernandez C & GarciaSanchez J (2009): Comparison of rebound tonometer and Goldmann handheld applanation tonometer in congenital glaucoma. J Glaucoma 18: 49–52. Muenzer J (2011): Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 50 (Suppl. 5): v4–v12. Mullaney P, Awad AH & Millar L (1996): Glaucoma in mucopolysaccharidosis 1-H/S. J Pediatr Ophthalmol Strabismus 33: 127– 131. Noh H & Lee JI (2014): Current and potential therapeutic strategies for mucopolysaccharidoses. J Clin Pharm Ther 39: 215–224. Nowaczyk MJ, Clarke JTR & Morin JD (1988): Glaucoma as an early complication of Hurler’s disease. Arch Dis Child 63: 1091–1093. Quigley HA, Maumenee AE & Stark WJ (1975): Acute glaucoma in systemic mucopolysaccharidosis I-S. Am J Ophthalmol 80: 70–72.

Acta Ophthalmologica 2015

Rehnman JB & Martin L (2008): Comparison of rebound and applanation tonometry in the management of patients treated for glaucoma or ocular hypertension. Ophthalmic Physiol Opt 28: 382–386. Sato S, Maeda N, Watanabe H, Tano Y, Inoue Y, Shimomura Y & Tanaka A (2002): Multiple iridociliary cysts in patients with mucopolysaccharidoses. Br J Ophthalmol 86: 933–934. Spellacy E, Bankes JL, Crow J, Dourmashkin R, Shah D & Watts RW (1980): Glaucoma in a case of Hurler disease. Br J Ophthalmol 64: 773–778. Summers CG & Ashworth JL (2011): Ocular manifestations as key features for diagnosing mucopolysaccharidoses. Rheumatology (Oxford) 50(Suppl. 5): v34–v40. Tchan MC, Devine KT & Sillence DO (2011): Three Adult Siblings with Mucopolysaccharidosis Type II (Hunter Syndrome): a Report on Clinical Heterogeneity and 12 Months of Therapy with Idursulfase. JIMD Rep 1: 57–64.

Tonnu PA, Ho T, Newson T, El Sheikh A, Sharma K, White E, Bunce C & GarwayHeath D (2005): The influence of central corneal thickness and age on intraocular pressure measured by pneumotonometry, non-contact tonometry, the Tono-Pen XL, and Goldmann applanation tonometry. Br J Ophthalmol 89: 851–854. Vincent SJ, Vincent RA, Shields D & Lee GA (2012): Comparison of intraocular pressure measurement between rebound, non-contact and Goldmann applanation tonometry in treated glaucoma patients. Clin Experiment Ophthalmol 40: e163–e170.

Received on June 9th, 2014. Accepted on October 25th, 2014. Correspondence: Dr. Jane L. Ashworth, BMBCh, FRCOphth, PhD Manchester Royal Eye Hospital Central Manchester University Hospitals NHS

Foundation Trust Manchester Academic Health Science Centre Oxford Road Manchester M13 9WL, UK Tel: +44 (161) 2761234 Fax: +44 (161) 2736354 Email: [email protected] This research was facilitated by the Manchester Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network. The authors are grateful to Ismar Healthcare NV for their data collection and writing assistance, which was funded by BioMarin Europe Ltd. Jane Ashworth received an educational grant and travel expenses from BioMarin Europe Ltd./Pharmaceutical Inc. Maree Flaherty received research grants from Genzyme Australia and BioMarin Pharmaceutical Inc., Asia Pacific. Susanne Pitz received travel grants, research grants and lecture honoraria from BioMarin, Shire and Genzyme. Azura Ramlee received a research grant from BioMarin Pharmaceutical Inc.

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Assessment and diagnosis of suspected glaucoma in patients with mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders, characterized by the accumulation of glycosaminoglycans within multip...
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