Intracranial hypertension

Definitions, etiologies and symptoms of intracranial hypertension included. Relevance of intracranial hypertension to ophthalmologist and grading of papilledema discussed. Detailed discussion of Idiopathic Intracranial Hypertension (IIH), including the diagnostic criteria, clinical and radiological diagnosis, management and monitoring of IIH discussed.

1. Intracranial Hypertension Dr. Obaidur Rehman Ophthalmology resident Government Medical College &Hospital Chandigarh

2. Contents Symptoms Relevance to ophthalmologist Modified Frisen’s grading Idiopathic Intracranial Hypertension

3. Definitions Intracranial pressure (ICP) - pressure exerted by cranium on the brain tissue, CSF, and the brain’s blood volume - constantly fluctuates in response to physical activities - normally less than 20 mm Hg i.e. 26 cm of water (usually 7-15 mm Hg in supine adults) ( J Neurosurg  1991; 74 :597–600) Intracranial volume ~ 1700 mL Brain 80% (1500 mL ) CSF 10% (150 mL ) Blood 10% (150 mL ) ( Neurology 2001: 56:1746-48)

4. Intracranial hypertension Generally, ICP above 20 mm Hg or 25 cm water is considered as raised Mild : 20-30 mm Hg Moderate : 31-40 mm Hg Severe : > 41 mm Hg ( Neurol Clin . 2008;26(2):521-x) The definition of raised ICP can vary with specific pathology - Hydrocephalus: >15 mm Hg regarded as elevated ( Journal of Neurology, Neurosurgery & Psychiatry  2004; 75: 813-82)

5. CSF circulation Production Choroid plexus of - lateral ventricles - third ventricle - fourth ventricle 500 cc/day i.e around 20 cc/hour ( Nature Communications 2018:9(1):2167)

6. CSF absorption Absorption through arachnoid villi Dural sinuses Jugular venous system Absorption of CSF also occurs though lymphatic system Neurol Med Chir 2015

7. Monro -Kellie doctrine Cranium is a rigid structure, with 3 main components Volume remains fixed Compensatory changes occur when one component increases ( Neurol. 2001: 56:1746-48) Increase in the volume of contents increased pressure within the cranial vault Autoregulation Cerebral perfusion pressure = Mean arterial pressure minus Intracranial pressure Clinical implication: ICP Cerebral blood flow Brain herniation

8. Etiology Neurologic clinics 2008:  26 (2): 521

9. Symptoms Headache: most prominent symptom - compression of duramater - traction on blood vessels Nausea Projectile vomiting Visual disturbances Lethargy, confusion Late symptoms: stupor, decreased level of consciousness Severity of intracranial hypertension has no correlation with severity of symptoms

10. Relevance to the ophthalmologist Variety of visual symptoms - decreased vision - diplopia - visual field loss - contrast deficits - transient visual obscurations Papilledema is the hallmark of intracranial hypertension Chronic intracranial hypertension can lead to irreversible visual loss

11. Development of papilledema High intracranial pressure High CSF pressure in subarachnoid space Compression of optic nerve Axoplasmic stasis & Venous stasis due to central retinal vein compression Swelling of the optic nerve head   Eye Brain . 2015;7:47-57

12. Modified Frisen’s grading     (J Neurol Neurosurg Psychiatry  1982;45 (1) 13- 18) Grade 0: Normal optic disc Well defined borders No halo of obscuration of the peripapillary nerve fiber layer Grade 1: Minimal degree C-shaped halo with a temporal gap Obscures underlying details Temporal margin normal

13. Grade 2: Low degree Circumferential halo Elevation of nasal border No major vessel obscuration Grade 3: Moderate degree Obscuration of 1 or more major vessels leaving the disc Circumferential halo All borders elevated

14. Grade 4: Marked degree Total obscuration of a segment of major vessel on the disc Elevation of all borders Total border obscuration Grade 5: Severe degree Obscuration of all vessels on disc and leaving disc

15. Papilledema is almost always bilateral - unilateral in Foster Kennedy syndrome - rarely in idiopathic intracranial hypertension   J Neurosci Rural Pract . 2017;8:106-10 Absence of papilledema does not rule out intracranial hypertension

16. Idiopathic Intracranial Hypertension (IIH) Rare disorder; ‘Idiopathic’ - No etiology is known Diagnosis of exclusion Historical perspective ‘Meningitis serosa ’ by Quincke in 1897 After introduction of lumbar puncture in medicine In 1937, Dandy demonstrated high CSF pressure in patients with suggestive symptoms ‘ Pseudotumor cerebri ’ : papilledema in absence of brain tumor ‘Benign Intracranial Hypertension’ : coined in 1950s Not used now; disease is not benign, as thought earlier

17. ‘Idiopathic Intracranial Hypertension’ preferred term - introduced by Corbett and Thompson Certain disorders and drugs have shown association with IIH Argument to use umbrella term ‘ Pseudotumor cerebri syndrome (PTCS)’ - only primary cases to be called IIH - others to be called ‘secondary intracranial hypertension’ - not yet universally accepted Neurology 2013;81;1159-1165 Despite being known for around 125 years, still no general consensus on this disease

18. Sociodemographics Worldwide incidence: 1.8 per 100,000 population Not known in India Mainly affects young, obese females Incidence in females 15-44 years: 11.1 per 100,000 Prevalence in men found to be 10% Incidence in children: 0.5 - 0.9 per 100,000 Ophthalmology 2017; 124:697-700

19. Pathophysiology Exact mechanism inconclusive Several theories have been put forward 1. Imbalance in CSF circulation - most accepted theory - decreased absorption from arachnoid villi or lymphatics (Am J Physiol 1998; 275:889–96) 2. Role of hormones - possible role of hormonal activity of Adipose tissue - Insulin modulation and leptin generation could hold a key in understanding pathogenesis - could explain the higher incidence in females ( Br J Neurosurg . 2008; 22:187–94.)

20. 3. Role of Vitamin A - few studies have noted high Retinol levels in CSF of IIH patients - toxic accumulation of Vit . A metabolites suggested as the cause - exact role not known ( J Neuroophthalmol . 2007; 27:258–62) 4. Transerve Sinus Stenosis - found in several IIH patients - still not established whether it is causative or is a result of IIH itself ( Eur Neurol  2011; 66:334–38)

21. Associations of IIH (secondary IIH) (Am J Clin Dermatol  2020; 21:163–72.) Called ‘secondary IIH’ Can also be addressed as ‘Drug induced IIH’ Strong Association Tetracyclines Vitamin A analogues Lithium Steroid withdrawal Weak association Oral Contraceptive Pills(OCPs) Cyclosporine Nalidixic acid Fluoroquinolones

22. Symptomatology Symptom Frequency Headache 84% Transient Visual obscurations 68% Backache 53% Pulsatile tinnitus 52% Dizziness 50% Vision loss 32% Double vision 18% JAMA Neurol 2014; 71:693-701

23. Headache - most common symptom - no characteristic phenotype: can be diffuse/frontal/ occipetal / ocular - associated with photophobia/ phonophobia /nausea - severity of headache related to quality of life Pulsatile tinnitus - patients report hearing ‘intracranial noises’ - due to turbulent flow in stenosed sinuses Radicular pain - dural sheaths of spine getting filled up by CSF under high pressure

24. Ocular signs and symptoms Visual acuity - remains unaffected in most patients - chronic papilledema may reach central 10 degrees of field and affect vision - visual acuity not a sufficient indicator of visual function loss Transient visual obscurations (TVOs) - episodic blurring of vision/black out - transient ischemia of optic nerve head - lasts for few seconds

25. Visual field defects - seen in around 92% patients - half are unaware of field deficits at presentation - enlarged blind spot: most common followed by nasal defects (Brain 1991; 114:155-80) Contrast sensitivity (CS) deficits - can pick up subtle visual function deficits even in presence of intact visual acuity - CS deficits have been seen in 75% patients - sensitive indicator of visual function loss (Ophthalmology 1986; 93:4-7)

26. Development of field defect - papilledema : forward protrusion of the optic nerve head and peripapillary retina - hyperopic peripapillary retina and a reduction in visual sensitivity blind spot enlargement - other defects: related to dysfunction or damage to nerve fiber bundles ( Invest Ophthalmol Vis Sci. 2016;57:805–812) CS deficit development - r etinogeniculate pathways between retina and visual cortex: Magnocellular pathway: contrast detection over a range of luminances Parvocellular : acuity and colour processing - Engorgement of these pathways due to papilledema may hold a key to CS loss . The Visual Neuroscience. Cambridge, MA: MIT Press 2004:481–93.

27. Diplopia - seen in 10-20% patients - due to 6 th nerve palsy (false localising sign) - owing to the long course 6 th nerve traverses intracranially (Eye 1998; 12:111-18) Fundus findings - papilledema is the ophthalmic hallmark of IIH - absence does not rule out IIH if suggestive signs and symptoms present - optic nerve dysfunction and vascular compromise may lead to optic atrophy in chronic cases permanent visual loss

28. Investigations OCT scan - non-invasive, sensitive and objective - provides quantitative, continuous data that correlates with the modified Frisen’s grade - ability to pick up subtle changes that may no be apparent on fundoscopy Parameters RNFL thickness: significantly increased in more than 90% eyes - sensitive indicator in monitoring IIH - higher thickness noted even in eyes of IIH patients without papilledema - only parameter seen to vary significantly before and after CSF removal Eur J Neurol 2019; 26:808-e57

29. Neuro -retinal rim thickness and area - significant increase seen in IIH patients ONH cup volume - reduction seen in IIH - zero cup volume seen in several patients fluid collection in ONH and expansion of neuro -retinal rim compress the cup Macular GCL plus inner plexiform layer (IPL) (GCL–IPL) - remains mostly unchanged - not affected by ONH swelling, even in severe papilledema Clinical Neurology and Neurosurgery 2015;130: 122–27

30. Enhanced depth imaging (EDI)-OCT - imaging deep ocular structures and to improve the image quality of deeper structures - visualize structures 500–800 μm deeper than with conventional OCT - anterior displacement of lamina cribrosa in IIH (due to reduced trans-LC pressure difference i.e. IOP – CSF pressure) Eur J Ophthalmol 2017; 27 (1): 55-61

31. Configuration of Bruch’s membrane on EDI-OCT - upward defection of Bruch’s membrane toward the vitreous - due to raised ICP - differentiating papilledema from pseudopapilledema Ann Eye Sci 2018;3:35

32. Magnetic Resonance Imaging Rule out other causes of raised ICP - space occupying mass lesions, hydrocephalus Venography – to look for thrombosed cerebral venous sinuses Most common finding in IIH : distended perioptic subarachnoid space (95% patients) - transmission of high ICP into subarachnoid space within optic nerve sheath - sensitivity: 80% - specificity: 96% - normal: 4.8-6.2 mm 2 (Current Problems in Diagnostic Radiology 2019; 49:205-14)

33. Partially empty sella (85% patients) - due to flattening of Pituitary gland - result of chronically elevated ICP - concavity of superior part of Pituitary - sensitivity: 88%; specificity: 92% - sella turcica houses the pituitary gland - CSF filling turcica compresses the pituitary Current Problems in Diagnostic Radiology 2019; 49:205-14

34. Tortuous optic nerve (62% patients) - optic nerve fixed proximally at orbital apex, distally at the globe - middle portion is free and mobile - High ICP leads to kinking of the mid portion - sensitivity: 40% specificity: 91% Flattening of posterior part of globe (43-71% patients) - due to high ICP - sensitivity: 43% - specificity: 100% Current Problems in Diagnostic Radiology 2019; 49:205-14

35. Other MRI findings - meningocoeles (incidence: 11%) - prominent Meckel’s cave (incidence 9-11%) - enlarged foramen ovale (incidence not known) Lumbar puncture (LP) Guarded LP should be performed when high ICP suspected Diagnostic as well as therapeutic Shows elevated CSF opening pressure in IIH ( >25 cm of water) CSF sample collected sent for analysis to rule out other pathologies

36. Diagnosis of IIH Modified Dandy's Criteria 1. Symptoms of raised intracranial pressure – headache, nausea, vomitting , transient visual obscurations or papilledema 2. No localizing signs with the exception of Abducens nerve palsy 3. Patient is awake and alert 4. Normal CT/MRI findings without evidence of thrombosis 5. Lumbar puncture (LP) opening pressure of >25 cm of water and, normal biochemical and cytological composition of CSF 6. No other explanation for raised intracranial pressure   J Clin Neuro-ophthalmol  1985; 5:55–6.

37. IIH diagnosis in absence of papilledema - suggestive signs and symptoms of raised ICP - CSF opening pressure on Lumbar puncture > 25 cm of water - characteristic MRI findings present

38. Adult IIH Pediatric IIH Incidence 1.8 per 100,000 0.9 per 100,000 Sex ratio F >> M F = M Relation with obesity High preponderance in obese individuals No such preponderance. Predilection for overweight patients begins only after puberty (hormonal change) Systemic associations With obstructive sleep apnoea . Not well established Hypoparathyroidism Thyroid replacement therapy T reatment with recombinant human growth hormone CSF opening pressure for diagnosis > 25 cm of water > 28 cm of water (sedation leads ro hypercapnia Leads to artefactual CSF pressure elevation)

39. Management No defined guidelines for treatment and monitoring exist

40. Acetazolamide - carbonic anhydrase inhibitor - decreases ion and water transport across choroid plexus - reduces CSF production - no standardised fixed regimen of dose/duration - previous studies have used doses of 1 gm daily to upto 4 gm daily (Invest Ophthalmol Vis Sci. 2016;57:805–812) - Side effects: parasthesias , lethargy - Monitor SERFT Contra-indicated in liver failure/renal failure

41. Topiramate - weak CA inhibitor Added advantages - weight reduction - side-effect profile better - used in migraine prophylaxis - no standardised regimen - has been used in doses of 25 mg to 100 mg daily - side effects: parasthesias , lethargy, drowsiness - inadequate as a lone treating agent; can be used in combination with Acetazolamide   Curr Treat Options Neurol . 2013;15(1):1-12

42. Surgical management No clear recommendations exist Tried in patients with rapidly progressive neuropathy and when medical treatment fails CSF diversion procedures - lumboperitoneal shunting (LPS) - ventriculo -peritoneal shunting (VPS) - failure rates high: LPS (11%) ad VPS (14%) - revision rates even higher: LPS (60%) and VPS (30%) Optic nerve sheath decompression - in patients with severe visual loss - improves papilledema but no effect on ICP Indian J Ophthalmol 2014;62:996-8.

43. VPS is more effective but more challenging ONSD

44. To study efficacy of Acetazolamide in conjunction with weight reduction in IIH with mild visual loss F:M = 30:1 1 gm Acetazolamide in divided doses versus placebo in 165 IIH patients Gradually raised to 4 gm in some patients, depending on severity At 6 months, patients receiving the drug had better visual field outcomes Patients receiving the drug also reported significant improvement in quality of life

45. 6% mean body weight loss was seen in patients who had complete resolution of marked papilledema Average 3% body weight loss in patients who had downgrading of papilledema ( BMC Ophthalmol 2007; 7:15) Patients receiving Acetazolamide and Topiramate - achieved significant improvement in visual fields - significantly lowered CSF pressure at 6 months than patients receiving Acetazolamide alone (Bali Medical Journal 2018; 7: 201‑4.)

46. Thesis data on IIH 30 IIH patients F 22 M 8 Mean age 33.27 ± 10.68 years Avg BMI 26.59 ± 4.76 kg/m 2 (obese category for Asians)

47. Baseline visual parameters recorded 70% eyes had 6/6 Snellen visual acuity at presentation 98.3% eyes had papilledema at presentation Follow up at 1 month and 3 month post treatment Contrast sensitivity and RNFL thickness: the only parameters that showed significant difference even after one month of therapy initiation RNFL thickness was the only parameter that correlated significantly with grade of disc edema

48. T. Acetazolamide 750-1000 mg/day in divided doses T. Topiramate 25-50 mg/day if intolerant to acetazolamide or not improving on Acetazolamide alone

49. Prognosis of IIH Difficult to ascertain for each individual patients Stable course in most while few may suffer permanent visual loss Lumbar puncture is associated with relief in headache symptoms Acetazolamide associated with improvement in visual outcome and quality of life Weight gain is a poor prognostic factor   J Obes . 2017;2017:5348928.

50. Take home message All patients with chronic headache must undergo fundus examination Even in absence of papilledema , diagnosis of intracranial hypertension should be kept in mind when suggestive signs and symptoms present Contrast sensitivity testing and RNFL thickness are useful for monitoring and follow up Thank you!