**4. Neurological conditions with ocular manifestations**

#### **4.1 Multiple sclerosis (MS)**

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination in CNS due to autoimmune-mediated inflammatory processes. Recently, vascular and metabolic factors are increasingly being recognized to play important roles in the neuroinflammatory mechanism of MS [4]. The optic nerve is commonly injured in MS with or without optic neuritis (ON). Optic neuritis (ON) is unilateral or bilateral inflammation of the optic nerve due to many causes, including multiple sclerosis (MS), optic neuritis associated with neuromyelitis optica (NMO), infectious, or isolated. In patients with MS, ON is the presenting symptom in 25% and occurs in 75% of cases during the disease course [3].

According to post-mortem studies, demyelinating plaques can be seen in the optic nerves of up to 99% of MS patients, making optic nerve involvement a common aspect *Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 6.**

*Optical coherence tomography angiography (OCT-A) of the optic nerve head (ONH) in a representative Multiple Sclerosis (MS) patient. Split-spectrum amplitude decorrelation angiography (SSADA) results (N = nasal,T = temporal) show that, in comparison to (c) a healthy control example, (a) MS eyes with a history of ON (MSON) and (b) MS eyes without a history of ON (MSNON) both exhibit an apparent qualitative reduction of the ONH microvascular density in the peripapillary area (between circles), mostly in the temporal region. (c). Bar = 0.5 mm (Reprinted from ref. [5]).*

of the disease process [5]. The parafoveal and ONH (**Figure 6**) flow index, a representation of relative blood flow velocity in the vasculature, was determined to be significantly lower in MS eyes with a history of ON (MSON) in comparison to eyes without a history of ON (MSNON), compared to healthy controls [5, 24, 25].

On the other hand, in the largest study of OCT-A on MS so far, Murphy *et al.* [26] showed retinal SVP densities measured by OCT-A are reduced in MS eyes in both MSON and MSNON [26]. They also found that reduced SVP densities correlate with reduced visual function, longer disease duration, and higher levels of global disability in expanded disability status scale (EDSS) and multiple sclerosis functional composite (MSFC) assessments. The group suggested that OCT-A may have additive value as a biomarker in MS, in addition to routine OCT evaluation. The suggestion is coherent with a previous study by Spain *et al.* [25] where they investigated 68 eyes from MS patients and 55 healthy eyes with OCT and OCT-A to assess the structural and vascular change in the peripapillary area. The results showed that MS patients, regardless of whether they had a history of optic neuritis (ON), had a lower ONH flow index and reduced thickness of the retinal nerve fiber layer compared to healthy control eyes. The differences were even more pronounced in MS patients with a history of ON. In comparison to their previous study with a smaller sample size, this study showed that MS patients without a history of ON had a 5.5% decrease in the ONH flow index compared to healthy controls, while MS patients with ON showed a 14.7% decrease compared to healthy controls [25].

Kleerekooper *et al.* summarized the current state of development of OCT-A in MS and some other neuroinflammatory disorders (e.g., neuromyelitis optica spectrum disorder (NMOSD)) and interested readers may refer to it [4]. Although, OCT-A gives new insight into various neuroinflammatory disorders using qualitative features of the retinal microvasculature. Prior to OCT-A being fully implemented into clinical practice, however, concerns with image quality and the creation of standardization must be resolved.

#### **4.2 Alzheimer's disease (AD)**

The neuropathology of Alzheimer's disease (AD) involves the buildup of betaamyloid plaques and neurofibrillary tangles, which cause inflammation and neurodegeneration [8]. It is now recognized that changes in vascular remodeling also play a role in AD, dementia, and mild cognitive impairment (MCI). Due to their similar anatomic, embryonic, and physiologic characteristics, there has been evidence that the retinal vascular network is a surrogate marker of small cerebral microvascular changes [6, 8, 15, 27]. As the retinal vascular network can be observed directly in AD by OCT-A, there has been evidence of decreased retinal vascular density in AD [8, 15]. In a recently conducted systematic review by Katsimpris *et al.* summarized the OCT-A metrics in AD [6]. They found whole and parafoveal superficial venous plexus (SVP) vessel density were inversely associated with AD. This conclusion was coherent with the systematic review of Rifai *et al.* where the authors reported a significant increase in the foveal avascular zone (FAZ) area and a significant decrease in parafoveal SVP and whole SVP density in AD [27]. However, a possible limitation of OCT-A in AD is less suitable for advanced AD patients. Advanced AD patients are easily fatigued by imaging and are more prone to fixation errors [8]. OCT-A may not be useful in subjects with advanced dementia and may be most useful for patients with a new-onset or milder form of the disease. Nevertheless, though recent advances in biomedical imaging modalities like positron emission tomography (PET) have revolutionized the visualization of amyloid-β plagues presence *in vivo* in cognitively healthy individuals, it is not yet feasible as a large-scale screening procedure due to its expensive nature [6]. Compared to this, quantitative OCT-A measurements might provide cost-effective useful biomarkers for assessing the course of AD-related neurodegeneration. From a clinical perspective, it would be really beneficial if a cost-effective retinal OCT-A screening can make an early diagnosis of AD and its disease progression even before severe brain degeneration. Though it requires further study, OCT-A shows promise to develop early retinal biomarkers for pre-clinical AD pathology and its progression from dementia.

Apart from these, there has been growing interest in OCT-A-based screening for cerebral small vessel diseases (CSVD). Lee *et al.* [28] conducted a prospective crosssectional study in the eyes of 69 (138 eyes) cognitively impaired patients to evaluate radial peripapillary capillary (RPC) network density through OCT-A and retinal nerve fiber layer (RNFL) thickness and determine their association with brain imaging markers. Among the 29 patients with amyloid-positive Alzheimer's disease-related cognitive impairment (ADCI), 25 patients with subcortical vascular cognitive impairment (SVCI), and 15 amyloid-negative cognitively normal (CN) subjects were enrolled in the study. The authors found the microvasculature of the RPC network was related to the CSVD burden. However, the RNFL thickness did not reflect cerebral neurodegeneration (**Figure 7** and **Table 4**).

#### **4.3 Stroke**

Stroke may be defined as a neurological deficit attributed to an acute focal injury of the central nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), and is a major cause of disability and death worldwide [29]. Of the two types of strokes: ischemic and hemorrhagic, ischemic stroke accounts for 80% of stroke cases and is characterized as an episode of neurological dysfunctions caused by focal cerebral, spinal, or retinal infarction [29, 30]. Lacunar infarctions, which are tiny infarctions (3–15 mm in diameter) in the deep perforating artery region, account for around 25% of ischemic strokes [31]. The causes of lacunar infarction and whether it differs from cortical stroke are still up for debate despite the fact that it has been acknowledged as a recognized subtype of stroke for more than 50 years. OCT-A allows the understanding of the pathophysiological processes underlying lacunar infarction in other vascular *Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 7.**

*Representative images according to diagnostic groups. Representative patient images of OCT-A and brain magnetic resonance imaging (MRI). Images demonstrate the subcortical vascular cognitive impairment (SVCI), the Alzheimer's disease-related cognitive impairment (ADCI), and the superficial radial peripapillary capillary network (upper row) and axial T2 fluid-attenuated inversion recovery (bottom row) of patients. The patient with SVCI has severe subcortical white matter hyperintensity and decreased peripapillary capillary network density in the temporal quadrant (arrows). (arrowheads). (Reprinted from ref. [28].)*

beds, such as the retina, where small vessels can be visualized easily. Very recently, Duan *et al.* conducted the first OCT-A study and compared its metrics in lacunar and non-lacunar strokes [31]. They found retinal microvascular changes using OCT-A several years after the diagnosis of ischemic stroke. Though OCT-A is not yet established for the diagnosis of acute stroke, the modality can increase our understanding of different stroke sub-types and cerebrovascular diseases. They detected that increased FAZ axis ratio (FAR) of the deep capillary plexus (DCP) and decreased FAZ circularity (FC) of the DCP were associated with ischemic stroke. Also, decreased vascular orientation distribution (VOD) of the superficial capillary plexus (SCP) is associated with lacunar infarction compared with non-lacunar infarction.

Moreover, in a very recent study, Pachade *et al.* demonstrated that microvasculature density features from OCT-A images have the potential to be used to diagnose acute cerebral stroke from the retina. They found decreased microvasculature density, signifying a sparser vessel network, was associated with acute stroke in their study group. Using a self-supervised learning of OCT-A and fundus imaging, their diagnostic system may have a future role in relatively lower cost acute stroke diagnosis and warrants further research [7].

Apart from it, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a rare autosomal dominant disease, is the leading cause of hereditary ischemic strokes. The vessel wall of the brain's vasculature thickens as a result of a mutation in the Notch-3 gene, leading to lumen stenosis [15]. OCT-A changes in CADASIL were found to be significantly reduced vessel density in the DCP in the macular region. When compared to the control group, there were no differences in any other macular or optic nerve head OCT-A parameters.


#### **Table 4.**

*Comparisons of capillary density in the radial peripapillary capillary (RPC) network and retinal nerve fiber layer (RNFL) thickness among the three groups.*

Finally, in addition to improving our understanding of CSVD as stated in the previous section, OCT-A vascular parameters may shed light on the progression of ongoing microvascular vascular events (e.g., in hypertension, stroke, endothelial dysfunction, and inflammation) in patients.

#### **4.4 Parkinson's disease (PD)**

Previous research on the retina in Parkinson's disease (PD) patients relied solely on structural OCT scans [9]. Although OCT allows for the analysis of morphological changes in various neurological conditions, the addition of OCT-A will significantly enhance the diagnostic capabilities by enabling a closer examination of the functional and vascular components. Now, it has been established that retinal microvasculature density is associated with PD progression (**Figure 8**) [9, 32]. It was first demonstrated by Kwapong et al. [33] that OCT-A revealed decreased retinal microvascular density in early PD patients, which was later confirmed by Robbins et al. [34] too [33, 34]. In an advanced approach by Zou et al. showed combination of OCT and OCT-A in PD had better diagnostic ability than either alone, and may provide an additional biomarker for disease progression [8].

However, the limitation of OCT-A in PD is that motion artifacts increase in advanced PD patients. The possible cause is PD's cardinal motor symptoms such as tremors, bradykinesia, and rigidity, as well as neuropsychiatric symptoms like reduced attention control and bradyphrenia. The motor symptoms worsen as the disease progresses and that is why motion artifacts also increase with the duration of PD, making it difficult to obtain artifact-free OCT-A recordings, especially in the advanced stages of the disease [9]. An interesting study by Lauermann *et al.* found that motion artifacts in OCT-A images are equally common in both medicated PD patients and healthy controls [9]. However, more advanced stages of PD, indicated by longer disease duration and more severe motor symptoms, were associated with

*Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 8.**

*Representative Optical Coherence Tomography Angiography (OCT-A) Images in PD vs control. OCT-A image and measurement of the density analysis of the superficial retinal capillary plexus (SCP). (A,B) Map of macular and peripapillary area. The inner and outer rings were divided into four quadrants: superior (SO & SI), nasal (NO & NI), inferior (IO & II), and temporal (TO & TI). (C,D) Foveal avascular zone (FAZ) area was significantly decreased in patients with Parkinson's disease (PD) (D) compared to healthy controls (HC) (C). (Reprinted from ref. [32].)*

higher levels of motion artifacts. Thus, caution and expertise are necessary when evaluating the quality and interpreting the results of OCT-A images, particularly in the advanced stages of PD. More importantly, the authors suggest that as like as MRI scans are evaluated by specialized radiologists or neuroradiologists to ensure accurate results for clinical interpretation by other departments. Specialized eye clinics should create and assess OCT-A recordings and then provide the revised results to nonspecialist colleagues for clinical use to mitigate such caveats. Nevertheless, OCT-A has opened a new avenue of research in early diagnosis, and disease progression from micro-perfusion changes in PD patients.

### **5. Conclusion**

Optical Coherence Tomography Angiography (OCT-A) has emerged as a powerful tool in imaging microvasculature in different neuro-ophthalmological and central nervous system disorders. With its unique capability to provide detailed

microvascular architecture, it has contributed to the diagnosis, monitoring progression, and prognosis of various conditions such as optic neuropathies, papilledema, glaucoma, multiple sclerosis, Alzheimer's disease, Parkinson's disease, different cerebral small vessel diseases, and stroke. Despite the current limitations, the future of OCT-A in neuro-ophthalmology and neurology is promising, as ongoing research continues to explore its potential applications, overcome its challenges, and further advance its capabilities.
