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Dr.Jayati Pandey, Dr.Mohan Shalini,Dr.Rajnath Singh Kushawaha,Prof.Gupta Ramesh Chandra

AIM: To compare Optic Nerve Sheath Diameter (ONSD) in Primary Open Angle Glaucoma (POAG), Primary Angle Closure Glaucoma (PACG) and Normal Tension Glaucoma (NTG).

MATERIAL AND METHOD: Patients with POAG (n=38), PACG (n=32), NTG (n=18) and Controls (n=48) underwent B-scan ultrasound and Computed Tomography Scan (CT scan) measurement of ONSD. Intraocular pressure (IOP) was measured in all groups and was correlated with ONSD.

RESULT: ONSD was significantly (p=<0.001) increased in NTG patients (mean=5.0mm ±0.48SD) compared with POAG (mean=4.20mm±0.32), PACG (mean=4.33mm±0.27) and control (mean=4.21mm±0.31). ONSD showed correlation with IOP in PACG group (r=0.392, p=0.02) while it did not in other groups.

CONCLUSION: ONSD in a group of NTG patients were significantly increased compared with POAG, PACG and controls indicating the role of translaminar cribriform pressure gradient in NTG patients.Indirect measurement of ICP by assessment of ONSD may provide further insight into retrolaminar pressure component and pathophysiology of glaucoma.

INTRODUCTION

Glaucoma  is  the  leading  cause  of  irreversible  blindness  affecting more  than  60  million  people  worldwide[1].  Glaucoma   is  a  chronic   progressive  optic  neuropathy  that  is   recognised  by  the appearance  of  characteristic  cupping  of  optic  disc  associated with  corresponding  visual  field  defects.  The  disease  is characterised  by  progressive  loss  of  retinal  ganglion  cells  &  their axons  associated  with  tissue  remodelling  of  the  optic  nerve head.

A  sustained  increase  in  intraocular  pressure(IOP)  may  be  due  to increased  formation  of  aquous  humor,  difficulty  in  exit  or  raised pressure  in  the  episcleral  veins.  Of  these  first  &  last  rarely occurs  and  it  follows  that  raised  intraocular  pressure  is essentially  due  to  an  increased  resistance  to  its  drainage  through  angle  of  anterior  chamber.

The  optic  nerve  is  derived  from an  out-pouching  of  the  diencephalon  (optic stalk)  during  embryonic  development.  As  a consequence,  the  fibres  of  the  optic  nerve  are  covered  with myelin  produced  by  oligodendrocytes,  rather  than  Schwann cells  of  the  peripheral  nervous  system,  and  are  encased  within  the meninges.  The  optic  nerve  is  ensheathed  in  all three  meningeal  layers  (dura,  arachnoid  and  pia  mater).  Its  diameter  increases from   about  1.6  mm  within  the  eye  to  3.5 mm  in  the  orbit  to  4.5 mm  within  the  cranial  space.  The  optic  nerve  component lengths  are  1 mm  in  the  globe,  24 mm  in  the  orbit,  9 mm  in  the  optic  canal,  and  16 mm  in  the  cranial  space  before  joining the  optic chiasm.[2]

The  optic  nerve  sheath  is  an  anatomical   extension  of  the duramater  and   so  the  subarachnoid  space  around  the  optic nerve  is  continuous  with  the  intracranial  subarachnoid  space. The  optic  nerve  is  separated  from  its  sheath  by  a  fluid  layer  of cerebral  spinal  fluid  (CSF),  which  is  in  continuity  with  the  rest  of  the  central  nervous  system.  The  lamina  cribrosa  at  the bottom  of  the  optic  nerve  head  acts  as  a  pressure  barrier between  the  intraocular  space  and  the  retrobulbar  space  of  the optic  nerve.  Increase  in  intra  cranial  pressure  (ICP)  lead  to  an increase  in  the  volume  of  the  fluid  layer,  thereby  increasing optic  nerve  sheath  diameter  (ONSD)  as  measured  in  the retrobulbar  portion  of  the  optic  nerve  trajectory.  Dilatation  of  the  optic  nerve  sheath  has  been  shown  to  be  a much  earlier  manifestation  of  ICP  rise.[3,4] The forces of IOP and CSF pressure meet at lamina cribrosa , a modified extension of peripapillary sclera flaps , composed of collagen and non collagen components.[5] The lamina cribrosa functions as barrier between the anterior force of IOP and posterior force of CSF-p within the orbit also known as Translaminar Cribriform Pressure Dfference(TLCPD)

TLCPD =   IOP – CSF-p     

The TLCPD depends on the IOP and the retrobulbar CSF pressure. The ability of lamina cribrosa to withstand pressure gradient without deformity is dependent on its thickness, the rigidity of extracellular matrix and peripheral sclera tension. The lamina cribrosa’s ability to maintain shape is important in protecting structures that pass through it. Increased TLCPD could cause bowing of the lamina cribrosa. Such deformity may damage optic nerve ganglion cells via mechanical compression or ischaemia as the vessels pass through the lamina cribrosa [6]. CSF-P and IOP have equivalent effects on TLCPD and optic disc surface movement. It was also found that CSF-P affects axonal transport of the optic nerve, which might have an effect on glaucoma aetiology and retinal venous outflow [7].

The ideal method to measure CSF pressure is lumbar puncture but it is an invasive modality with increased risk with various life threatening complications. It has been found that raised CSF pressure causes increased ONSD and vice versa [3, 4]. Therefore, measuring ONSD can be surrogate method to measure the CSF pressure and can throw some light in pathophysiology of various types of glaucoma.   The  optic  nerve  sheath  is  fairly  easy  to  visualize  by ultrasonography  by  insonation  across  the  orbit  in  the  axial  plane.  A-mode  ultrasonography  was  used  to  view  the  optic nerve  sheath  more  than  four  decades  ago;  B-mode  scanning  was  performed  subsequently  to  assess  intraocular  lesions[8]. Evolution  of  ultrasound  technology  and  the  development  of  high frequency  (> 7.5 MHz)  linear  probes  with  improved  spatial resolution  have  enabled  excellent  views  of  the  optic  nerve sheath.  The  ONSD,  measured  at  a  fixed  distance  behind  the retina  has  been  evaluated  to  diagnose  and  measure  intracranial hypertension  in  traumatic  brain  injury  and  intracranial haemorrhage[9,10]. Ultrasound-based  assessment  of  the  ONSD  is  a validated  method  for  indirect  measurement  of  the  ICP [10,11,12]. ONSD  is  much  easier  to  measure  on  Computed  Tomography scan   (CT scan)  than  with  sonography  due  to  the  good reproducibility  of  CT  and  the  lack  of  a  learning  curve.

OBJECTIVES : The objective of the study is to study  Optic  Nerve  Sheath  Diameter  in  patients  of  POAG , PACG and  NTG and to correlate it with IOP

MATERIALS AND METHODS

STUDY DESIGN

It is a hospital based cross sectional study.

Three cohorts of individuals over 18 years old were recruited for the study from department of  Ophthalmology LLR hospital Kanpur: patients with POAG (n=38),PACG (n=32), NTG(n=18) and healthy control (n=42). Glaucoma patients were defined on basis of intraocular pressure , having characteristic optic disc damage and visual field loss as described previously in the literature [13,14]. The healthy volunteers were screened by experienced ophthalmologists. Those with a family history of glaucoma, or an increased or asymmetrical cup/disc ratio or any other optic disc structural change (notching, disc hemorrhage), or an IOP above 21mmHg, were excluded as possible glaucoma suspects. Patients with a history of ocular trauma or eye disease (except glaucoma) that could not be accounted for by refractive error were excluded. Patients on antiglaucoma drugs or with any known neurological disorder was also an exclusion criterion.

The study was approved by the ethical review committee (Institutional Review Board) of our own institution and was conducted in accordance with Good Clinical Practice within the tenets of the Helsinki’s agreement. Each patient/subject was required to sign an informed consent statement before being enrolled into the study and prior to any study measurements being taken.

MEASURING DEVICES

IOP was measured with the Goldmann applanation tonometer (GAT). Central corneal thickness (CCT) was measured using a pachymeter (Pachscan, Sonomed, and U.S.A). Angle of anterior chamber was assessed by 2 mirror goniolens. Visual fields were assessed by Humphrey’s Perimeter (Zeiss, Germany ). Disc photograph was taken by Fundus camera (Zeiss Visucam Lite, Germany). Measurement of the ONSD was performed with a B-scan ultrasound probe (Sonomax, Montreal, Canada) and CT scan (Siemens, Germany).

EXPERIMENTAL DESIGN

During  the  study  visit,  the  following  examinations  were  be performed  in  the  same  order  :  BCVA   using  the  Snellen’s  chart placed  in  the  same  location  at  the  same  distance  from  the patient  under  the  same  illumination  for  all  subjects,  IOP measurement  by  Applanation  tonometer,  Angle  of  anterior chamber  by  goniolens,  Disc  photo  by  Fundus  Camera,  Visual field  by  Humphrey’s  perimeter,  and  finally  ONSD   measurements. Latter was performed by an observer masked to the patient diagnosis.  The  patient was made to  lie  in  the  supine  position  with  the  head in  a  neutral  position  and  both  eyes  closed  and  in  primary  gaze position.  After  application  of  coupling  gel    the  insonation  depth was  set  to  5–8  cm,  the  transducer was  softly  placed  over  the  upper eyelid  in  an  axial  plane.  This  sonographic  section  provides  a transverse  view  of  the  globe  and  the  structures  of  the retrobulbar  area .  The  ONSD  was   calculated  perpendicular  to  the  vertical  axis  of  the  scanning  plane  3mm  behind  the  globe,  where  the  optic  nerve  sheath  structure  is  more  prone  to expansion  due  to  increase  in ICP[15]  probably  due  to  a  decrease  in  sheath  thickness  in  that  retrobulbar  segment  of  the  optic nerve[4,16] .  Only  one  eye  per patient  was  included  in  the  study.  The  eye  with  greater glaucomatous  damage  was  selected  in  the  glaucoma  patients.

Brain  CT  scan  was  performed  with  a  series  of  millimetre  slices (one  slice  every  0.6  mm).  As  for  ultrasound, ONSD  was   measured  at  a  distance  of  3mm  behind  the  eyeball,  immediately  below  the  sclera[9,17] . ONSD  was  measured  transversely  as  a  section  through  the centre  of  the  optic  nerve.

STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS 21.0 (IBM SPSS Inc., Chicago, IL, USA) for Windows statistical package. The Mann-Whitney test was used to compare between two variables. The Kruskal-Wallis test was used to compare variables between four diagnostic groups. Spearman’s correlation coefficient was used to study association between variables. Probabilities are two-tailed and considered statistically significant if p<0.05.

RESULTS

VARIABLE POAG PACG NTG CONTROL
Number 38 32 18 48
AGE(in years) 50.50±6.49 50.94±7.35 56.4±10.4 50.23±6.48
VA (log MAR) 0.44±0.32 1.76±0.26 1.13±0.55 0.06±0.09
Mean IOP (in mmHg) 27.29±3.45 49.75±11.13 16.72±3.84 15.19±2.51
CCT( in µm) 527.60±10.26 543.19±8.24 504.83±14.27 520.1±13.66
MD -6.17±2.14 -11.35±2.02 -5.11±0.94 0.39±0.65
ONSD  on USG (in mm) 4.20±0.32 4.33±0.27 5.0±0.48 4.21±0.31
ONSD on CT (in mm) 4.23±0.33 4.35±0.26 5.01±0.5 4.20±0.27

VA – Visual Acuity ; IOP – Intra ocular pressure ; CCT – Central Corneal Thickness ; MD – Mean Deviation ; ONSD – Optic Nerve Sheath Diameter

In our study a total of 136 patients were evaluated out of which most were in 41-50 years age group (54.17%) whereas 41.67% were in 51-60 years and 4.16% in > 60 years age group. Overall prevalence in males were 61.76% and in females were 38.24%. Males outnumbered females in all the groups except in PACG group where females outnumbered males (62.5% females; 37.5% males). In our study ONSD was significantly increased in Normal Tension Glaucoma (5.0±0.48; p=0.00) compared to other groups and no significant correlation was found between IOP and ONSD in NTG group and POAG group(r=-0.209, p= 0.406; r=0.141, p= 0.398 respectively) while in PACG group there was mild positive correlation between IOP and ONSD which was significant(r=0.392, p=0.02).

DISCUSSION

The present study was conducted to evaluate the relevance of studying ONSD in glaucoma patients, and to study whether this indirect measurement of ICP correlates with IOP in these patients.

In the present study the ONSD in Caucasian NTG patients measured significantly (P=0.00) larger diameters compared to controls without ON diseases. The findings of larger ONSDs in NTG patients are in accordance with measurements in a study from Jaggi et al  (7.9±0.9mm) [18] and A Pircher et al (6.4±0.9mm) [19] who showed that ONSD in NTG patients was significantly increased (p<0.001) and contradictory to  Abegao Pinto et al[20] who did not find any significant difference in ONSD among NTG , POAG and Control (p=0.08) which may be due to difference in  the methodology used or difference in head position scanning between these two groups.

The TLCPD is not the only factor affecting optic nerve head but it is also the thickness of the wall separating these compartments i.e. lamina cribrosa. An abnormally thin sclera has been seen in NTG patients [21] which results in increased stress on optic nerve in these patients.

Two mechanisms explain the enlarged ONSDs in NTG patients. First a localized CSF-Pressure elevation behind the globe due to impaired CSF outflow might lead to increased radial stress to the optic nerve sheath and thereby stretching the optic nerve sheath. Second, an accumulation of proteins of different biological functions [22].

In our study no significant correlation was found between IOP and ONSD in NTG group and POAG group(r=-0.209, p= 0.406; r=0.141, p= 0.398 respectively)  while  in PACG group there was  mild positive correlation between IOP and ONSD which was significant(r=0.392, p=0.02) whereas study conducted by Abegao  Pinto  L et  al[20] showed that  OSND did  correlate  with  IOP  in  NTG  patients(r=0.53; p<0.001)  but  not   in  POAG  patients  and  healthy controls(p=0.46 , P=0.86). The difference in Pinto et al study from our study may be because in all the patients IOP and ONSD was not measured on same day or same point of time, diurnal variation of IOP was not taken in to consideration. Since no study has been conducted regarding ONSD in PACG group hence, result cannot be compared.

LIMITATIONS OF STUDY

Our work has several limitations. As a full neurological examination was not performed in these patients, a direct measurement of intracranial pressure was not included thus intracranial pressure was presumed to be normal by taking history so there is possibility of  contamination of the experimental groups by individuals with a yet undiagnosed neurological clinical  condition. The sample size in NTG group was very small compared to other groups so further studies with larger sample size is required to confirm our result. In some patients IOP and ONSD could not be measured on same day or same point of time , hence changes due to diurnal variation in IOP could give different result.

CONCLUSION

It is the trans-lamina cribrosa pressure difference (and not the transcorneal pressure difference, i.e. the so called intraocular pressure) which is of importance for the physiology and pathophysiology of glaucoma.Indirect measurement of ICP by assessment of ONSD may provide further insight into retrolaminar pressure component and pathophysiology of glaucoma.ONSD measurement can be used as a useful tool for diagnosing NTG in early stage as ONSD greater than 5 mm might be indicator of greater glaucomatous damage in NTG patients. ONSD measurement through USG-B scan and CT scan being a non invasive procedure can be used as an alternate method of measuring CSF-pressure in glaucoma patients as well as in other neurological diseases.

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