179 Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 REVIEW ARTICLE Neuroimaging in Neuro-Ophthalmology (Systematic Review) Tayyaba Gul Malik 1 , Khalid Farooq 2 1 Department of Ophthalmology, Rashid Latif Medical College/Arif Memorial Teaching Hospital, Lahore 2 Department of Radiology, Lahore Medical and Dental College/Ghurki Trust Teaching Hospital, Lahore ABSTRACT There are quite a number of neurological diseases, which initially present to the ophthalmologists. Based on the proper history and clinical findings ophthalmologist have to suggest the ancillary neuro-imaging to support their provisional diagnosis and reach the site of lesion. Unless the ophthalmologists are aware of the right imaging at right time and at right area to focus, there are many pitfalls. MRI and CT of the brain and orbit are important investigations in neuro-ophthalmology which if intelligently ordered can add to the diagnostic and management process. In general, MRI is the most commonly ordered investigation in neuro-ophthalmology with so many additional sequences as FLAIR, GRE, diffusion weighted imaging, spectroscopy, in addition to T1 and T2 weighted imaging. Having said that CT scan has its advantages in cases of bony pathologies and acute brain hemorrhages. This article reviews the indications and importance of different neuro-imaging techniques, based on the previous studies from 1997 to 2019. Key Words: Neuro-ophthalmology, Magnetic Resonance imaging, Optic neuritis, Papilledema, Visual Pathway, Optic tract, Optic nerve, Meningioma, Glioma. How to Cite this Article: Malik TG, Farooq K. Neuroimaging in Neuro-Ophthalmology (Systematic Review). Pak J Ophthalmol. 2020, 36 (2): 179-188. Doi: 10.36351/pjo.v36i2.1026 INTRODUCTION Neuro-imaging is an important part of neuro- ophthalmology but it cannot replace a thorough clinical examination. Rather ordering a relevant neuro- imaging test depends upon a detailed history and thorough evaluation in the clinics. Suggesting a right investigation at a right time can save time as well as money. It is very important for the ophthalmologists to have sufficient knowledge about which investigation is required in a particular case, when to use contrast, which views (coronal, axial, sagittal) are important in which case and which sequence is necessary. Keeping Correspondence: Tayyaba Gul Malik Department of Ophthalmology, Rashid Latif Medical College/Arif Memorial Teaching Hospital, Lahore Received: January 1, 2020 Accepted: March 20, 2020 a radiologist fully informed about the positive clinical findings and the provisional diagnosis along with the area of interest in neuro-imaging is also a mandatory part of neuro-imaging, failing which can lead to pitfalls in diagnosis. At times, the definite clinical findings are not supported by neuro-imaging, in which case it is important to have a detailed discussion of the case with the radiologist. Sometimes very thin slices of a particular area of interest are required and which are missed in general thick slice scans. At other times, some additional investigation is needed to prove a definite clinical diagnosis. The purpose of this review article was to find out which neuro-imaging tests are commonly used in neuro-ophthalmology and what were the presenting complaints of the patients for which these investigations were suggested. Keeping in view the published data an exercise is done to make clear when Neuroimaging in Neuro-Ophthalmology Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 180 to order which of the neuro-imaging test to save time and money by avoiding wrong investigation or right investigation in wrong time and area. METHODS PRISMA guidelines were followed for this systematic review. A literature search was conducted on the 11 th November 2019. NCBI Pubmed database was used with search terms „neuroimaging‟ and „neuro- ophthalmology‟ (1997 to 2019). One hundred and eighteen results were found. Articles with un- accessible full articles, duplicates and irrelevant articles were excluded. We were left with 70 items. This produced a list of 19 review articles, 19 original articles and 29 case reports or case series. Review articles were not included in this review. Studies, which did not use neuro-imaging in diagnosis of neuro-ophthalmology cases, were excluded from our study. We also excluded articles, which were published only as abstracts or were presented only in conferences without publication. One of the study was also removed because it did not mention the type of imaging used in the study. The flow chart for data retrieval is shown below. RESULTS In 19 original articles, total number of patients were 1350 (858 females and 492 males), with age ranging from 1 year to 81 years. There were 14 retrospective studies, 2 case control studies, 2 cross sectional studies and 1 interventional study. There were 29 case reports/case series, which included 72 patients (45 females and 27 males) with age ranging from 3 months to 89 years. Neuro-imaging was done for complaints of diplopia, decreased vision, visual field defects, swollen optic discs, headache, pulsatile tinnitis, nausea, vomiting associated with headache, ocular motor nerve palsies, Horner syndrome, nystagmus, presumed cortical blindness, supranuclear gaze palsy, ptosis and as part of investigation in cases of neurofibromatosis. The final diagnoses included idiopathic intracranial hypertension, meningioma, glioma of visual pathway, multiple sclerosis, trochlear headache, Pituitary adenoma, Craniopharyngioma, ischemic strokes, hemorrhages, aneurysms, herpes simplex encephalitis, Stenosis of dural sinuses and cerebral venous sinus thrombosis. Diagnoses of case reports and series included; Hair dresser syndrome, Pseudotumor Cerebri, Horner Syndrome, Tolosa-Hunt Syndrome, Sixth Nerve Palsy, Migraine, Amyloidosis, Encephalopathy Syndrome, Orbital Apex Syndrome, Behr Syndrome, Optic Nerve Hypoplasia, 4th Nerve Palsy, Pituitary Apoplexy, Eight and a half syndrome, Cholesterol Granuloma of the Sphenoidal sinus, Craniopharyngioma and Alzheimers Disease. Other neuro-imaging results included Arnold Chiari Malformation, Carotico-Cavernous Fistula, Vertebrobasilar ischemia, cerebral edema, non- Hodgkin's Lymphoma, ectopic posterior pituitary gland, Rathke's cleft cyst, carcinomatous meningitis secondary to metastatic breast cancer, neurosarcoidosis and Carotid artery dissection. MRI scan was the most commonly ordered investigation followed by CT scan. Other ancillary sequences were done when initial MRI and CT were normal. The investigations, which were done in decreasing order of frequency were as follows: MRI, CT, MRV, CT Angiography, MRA, FLAIR, PET, DTI and Diffusion Tensor Tractography, Arteriography. After excluding review articles, we were left with 19 original articles and 29 case reports/ case series. Medline search was done on 11 th November 2019 with words „Neuro-Imaging‟ and „Neuro- Ophthalmology‟ (data between 1997 to 2019). 118 articles found. Articles with un-accessible full articles, duplicates and irrelevant articles were excluded. Tayyaba Gul Malik, et al 181 Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 Table 1: Details of original articles (neuro-imaging in neuro-ophthalmology from 1997 to 2019). Author Study Design Sample Size Provisional Diagnosis Neuroimaging Findings Gondi KT, et al, 13 2019 Case control study 53 IIH (Idiopathic intracranial hypertension) MRI, CT, MRV Empty sella, globe flattening, prominent perioptic cerebrospinal fluid, venous sinus stenosis Park KA, et al, 14 2019 Retrospective 127 Ocular motor nerve palsies MRI Inflammatory lesions and neoplasms Koytak PK, et al, 15 2018 Retrospective 35 Optic nerve sheath meningioma MRI Diagnosis of Optic nerve sheath meningioma was confirmed Bursztyn LLCD, et al, 16 2018 Retrospective 92 Optic Neuritis MRI 83.7% positive results for on MRI Khadse R et al, 17 2017 Retrospective 40 Optic Neuritis MRI Isolated optic nerve enhancement, demyelinating foci in frontal lobe and parieto-occipital lobe Kowal et al, 18 2017 Retrospective 24 Optic tract lesions MRI, FLAIR Ischemic strokes, tumors, hemorrhages, vascular malformation, demyelination, encephalitis Aguilar-Pérez M et al, 19 2017 Retrospective 51 IIH MRI, MRV Empty sella, Stenotic dural sinuses Chang RO, et al, 20 2016 Retrospective 12 IIH MRI Empty sella Ming Ge, et al, 21 2015 interventional 11 Optic pathway gliomas Diffusion Tensor Tractography Diagnosis of Optic nerve Gioma was confirmed J. H. Smith, et al, 22 2014 Retrospective 25 Trochlear headaches MRI and CT Normal imaging Balk LJ, et al, 23 2014 case control study 222 MS MRI, FLAIR, DTI Integrity of the optic radiations (FA) was significantly impaired in patients with MS. Atrophy of the visual cortex, grey and white matter. Kennedy de Blank PM, et al, 24 2013 Retrospective 50 Optic pathway gliomas MRI /DTI Optic nerve axons and myelin sheath integrity was disturbed Mehta et al, 25 2012 Retrospective 157 Optic neuropathy and cranial nerve palsies. CT, CTA, MRI, MRA, MRV 28.9% of neuroimaging tests requested by neuro-ophthalmologists resulted in an abnormal finding S. Ambika, et al, 26 2010 Retrospective 50 IIH CT, MRI, MRV 25 normal, others had empty sella and stenotic dural sinus Agarwal P, et al, 27 2010 Retrospective 308 IIH MRI, MRV 35 patients had cerebral venous sinus thrombosis Wolfe S, et al, 28 2008 Cross sectional 125 Miscellaneous conditions MRI, CT .18% Positive imaging Lee AG, et al, 29 2005 Retrospective 91 Optic tract lesions MRI, CT 93 normal, lesions found in 18 cases Mcfadzean R, et al, 30 1998 Cross sectional 100 Isolated 3rd nerve palsy CTA 72 were normal, aneurysm in 18 and 10 had other abnormalities Jacobson DM, 31 1997 Retrospective 71 Parieto occipital lobe lesions MRI Parieto occipital lobe lesions confirmed Table 2: Details of case reports/case series (neuro-imaging in neuro-ophthalmology; 1997 to2019). Authors No. of Cases Diagnosis Neuroimaging Findings Jonathan A, et al, 32 2019 3 Hair dresser syndrome CT/CTA or MRI/MRA) Vertebrobasilar ischemia Tommy L.H. et al, 33 2018 3 IIH MRI, MRV Bilateral Dural Venous Sinus Stenosis Karti DT, et al, 4 2018 1 Horner syndrome CT, MRI (cervical) Multiple spinal root cysts between C7 and T1 segments Ravindran K, et al, 35 2017 1 Tolosa–Hunt Syndrome MRI/Cerebral Angiogram Inflammatory stranding of the right orbital apex and extension into the lateral wall of the right cavernous sinus Neuroimaging in Neuro-Ophthalmology Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 182 Authors No. of Cases Diagnosis Neuroimaging Findings Brandon J, et al, 36 2017 1 Sixth Nerve Palsy MRI and MRA Normal Nadha A, et al, 37 2017 1 Migraine MRI, CT Normal Oana M, et al, 38 2017 1 Amyloidosis CTA/MRA/ MRI Multifocal patchy and confluent vasogenic edema in the cerebral hemispheres, hemosiderin deposition from microhemorrhages Chou MC, et al, 39 2017 1 Encephalopathy Syndrome MRI/MRA/CT/ FLAIR Hyperintense signal change at periventricular, parieto- occipital, cerebellar, and brainstem areas visualised in FLAIR Carlen A, et al, 40 2017 1 Orbital Apex syndrome CT Retrro-orbital mass. Excision biopsy showed non- Hodgkin's lymphoma Hidehiro Oku, et al, 41 2016 1 Sixth Nerve Palsy MRI and MRA Aneurysm of intracavernous carotid artery Raoof N, et al, 42 2015 1 Sixth Nerve Palsy MRI and CT Skull base Endochondroma Kleffner I, et al, 43 2015 2 Behr syndrome MRI Bilateral hypointense signals in the globus pallidus, the putamen, and the substantia nigra as well as a cerebellar atrophy Vaphiades MS, et al, 44 2015 1 Progressive Supranuclear Palsy-Like Syndrome MRI/MRI tractography/ (fMRI), normal Koukkoulli A, et al, 45 2015 1 Ophthalmoplegia with lid SCC MRI Perineural Spread of Cutaneous Squamous Cell Carcinoma Cheng HC, et al, 46 2015 5 Optic nerve hypoplasia MRI Ectopic posterior pituitary gland, agenesis of septum pellucidum, Rathke's cleft cyst Madgula, et al, 47 2014 1 4th nerve palsy MRI Metastatic breast cancer Berkenstock M, et al, 48 2014 1 Pituitary Apoplexy MRI and MRA Pituitary adenoma with haemorrhage Bansal S, et al, 49 2014 1 Third nerve palsy MRI Neurosarcoidosis Rosini F, et al, 50 2013 1 8 ½ Syndrome with Hemiparesis and Hemihypesthesia: The Nine Syndrome? MRI Ischemia of right pons involving the abducens nucleus, adjacent medial longitudinal fasciculus(MLF), and facial colliculus, extending to the ipsilateral mediallemniscus and corticospinal tract Pehere N, et al, 51 2011 1 Cholesterol Granuloma of the sphenoidal Sinus MRI A homogenous T1 and T2 hyperintense lesion causing expansion of sphenoidal sinus Reyes KB, et al, 52 2011 1 Craniopharyngioma MRI Suprasellar cystic lesion compressing the chiasm, flattening the pituitary gland Raghavendra S, et al, 53 2010 1 4th nerve palsy MRI Mid brain hemorrhage Sánchez VM, et al, 54 2006 1 Alzheimer's Disease PET scan Parietal-occipital bilateral hypo-metabolism Andrew GL, et al, 55 2004 8 Alzheimer's Disease MRI AND PET Hypoperfusion in the parieto-occipital areas.MRI showed pariet-occipital atrophy Freedman KA, et al, 56 2004 1 Nonketotic Hyperglycemic patient MRI Normal Madhura A. et al, 57 2004 2 third nerve palsy MRI and MRA Internal carotid artery aneurysm and arteriovenous fistula arising Parsa CF, et al, 58 2001 13 Optic nerve gliomas CT and MRI Gliomas of optic nerve and chiasma Andrew GL, et al, 59 2000 8 Acute optic neuropathy MRI 3 sarcoidosis, 4 meningioma, metastasis Mark L, et al, 60 1998 9 Miscellaneous MRI, CT, Arteriography Carotid artery dissection, pituitary tumour, ischemic occipital lobe injury, Arnold Chiari Malformation, CCF, Carotid stenosis, MS, optic nerve sheath meningioma Tayyaba Gul Malik, et al 183 Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 Fig. 1: Axial T2 images; 1) Eyeball, 2) Lateral Rectus, 3) Medial Rectus 4) Optic Nerve. Fig. 2: Coronal T1 images through orbit; 1) Optic nerve 2) Medial Rectus 3) Superior Rectus 4) Lateral Rectus 5) Inferior Rectus 6) Optic chiasm. Fig. 3: Coronal T2 images; 1) Eyeball, 2) Optic nerve, 3) Medial Rectus, 4) Inferior Rectus, 5) Lateral Rectus, 6) Superior Rectus 7) Superior Oblique 8) Optic chiasm. Fig. 4: Sagittal T1 images; 1) Eyeball, 2) Superior Rectus, 3) Optic Nerve, 4) Inferior Rectus. Fig. 5: Gadolinium contrast with fat suppression showing enhancement of optic nerve sheath. Fig. 6: Axial Flair images; 1) Eyeball, 2) Optic nerve, 3) Medial Rectus 4) Lateral Rectus, 5) Optic Chiasma. DISCUSSION In this systematic review only NCBI Pubmed database was used with search terms neuroimaging AND neuro- ophthalmology (1997 to 2019). The details of the studies and case reports are depicted in table 1 and 2. When we searched Pakistan Journal of Ophthalmology website from 2006 to 2019, only 14 articles were found related to neuro-ophthalmology. After excluding the articles, which did not include neuro-imaging, we were left with 5 case reports and 5 original articles. Case reports included CSF rhinorrhea, Ewing Sarcoma, Optic disc drusen, traumatic optic neuropathy and tuberous sclerosis. 1-5 Neuroimaging in Neuro-Ophthalmology Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 184 Original articles included headache, head trauma, meningiomas of visual pathway, Retinoblastoma and systemic associations of optic nerve diseases. 6-10 . In the following paragraphs, the commonly used neuro-imaging techniques and important sequences are discussed based on the articles reviewed through Pubmed search. Magnetic Resonance Imaging (MRI) The basic mechanism of MRI is the rearrangement of charged hydrogen ions after exposure of a tissue to a short electromagnetic pulse. Relaxation times of the tissues depend upon their characteristics and a tissue may be T1 weighted or T2 weighted. The magnetic field in MRI is expressed in Tesla (T). The commonly used field is 1.5T to 3.0T. 11 In T1 weighted images, CSF and vitreous appear dark and it is good for studying normal anatomy. In T2 weighted images, water appears hyperintense. Hence, the edematous tissues will be differentiated from the surrounding tissues as hyperintense. Optic nerve gliomas can be seen as tubular or fusiform enlargement of the nerve, which appear isointense to hypointense when compared with the adjacent tissues on T1-weighted MRI and enhance after gadolinium injection. 12 Optic nerve meningiomas appear separate from the optic nerve on coronal views. It is visible in the form of a concentric ring around the nerve. In patients with Idiopathic Intracranial Hypertension (IIH), T1-weighted images of the brain may show an empty sella turcica while axial T2- weighted MRI images of the orbit show distension and tortuosity of the optic nerve sheaths. Flattening of the posterior globe is also an MRI sign of IIH. 12 Afferent and efferent visual pathways are also best detected by MRI studies (Figures 1, 2, 3, 4). However, in the presence of acute hemorrhage and bony abnormalities, CT is a better option. Gadolinium contrast studies is a special contrast medium, which shows up when placed in a magnetic field. When given through intravenous route, it remains inside the vessels unless there is a defect in the blood brain barrier. It is used with T1 weighted images. It helps in enhancing the brightness of tumour images and inflammatory lesions. Sellar masses are also best visualized with contrast enhanced T1 weighted images. PostcontrastT1-weighted images can be helpful in diagnosing Giant cell arteritis, in which case there is increased vessel wall thickness and edema. Fat-suppression techniques are used in various conditions including orbital pathologies. Orbital fat on conventional T1-weighted imaging makes it difficult to differentiate from other normal tissues (optic nerve and Extraocular muscles), tumors, inflammatory lesions and vascular malformations. There are two types of fat-suppression sequence used in neuro- ophthalmology. 1. T1 weighted images with gadolinium contrast and fat suppression allows the optic nerve sheath lesions to be enhanced. 12 2. STIR (short T1 inversion recovery) is used without contrast and is quite optimal sequence for diagnosing intrinsic lesions of the intraorbital optic nerve (e.g. optic neuritis). Inflammation of the Optic nerve sheath is better detected by gadolinium-enhanced fat-saturated T1- weighted MRI, in which they appear as circumferential optic nerve sheath enhancement and on axial views these are seen as tram-track sign (Figure 5). Fat suppression techniques are also useful in confirming the fat-containing lesions, such as Dermoid cysts and lipomas. Thus for optic nerve sheath and optic nerve lesions, fat suppression is a gold standard. Diffusion-Weighted Imaging Diffusion-weighted imaging (DWI) is a special MRI technique that is based on the microscopic random Brownian motion of water. It is useful in detecting acute ischemic strokes. This technique is useful in very early stage of ischemic stroke when the changes are undetectable on T1 and T2 weighted MRI. 12 As different stages of infarction can also be identified by DWI, this technique is helpful in distinguishing vasogenic reversible ischemia from irreversible ischemia in patients with cortical blindness and brainstem ischemia. (FLAIR) Sequence As CSF is bright onT2-weighted images, it becomes difficult to differentiate periventricular lesions from CSF signal. In fluid-attenuated inversion recovery, a T2-weighted image of CSF signal is suppressed to allow better detection of adjacent pathology. FLAIR sequences also help to highlight inflammatory changes 12 (Figure 6). Tayyaba Gul Malik, et al 185 Pak J Ophthalmol. 2020, Vol. 36 (2): 179-188 Gradient Recalled Echo (GRE) or susceptibility- weighted imaging (SWI) is helpful in diagnosing micro hemorrhages (within the first few hours) (Figure 2). FIESTA and CISS (fast imaging employing steady-state acquisition and constructive interference in steady-state). The structures surrounded by CSF and isodense to CSF in T1 and T2 weighted images are better visualized by this technique. Orbital masses, which arise from the orbital nerves can be better detected with this technique. Magnetic Resonance Venography (MRV) and Magnetic Resonance Arteriography (MRA) MRA is a very good technique, which has reduced dependency on Conventional invasive angiography. MRA relies on blood flow within the vessels and hence contrast is not required. However, the thrombosed aneurysm and small aneurysms are missed. MRV is used to detect venous sinus thrombosis or venous stenosis. 11 Diffusion Tensor Imaging and Diffusion Tensor Tractography DTI and DTT can be helpful in visualizing the axon and myelin integrity. Data from DTI is used to reconstruct a 3D images in DTT. Magnetic Resonance Spectroscopyis capable of detecting brain metabolites and hence help in distinguishing between neoplasms, demyelinating lesions, radiation necrosis, inflammatory lesions and mitochondrial disorders that can affect the visual pathways. Limitations of MRI include bony defects and acute haemorrhages, which are not detected on MRI. Magnetic foreign bodies, cardiac pace markers, ferromagnetic aneurysm clips are contraindications for MRI. The test is also not suitable for claustrophobic patients. Computed Tomography (CT) uses X-rays to obtain images, which are then computed to form cross- sectional images. White is the maximum density of the tissue as in bones and black is the minimum density as in air. Iodinated contrast is used to improve the visualization of structures but allergy to iodine and renal failure are contraindications. Use of contrast in acute hemorrhage, bony injury and in case of foreign bodies, can mask the visibility. Optic nerve head drusen and tumours that show calcification e.g., Craniopharyngiomas, Meningiomas and Retinoblastomas can be detected with CT scan. Especially in cases of optic nerve sheath meningioma, CT shows perineural calcification in the form of “tram-tracking”. Hyperostosis of the neighboring bones is also a diagnostic sign. 12 In cases of traumatic optic neuropathy, CT scan can help in detecting the optic canal fracture, edema (or blood) within the optic canal (or optic nerve sheath), intraconal hematoma, or foreign body/fracture fragments causing impingement on the optic nerve. Fludeoxy Glucose (FDG)–PET: Positron emission tomography (PET) is a sequence, which is used in diagnosing inflammatory and/or neoplastic processes. Fluorodeoxy glucose (FDG) is a metabolic marker. Greater uptake of glucose by the inflammatory and neoplastic lesions can be helpful in diagnosis. Large vessel vasculitis in GCA and extraocular muscle inflammation in Graves disease is detected by this technique. 12 Computed Tomographic Angiography and Venography (CTA, CTV): Extremely thin slices of brain are taken to investigate intracranial aneurysms. CTV is a good diagnostic technique for cerebral venous sinus thrombosis. Contrast is injected and the patient is exposed to radiations. Conventional catheter angiography was once the only diagnostic test for intracranial aneurysm but now CTA and MRA have surpassed its use and it is only reserved for the patients in which the CTA and MRA are not diagnostic. 12 Limitation of this systematic review is the use of only one database (Pubmed). Other databases and gray literature/unpublished data were also not included. 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Authors’ Designation and Contribution Tayyaba Gul Malik; Professor: Study design, literature search, data acquisition, data analysis, manuscript writing, final review. Khalid Farooq; Professor: Study design, data acquisition, final review. .…  ….