\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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The clinical findings by OCT in these pathologies are well known. SD-OCT allows detail assessment of the retinal thickness and morphologic evaluation of the retinal layers. Currently, due to the development of this technology and its extensive use, new OCT findings have been reported in the literature. The higher resolution and speed of SD-OCT have improved the accuracy and reproducibility of macular imaging and have allowed an enhanced assessment of the integrity of the outer retinal bands.
OCT imaging is similar to ultrasonography, except that it uses infrared light reflections instead of acoustic waves. The OCT image is displayed using a false color map that corresponds to detected backscattered light levels from the incident light. White and red colors represent high reflectivity signals, while the low reflectivity signals correspond to black and blue colors [1]. OCT interpretations make necessary knowledge of the normal anatomy of the retina. In a usual SD-OCT scan, a highly scattering layer delineates the posterior boundary of the retina and corresponds to the retinal pigment epithelium (RPE) and choriocapillaris complex. The nerve fiber layer is manifest as a highly backscattering red layer at the vitreoretinal interface. Both layers are the posterior and anterior boundaries of the sensory retina and are essential to quantify the neurosensorial retinal thickness [2]. The rest of the layers of the neurosensorial retina are disposed between the two limits, and they are observed with OCT in a similar way to a histological section. The high reflectivity signal (yellow and red colors) come from the retinal nerve fiber layer (RNFL), inner plexiform layer, outer plexiform layer (OPL), internal limiting membrane (ILM), junction between inner and outer segments of photoreceptors (IS/OS), and RPE and choriocapillaris complex. The low reflectivity signals (black and blue colors) correspond to the nuclear layers [3]. In 2014, an international panel of OCT experts agreed on the adequate nomenclature for the retinal layers as visualized on OCT [4]. The new terminology of the outer retinal bands and their anatomical correspondence are described below, from the innermost to the outermost (Figure 1) [4, 5]:
The external limiting membrane band (ELM) is located at the boundary between the nuclei (cell bodies) and the inner segments of the photoreceptors and comprises clusters of junctional complexes between the Müller cells and the photoreceptors.
The ellipsoid zone (EZ), which was previously referred as the photoreceptor inner segment/outer segment (IS/OS) junction, is considered to be formed mainly by mitochondria within the ellipsoid layer of the outer portion of the inner segments of the photoreceptors. In a normal fovea, the distance from the EZ line to the ELM line is shorter than that from the EZ line to the RPE. The EZ “elevation” in the foveal center is due to elongated foveal cone outer segments.
The interdigitation zone (IZ) is considered to be the contact cylinders formed by the apices of the RPE cells that encase the part of the cone outer segments. This layer is not always recognizable from the underlying RPE layer, even in healthy subjects.
The retinal pigment epithelial band is formed by the RPE and Bruch’s membrane. Both structures are indistinguishable from each other using the currently commercial SD-OCT. In the fovea, this band is thicker compared to other regions, which indicates that choroidal structures may also participate in the hyperreflectivity of the RPE band at this location.
Spectral domain optical coherence tomography (SD-OCT) scan with external retinal landmarks from a healthy subject. RPE: retina pigment epithelium; IZ: interdigitation zone; EZ: ellipsoid zone; and ELM: external limiting membrane.
Recent publications have reported that the damage or the alteration of the photoreceptors supposes a loss of integrity of some of these four bands previously described [6, 7]. Series of OCT images in different phases of degenerative diseases of the retina have demonstrated that IZ, EZ, and ELM lengths are highly correlated with each other. The affectation seems to occur in a stepwise sequence: first at the IZ, followed by the EZ, and finally the ELM band [7, 8, 9]. Similarly, photoreceptor restoration seems to occur in the reverse order. After closing a macular hole, it has been documented that the ELM zone is the first structure to recover, and its recovery has been considered a sign of intact Müller cells and photoreceptor cell bodies [10]. Also, OCT findings after ERM and macular hole surgeries showed that recovery of EZ line only occurred in areas with intact ELM, and IZ recovery was only observed in eyes with EZ and ELM uninjured [11, 12]. The recovery of the ELM line following treatment has been correlated with visual acuity outcomes for macular hole [11, 13], retinal detachment [9], and AMD [14]. After macular hole closure, the presence of injured ELM was associated with reduced visual acuity [12]. In retinal detachment (RD), preservation of the ELM line postoperatively was related with better visual acuity result and also seems to predict the subsequent restoration of the photoreceptor layer [9]. Disruption or absence of the EZ line has been shown to correlate with visual acuity and severity in several retinal diseases [5]. In nonneovascular AMD, disruption of the EZ has been associated with visual impairment [15, 16, 17]. Furthermore, retinal sensitivity in patients with geographic atrophy was significantly higher in areas with an uninjured EZ [18]. In neovascular AMD, intact EZ at baseline was reported as a favorable prognostic factor for visual acuity outcome following intravitreal anti-vascular endothelium growth factor (anti-VEGF) treatment [14]. In diabetic patients with macular edema, the EZ disruption at the fovea was reported as a significant predictor of visual acuity [19, 20]. In eyes with ERM, preoperative disruptions of the EZ line were also associated with poorer visual acuity outcomes [21, 22, 23]. The IZ line is very difficult to identify even in healthy subjects. A correlation between the postoperative status of IZ and visual acuity has been described for macular hole [11], ERM [21], and RD [24]. Gharbiya and collaborators reported that the integrity of the IZ line was the strongest predictor of visual acuity outcome after primary RD repair (Figure 2) [24]. Following macular hole surgery, patients with irregular or discrete IZ line had significantly better visual acuity compared with those eyes with a disrupted or absent IZ line at the one-year visit follow-up [14]. In recent years, new OCT findings and signs have been reported for different retinal diseases. We will describe them with more clinical relevance.
SD-OCT in a patient with retinal detachment macula off (A). Post-surgical aspect through OCT of the same patient in which the integrity of the outer layers is observed (B). The visual acuity was 20/30.
Coscas and cols were the first authors to report the presence of HRS on SD-OCT in exudative AMD [25]. These dots are described as small in size (20–40 μm in diameter), punctiform hyperreflective elements (equal or higher reflectivity than the RPE band), distributed throughout all retinal layers. HRS are mainly located at the border of the ONL and within the OPL [26]. They have also been reported in early stages of DR and also in diabetics without any clinical sign of DR, DME, retinal venous occlusion (RVO), central serous chorioretinopathy (CSCR), macular telangiectasias, and certain types of uveitis (Figure 3) [27]. It has been hypothesized that HRS represent aggregates of microglial activated cells and could indicate a retinal inflammatory response. Therefore, it has been reported reduction of HRS number following intravitreal anti-VEGF or dexamethasone therapies [28]. There are various theories on the pathogenesis of HRS. Some authors hypothesize that HRS are focal pigment accumulations of lipofuscin granules. Others consider that there could be small intraretinal protein or lipid deposits/exudates secondary to the breakdown of the blood-retinal barrier in retinal vascular diseases [26, 27, 28, 29, 30]. According to other theory, HRS might be derived from the degenerated photoreceptors or from the macrophages that phagocyted them [31]. Concerning the clinical implications of the HRS, we have already commented that they represent a certain degree of retinal inflammation. HRS are associated with poorer visual outcome in patients with macular edema due to retinal vascular diseases such as RD or RVO. The therapeutic response to specific treatments might be different according to the number of HRS. Hwang et al. reported an inadequate response to intravitreal bevacizumab for DME and macular edema due to RVO in eyes with a greater number of HRS. Eyes that responded poorly to bevacizumab were treated with dexamethasone implants. About 75% of such eyes showed a good response and corresponded to the eyes with a higher number of HRS [32]. Vujosevic and cols have also suggested that DME with a high number of HRS and a large area of increased foveal autofluorescence showed better morphologic and functional results (better retinal sensitivity) if, at least initially, was treated with intravitreal steroids versus anti-VEGF [28]. These findings suggest that in eyes with several HRS, the inflammatory pathway might contribute to the pathogenesis of the macular edema more than the VEGF pathway. Therefore, in patients with macular edema and many HRS, anti-inflammatory drugs (e.g., dexamethasone intravitreal implant) might be more effective than intravitreal anti-VEGF treatment [32].
Hyperreflective retinal spots (HRS) observed in a patient affected of tuberculosis posterior uveitis.
The use of hydroxychloroquine (HCQ), an antimalarial drug utilized for a range of rheumatologic and dermatologic diseases, is associated with a low incidence of retinopathy (1% after 5 years) when used at recommended doses (<6.5 mg/kg/day) [33]. However, the retinopathy described as a bull’s-eye is untreatable and tends to progress even after cessation of the drug. In recent years, there is an increased interest in screening by using multimodal imaging techniques to detect early signs of retinal toxicity. SD-OCT may detect significant structural alterations before the development of visible HCQ retinopathy. Several OCT findings have been described in the literature such as disruption of the EZ line, loss of the ELM, parafoveal thinning of the ONL, and RPE damage. These studies suggest that there is a foveal resistance to HCQ damage as demonstrated by the preservation of the subfoveal outer retinal layers. This foveal sparing originates the “flying saucer” sign on HCQ retinopathy (Figure 4) [34]. The main characteristics of this sign include the loss of the normal foveal depression, perifoveal thinning of the ONL, an ovoid appearance of the central fovea, conservation of the outer retinal structures and photoreceptor IS/OS junction in the central fovea, an apparent posterior displacement of the inner retinal structures toward RPE, and perifoveal loss of the photoreceptor IS/OS junction [3]. All these alterations originate an ovoid appearance in the central fovea [35]. This sign is neither pathognomonic nor necessary for the diagnosis of HCQ retinopathy. Nevertheless, its visualization on SD-OCT images should alert us to possible retinal toxicity due to HCQ toxicity.
SD-OCT revealed the “flying saucer” sign in a woman treated with oral chloroquine at a dosage of 3 mg/kg once daily for 8 years.
ORT is a degenerative process of outer retinal reorganization located primarily in eyes where the macula is disrupted and RPE is absent. ORTs are ovoid or circular hyporeflective lesions surrounded by a hyperreflective ring always located in the ONL in eyes with advanced outer retinal diseases (Figure 5) [36]. It has been described in numerous retinal disorders showing macular atrophy involving RPE, such as AMD [36], mitochondrial diseases [37], and retinal dystrophies [38]. They have also been reported in cases of macular neovascularization including AMD, choroidal nevus, pseudoxanthoma elasticum [39], multifocal choroiditis with uveitis and CNMV, choroideremia [36], and enhanced S-cone syndrome [40]. Histologic studies showed interconnecting tubes of surviving cone photoreceptors interleaved with and contained by processes of Müller cells [41]. Histologically, the hyperreflective border of ORS seen in SD-OCT images corresponds with the presence of both an EML delimiting the lumen and mitochondria migrating from the inner segments to the cell bodies of degenerating cone photoreceptor. The main histologic characteristics of ORTs are [41]:
location at the level of ONL
presence of an ELM surrounding all or part of the lumen
presence of enclosing radially oriented photoreceptors pointing to the lumen
disruption or absence of the underlying RPE
Outer external tabulation in atrophic age-macular degeneration.
There are different shapes of ORTs: open, closed, forming, and branching. A branching or pseudodendritic pattern is observed mainly in macular neovascularization, whereas a single tube is more frequent in the border of geographic atrophy [42]. Regarding the etiology of these tubulations, it has been hypothesized to be related to the different shapes of the ELM descent (flat, curved, and reflected). As the RPE begins to atrophy, the ELM descent changes from flat to curved, then reflected to scrolled, and finally, an area of ORT may appear. In this process, Müller cells expand and fill the spaces created by the loss of photoreceptors, as they are the only structure persisting in end-stage of ORT. The presence of a scrolled ELM descent may represent a predictive factor for progression toward ORT. It has been reported that in cases of neovascularization, the progression to ORT experienced a shorter period between the steps of flat and curved ELM than eyes only with atrophic [42]. ORTs have a significant prognostic value since their presence suggests a poor visual acuity. They should be differentiated from intraretinal or subretinal fluid cysts located at the outer retinal layers. Intraretinal fluid cysts in cystoid macular edema (CME) have the arrangement as a petaloid manner, while ORTs are randomly arranged at the macula. Pseudocysts are usually distinguished from ORTs because they are located in the inner nuclear layer. Retinal tubulations are always located at the level of the ONL [3]. ORTs are circular hyporeflective lesions surrounded by a hyperreflective ring. This hyperreflective border is absent in cysts. Likewise, ORTs may contain a few focal hyperreflective spots in contrast to the completely hyporeflective cystoid lesions. The recognition of ORT may avoid unnecessary treatment because it is more refractory to anti-VEGF treatment compared to the cysts. Because outer tubulations tend to change slowly over time, it is unlikely to be associated with an active exudative or inflammatory process. For that reason, they do not require treatment [3, 42]. ORT can also be differentiated from rosettes described in retinoblastoma by their large size, tubular structure, and degenerative instead of developmental nature. In retinitis pigmentosa, there are also rosettes which are distinguished from ORTs by their location outside the macula and absence of degeneration of the underlying RPE [42].
Dome-shaped macula (DSM) is an inward protrusion of the macula as visualized by OCT (Figure 6). Different patterns have been described by OCT: a horizontal or vertical oval-shaped dome and a round dome [43]. DSM was first reported in myopic eyes with posterior staphyloma, but more recently has also been described in patients without staphyloma, emmetropic, or hypermetropic eyes [44, 45]. A variety of hypotheses have been postulated to explain it: an adaptive mechanism to minimize defocus in highly myopic eyes [46], vitreomacular traction [47], ocular hypotony [47], resistance of the sclera to the staphylomatous deformation [48], or localized choroidal thickening [48]. However, it has been recently indicated that the main problem is the different degrees of scleral thinning in the foveal region [46, 49, 50]. Subretinal fluid (SRF) in the fovea has been associated continuously with DSM in 28.5–66.6% of patients [51]. It may be due to RPE dysfunction [48] or as a consequence of not uniform scleral thickness that can affect choroidal fluid [46]. Although photodynamic therapy and anti-VEGF agents have been applied, they had no effects in terms of improvement in BCVA and resolution of SRF, because the fluid remained chronic and stable in most of the eyes over time [51], and it was even spontaneously resolved in 47% of the cases [52].
SD-OCT showing a dome-shaped macula.
Brush border pattern is defined as an accumulation of waste products in the photoreceptor outer segment on the outer surface of the detached neurosensory retina over subretinal fluid (Figure 7). This provides an irregular, serrated, and thicker appearance of the detached neurosensory retina. Other authors denominate it as “elongation of the outer photoreceptor segment”, and it can be found in almost 73–75% of OCT images from patients who suffer CSCR [53]. The loss of the contact between RPE and photoreceptor outer segments that occur in CSCR prevents the waste product of photoreceptors being phagocytosed by RPE [54]. These subretinal proteins or accumulated macrophages with outer photoreceptor segments can be observed as hyperfluorescent white-yellowish precipitates in the retinal examination if they contain precursors of lipofuscin [55]. If this process persists, despite subretinal fluid absorption, subretinal deposits may progress to be permanent with the subsequent poor visual outcome. Complete disappearance of outer segments as observed in very long-standing CSCR correlates with poor visual prognosis [53].
Brush border pattern in patient affected of chronic central serous chorioretinopathy (CSCR).
Patients at intermediate clinical stages in Best vitelliform macular dystrophy (BVMD) show split in the ORCC by OCT. The ORCC has multiple components, and it is split into subcomponents showing different patterns [56]. Such patterns of ORCC splitting represent the separation between the apical surface of the RPE and photoreceptors causing neurosensory macular retinal detachment (Figure 8) [57]. OCT shows a diffuse, irregular, and thickened ORCC by underlying hyporeflective area [3].
SD-OCT shows a splitting of outer retina-choroid complex by hyporeflective area in a patient with Best vitelliform macular dystrophy.
DRIL is observed on OCT as the difficulty to identify limits between the ganglion cell-inner plexiform layer complex, inner nuclear layer, and OPL (Figure 9). It represents an interrupted transmission pathway between the photoreceptors and ganglion cells due to the disruptions of synaptic connections of amacrine, bipolar, and horizontal cells [58]. Several hypotheses explain the pathogenesis:
DRIL areas in SD-OCT.
The pearl necklace sign refers to HRD in a continuous ring around the cystoid spaces in the retina that has been seen in diseases with exudative maculopathy, vascular leakage, and chronic CME such as neovascular AMD, DME, retinal vein occlusion, retinal arterial macroaneurysm, or Coats disease (Figure 10) [70]. The authors speculated that HRD indicated the presence of lipid material from retinal vascular leakage similar to hard exudates. These pearls may represent lipid-filled macrophages along the inner wall of retinal edema [70]. Moreover, it is considered a frequent precursor sign on the location of the hard exudates which appear later. Therefore, this sign can change shape and may resolve under treatment or spontaneously. The presence of pearl necklace sign has not been associated with worse visual acuity in RD [71].
Pearl necklace sign in patients with severe diabetic macular edema.
The pearl necklace sign should be differentiated from ORTs, which are located deeper in the ONL of the retina. In ORT, the ring is continuous and homogeneous, whereas the hyperreflective ring is as small foci in the pearl necklace sign [3].
FCE is a localized depression of the choroid detected only by using OCT, without any evidence of posterior staphyloma or scleral ectasia. It affects Bruch’s membrane-RPE-choriocapillaris line complex line and photoreceptors (Figure 11). Patients are mostly asymptomatic and have good visual acuity. Nevertheless, some lesions may be associated with the development of choroidal neovascular membrane. It has been reported that FCE may appear in certain macular disorders such as CSCR, AMD, ERM, CNVM, polypoidal choroidal vasculopathy, BVMD, Vogt-Koyanagi-Harada disease, punctate inner choroidopathy, focal retinochoroiditis, foveoschisis, torpedo maculopathy, multiple evanescent white dot syndrome, multifocal choroiditis, and combined hamartoma of the retina and RPE [3]. OCT allows to identify retinal and choroidal structures that are affected in the excavation, which usually includes RPE, Bruch’s membrane, EZ line, ELM, and ONL which followed the contour of the FCE. In some cases, it can be appreciated an attenuation or absence of IS/OS junction at the excavation, and ONL was thickened in most conforming eyes [72]. However, the layers from the OPL to the ILM were undisturbed, and also the sclerochoroidal junction appeared reasonably preserved without scleral excavation [72, 73]. FCE may be organized in two patterns, whether or not the photoreceptor layer is detached from the RPE. Thus, conforming FCE describes those types of lesions without separation between the two layers and the photoreceptors adapt to the contour of the RPE layer. On the other hand, in nonconforming FCE, photoreceptors appeared to be detached from the RPE showing a hyporeflective space. Factors contributing to the formation of each pattern are unknown [74]. Other authors have classified the lesions into three morphological patterns based on SD-OCT findings: bowl shaped, cone shaped, and mixed shaped [75]. They observed that all bowl-shaped types showed atrophic changes and RPE irregularities, whereas in cone-shaped FCE, a less atrophic change is detected at the center of the lesion. The pathogenesis of FCE is still unknown. Some authors suggest it could be related to a congenital defect within the choroid, which is supported by the fact that shape and size remained stable during the follow-up in most of the reported cases [73]. Nevertheless, no family history and low prevalence in young people suggest that it may be an acquired condition [74]. Some authors proposed FCE is an entity related to inflammatory diseases like Vogt-Koyanagi-Harada disease, multiple evanescent white dot syndrome, and other types of retinochoroiditis [76].
Focal choroidal excavation (FCE) revealed by SD-OCT in a patient with chronic CSCR and systemic lupus erythematosus.
Foveal pseudocyst is an OCT pathologic sign that is caused by subretinal retention of perfluorocarbon liquid (PFCL) after vitreoretinal surgery. Subretinal PFCL is a serious complication if it affects fovea. The incidence ranges from 1 to 11% after retinal detachment surgery [77]. Main risk factors for this entity are the presence of a large size retinal tear, large retinotomy (especially in 360°), and retinal traction at retinal breaks [78]. It is rare to find it in conventional surgery, but in these cases, it is usually caused by small bubbles which can be produced by turbulence by the interface between PFCL and saline solution [77]. OCT is a useful tool to identify intraretinal bubbles of PFCL. In many cases, the bubbles remain stable without size changing. The most common signs in OCT are RPE pigment disorganization, disruption of ellipsoid layer, and hyperreflectivity at the base of the PFCL bubble (Figure 12) [77]. It has been reported several cases with retinal hole secondary to long-standing subretinal PFCL [79]. Subretinal PFCL is responsible for retinal damage resulting in loss of visual acuity, scotomas, and retinal thinning. Long-time exposure to PFCL can lead to RPE atrophy, photoreceptor damage because there is a direct toxic defect, or inflammatory response including macrophages phagocyted PFCL [77]. It is recommended to remove PFCL bubbles located beneath the macula or if there is a tendency to move to the macular area [80].
Subretinal retention of perfluorocarbon liquid (PFCL) after retinal detachment surgery.
It is a rare ocular lesion which appears on fundus examination as an abnormal, tortuous vessel deep to the retina. It was first described as a serpiginoid atrophic lesion in the temporal macula, with an orange-red aspect and several unspecific choroidal spots in the posterior pole [81]. Choroidal macrovessel is not associated with acute inflammation and symptoms. Some reports have shown hyperpigmentation of the RPE, debris in the subretinal space, and changes in the outer nuclear layer (ONL) thickness [82, 83]. SD-OCT reveals a tubular structure which shows hyperreflectivity band below RPE representing the superior edge of the lesion, with an elevation of RPE and photoreceptor and posterior shadowing [81]. In recent studies, it has been explored with enhanced-depth imaging spectral domain optical coherence tomography (EDI SD-OCT) showing a vascular structure that traversed the entire choroidal thickness and produces an indentation at the choroidal-scleral junction and the ellipsoid zone (EZ) causing a reduction of the ONL thickness [82, 83]. A differential diagnosis from choroidal macrovessel should be made with subretinal nematode tract, choroidal hemangioma, inflammatory choroidopathy, retinochoroidal anastomosis, vortex varix, and aberrant long posterior ciliary artery [81, 83].
It is a pathologic retinal sign that may be appreciated with high-resolution OCT images in some patients with acute CSCR. It is characterized by getting an inverted triangle shape at the outer surface of the detached retina, in those eyes with fibrinous exudate in the subretinal space that protrudes over the RPE [3]. The primary cause of dipping sign seems to be traction due to the fibrinous exudates and the swelling of the ONL. It has been reported that some of the leakage sites (20.3%) show fibrinous exudate as a highly reflective area in the subretinal space, around the leakage site [84]. Additional observations with SD-OCT include thickening of the outer photoreceptor segment layer with invisibility of the inner segment-outer segment junction line and “dipping” of the posterior retinal layer toward the RPE [84, 85]. In later stages, granular deposits may become visible at the posterior surface of the detached retina [85]. It has been documented a decrease in foveal thickness once CSCR is resolved.
CDF is a rare form of macular pathology that can be precisely diagnosed only with OCT. It is characterized by large cystic spaces, or in some cases, giant single cyst in the fovea. It can occur with or without thinned septa between cystic spaces. Usually, it affects patients with diabetic maculopathy, uveitis, RVO, AMD, associated with Streptococcus constellatus endocarditis, and CSR [3, 86]. The hyperreflective OCT appearance of these lesions, followed by cystic change and permanent visual loss, suggests that they might represent retinal infarctions. Their predilection for the fovea may reflect the high metabolic demand at this area of the retina and the narrow-bore capillaries of the perifoveal vasculature.
This pathology is associated with a distortion of IS/OS layer and loss of outer segment of photoreceptors. In comparison with CME, CDF has a more extensive and multitude cysts. As opposed to CME, although CDF cysts may shrink or disappear, there is a limited improvement in visual acuity [3]. FA and fundus autofluorescence (FAF) are not capable of distinguishing CME from CDF.
Thanks to Antonio Arias Palomero and José Juan Valdés González for the effort of searching some of the images showed in this chapter.
Dr. Ascaso reports nonfinancial support from Topcon and Zeiss. All remaining authors have declared no conflicts of interest. All coauthors have seen and agreed with the contents of the manuscript.
Recently, there has been renewed interest in the use of cannabis in patients with treatment resistant epilepsy. This has, in large part, been driven by a public perception that cannabis offers a safe and natural alternative to conventional anticonvulsant therapies. However, the phytocannabinoids found in the cannabis plant do offer some very unique anticonvulsant pharmacological properties that warrant further exploration.
\nIn this chapter the authors will provide a brief review of epilepsy and epileptogenesis followed by a review of how the endocannabinoid system can alter the processes involved in the propagation and suppression of epileptic seizures. This is then followed by a review of the phytocannabinoids and their anticonvulsant mechanisms of action. Finally, the authors provide a historical background on the use of cannabis to treat patients with epilepsy and a review of the most recent clinical trials.
\nEpilepsy is a chronic disease characterized by recurrent unprovoked seizures. It is defined as a disease of the brain in which the patient has either (1) two or more unprovoked seizures occurring more than 24 hours apart or (2) one unprovoked seizure and a probability of further seizures to be greater than 60% [1]. The prevalence of epilepsy worldwide is estimated to be between 4 and 10/1000 people with epilepsy accounting for up to 0.5% of the global burden of disease [2, 3]. There is significant geographic variation with prevalence rates of epilepsy prevalence rates being much higher in the developing world [4].
\nMost children and adults with epilepsy respond well to anticonvulsant therapy with approximately 50% of adults and 70% of children becoming seizure free with their first anticonvulsant medication [5, 6, 7]. Up to 30% of patients with epilepsy can be considered to be drug resistant which is defined by the International League Against Epilepsy as having failed two or more appropriate anticonvulsant treatments at an appropriate dosage [8, 9].
\nIn patients who have failed two appropriate anticonvulsants the likelihood of seizure freedom with the addition of further anticonvulsant therapies is low. Treatment options for patients with drug resistant epilepsy include further trials of anticonvulsants, resective surgery, neural pathway stimulation with receptive or vagal nerve stimulation and dietary therapies [10]. Further trials of anticonvulsants in adults will result in 16% of patients who had failed their first two medications becoming seizure free [11]. In pediatric patients while the likelihood of achieving remission for 1 year or more with further medication trials is higher at 57%, many will continue to have relapses over time [12]. Resective surgery success rates (as defined as obtaining Engel Class 1 seizure freedom) in pediatric and adult patients with surgically amenable epileptogenic lesions range from 34 to 90% depending on the nature and extent of the lesion [10, 13].
\nA full review of the processes that result in brain abnormalities causing seizures (epileptogenesis) is beyond the scope of this chapter. However, in order to understand how cannabinoids can have potential in treating epilepsy it is worth knowing the basic principles of these processes. One of the major hallmarks of epilepsy is the presence of abnormal oscillatory events within neuronal networks in the form of recurrent interictal spikes and high frequency oscillations within the epileptic zones of the patients’ brain [14]. These abnormal oscillations then result in excessive synchronous firing of neurons causing an epileptic seizure with alteration in the patient’s behavior, motor activity or sensorium. Epilepsy can result from injury (either ischemic or traumatic) to cortical brain structures or genetic, inflammatory, structural and metabolic disturbances within the brain. The main components of the development of the abnormal oscillations within neuronal networks and epileptogenesis (seizure development) are (a) neuronal hyperexcitability—the ability of neurons to generate abnormal intrinsic burst discharges (b) a loss of GABA mediated interneuron neuronal inhibition that would normally prevent these discharges from spreading to adjacent neurons and (c) neuronal hypersynchrony in which excessive synaptic enhancement of neighboring neurons through the development of excitatory pathways allows these bursts to spread in a synchronous manner within a group of neurons [15]. Neuronal hyperexcitability can arise from abnormalities in excitatory or inhibitory neurotransmitter receptors resulting in a loss of the normal balance between neuronal excitation and inhibition. Of particular interest in epileptogenesis are the excitatory glutamatergic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors [16]. Alterations in ion channel function as is seen in the channelopathy associated epilepsies such as Dravet syndrome also lead to neuronal hyperexcitability [17].
\nThe endocannabinoid system comprises the two endogenous endocannabinoid receptors (CB1R and CB2R) their two endogenously produced endocannabinoids; anandamide (
Although CB1R is one of the most abundantly expressed GPCRs in the brain, its expression is concentrated within certain groups of neurons. For example, in the hippocampus, CB1R expression is concentrated on the axon terminals of inhibitory GABAergic CA1 region interneurons and Schaffer collaterals arising from CA3 pyramidal cells [22]. These interneurons play a key role in the formation and maintenance of normal oscillatory behavior in the hippocampus essential for memory formation [18]. The effect of stimulation of CB1R is very localized within neuronal networks both from a spatial and temporal point of view. This is achieved by the production of monoacylglycerol lipase (MAGL) by astrocytes and nerve terminals which breaks down 2-AG in the synaptic cleft. This temporal and spatial control allows for precise regulation of oscillations within neuronal networks by the endocannabinoid system [18].
\nDuring an epileptic seizure there is excessive glutamate release from presynaptic excitatory neurons. In rodent models of epilepsy this has been shown to cause increased production of both 2-AG and anandamide that in turn active CB1R on the glutamatergic axon terminals to decrease the release of further excessive glutamate. This prevents further neuronal hyperexcitability which may play a role in terminating seizures. The increased anandamide is felt to play a role in preventing seizure induced excitatory neurotoxic effects [18, 21].
\nTemporal lobe epilepsy secondary to mesial temporal sclerosis (scarring of the hippocampi) is a common cause of epilepsy in adults that is often amenable to surgical resection of the mesial temporal structures. Pathological examination of surgically resected specimens has shown alterations in expression of CB1R of neurons within the hippocampi that provide insight into how disruption of the endocannabinoid system could predispose to epileptogenesis. In resected hippocampi there is a downregulation of CB1R expression on the axon terminals of excitatory (glutamatergic) neurons within the inner molecular layer of the dentate gyrus and an upregulation of CB1R expression on inhibitory (GABAergic) axon terminals within the dentate molecular layer [18]. These changes in CB1R expression result in both a loss of the normal inhibition of excessive glutamate release and increased suppression of GABAergic activity both of which result in increased neuronal hyperexcitability and subsequent seizure generation [22]. In patients with chronic epilepsy, there is also a decrease in the amount of anandamide and 2-AG released with excessive neuronal activation further contributing to a loss of the endocannabinoid mediated inhibition of excessive neuronal activation [18].
\nThe growing body of evidence demonstrating the role the endocannabinoid system plays in the brains’ mechanisms in regulating neuronal network oscillations and preventing excessive neuronal hyperexcitability coupled with alterations in the endocannabinoid receptors seen in epileptogenic tissue make the endocannabinoid system an attractive therapeutic target in the treatment of epilepsy. Modulation of the endocannabinoid system would provide a potential novel anticonvulsant mechanism not provided by other anticonvulsant therapies.
\nThe phytocannabinoids are a class of cannabinoids that are produced by plants of the cannabis species. The phytocannabinoids are C21 aromatic compounds consisting of an aromatic isoprenyl terpenophenolic core and resorcinyl side chain. Based on the structure of the oxygen bond between the isoprenyl and resorcinyl moieties the phytocannabinoids can be placed into 6 main families. Within each family, variations of the R-chain on the resorcinyl moiety differentiate each individual cannabinoid [23]. To date, over 140 different phytocannabinoids have been identified in
Initial research focused on the anticonvulsant effects of Δ9-THC and other CB1R agonists such as anandamide. Through their activation of CB1R, anandamide and the synthetic cannabinoid WIN 55,212-2 were able to block the production of postsynaptic neuronal spiking and excitatory post synaptic potential production. Both compounds were also able to suppress the production of abnormal burst activity in neurons placed in Mg2+ depleted solution. Depletion of Mg2+ in solution allows activation of NMDA receptors at normal resting potentials without the usual prerequisite neuronal depolarization. This effect was abolished when CB1R antagonists were added, suggesting that the effect was secondary to activation of CB1R by these agents [26]. Δ9-THC is a major phytocannabinoid in
In a rat model of electrically induced limbic seizures Δ9-THC increased the threshold of electrically induced after discharges at the site of electrode implantation in the left subiculum. However, Δ9-THC increased the duration of cortically recorded after discharges in electrodes remote from the site of stimulation. This suggested that Δ9-THC may have both anticonvulsant and proconvulsant effects in focal onset epilepsies [27]. In the cobalt model of focal epilepsy in rats Δ9-THC increased the frequency of epileptic potentials at the site of the cobalt-induced lesion. This was not seen with Δ9-THC’s main metabolite 11-OH-Δ9-THC. Both Δ9-THC and 11-OH-Δ9-THC seemed to increase generalized cortical excitation as seen by the production of brief intermittent cortically recorded after discharges [27]. Similar findings were seen in a rat model using iron to induce a seizure focus. While both Δ9-THC and 11-OH-Δ9-THC both caused increased cortical excitability, only Δ9-THC provoked clinical seizures. As well, the dose of Δ9-THC required to induce seizures was much higher than that required to induce electrographic changes in keeping with cortical excitation [29]. In mice, Δ9-THC has also been shown to induce kindling of a second epileptic focus in response to both electroconvulsive therapy as well as pentylenetetrazol (PTZ) and picrotoxin induced seizures [30]. When administered to rabbits with a genetic mutation causing audiogenic seizures Δ9-THC caused signs of neurotoxicity but prevented seizures when the rabbits were stimulated with a sound stimulus above their normal seizure threshold range. Conversely, in another breed of rabbits, injection with Δ9-THC induced both neurotoxicity and behavioral seizures in a dosage dependent manner [31].
\nThe results of these studies show that Δ9-THC and its metabolites display anticonvulsant activity in animal models using seizure models with rapidly evoked tonic discharges which mimics certain types of generalized onset seizures in humans. However, in models mimicking focal onset seizures, Δ9-THC and its metabolites seem to display a proconvulsant effect. This is manifested by increasing the activity at the site of the focal lesion and increasing generalized cortical activity [27]. A proconvulsant effect is also seen in models mimicking genetic based generalized epilepsies and absence seizures. Δ9-THC and its metabolites seem to induce hypersynchrony with slowly propagating epileptic discharges [32]. While Δ9-THC showed some potential as an anticonvulsant agent the potential to increase seizure activity along with its neurotoxic and psychotropic side effect profile limited its potential benefit in patients with epilepsy.
\nCBD is a low affinity negative allosteric modulator of CB1R with no psychotropic side effects due to the fact it does not cause activation of CB1R. It modulates the influx of both Ca2+ and Na+ into neurons by binding to human T-type voltage gated Ca2+ channels, Melastatin and Vanilloid type Transient Receptor Potential membrane receptors (TRPM and TRPV) and voltage gated Na+ channels [19]. This decreases neuronal excitability in response to stimulation. CBD has also been shown to inhibit intrasynaptic re-uptake of adenosine as well as activation of neuronal Serotonin, Glycine and Vanilloid receptors [33, 34]. The anticonvulsant effect of CBD is felt to be independent of activation of the endogenous CBR pathways. While the exact mechanism of anticonvulsant activity of CBD remains uncertain it appears to have a poly-pharmacological effect on modulating neuronal excitability.
\nIn the Cobalt induced focal epilepsy rat model CBD had no effect on focal discharges at the lesion site but decreased the frequency of seizures. CBD also blocked the proconvulsant effects in of Δ9-THC [27, 35]. In the limbic seizure rat model CBD decreased the frequency, duration and amplitude of electrically induced after discharges at the site of stimulation in the left subiculum but did not prevent the spread of after discharges from the site of focal stimulation to distal electrodes. It had no apparent effect on generalized cortical excitability. This suggests that in focal models of epilepsy, CBD acts directly on the site of focal seizure onset [27].
\nOther animal studies continued to show the anticonvulsant effect of CBD in both transcorneal electroshock, drug induced and lesional epilepsies. This anticonvulsant effect was seen when a single intraperitoneal (i.p.) dose of CBD was administered alone but like Δ9-THC it also potentiated the effects of several anticonvulsant medications [33, 36, 37]. While CBD had potent anticonvulsant effect against tonic seizures its effect against clonic seizures was minimal. Consroe et al. hypothesized that this effect was due to the fact that tonic seizures are spread rapidly throughout the brain from a focal lesion via post-tetanic stimulation. Unlike Δ9-THC, CBD suppressed tetanic potentiation in isolated bullfrog ganglia [27]. This coupled with the fact that CBD is effective in preventing 3-Mercaptoproprionic acid (3-MPA) induced seizures suggested that some of the anticonvulsant effect of CBD may result from its ability to increase production of GABA in presynaptic GABAergic neurons [36]. Unlike Δ9-THC, the brain concentrations of CBD correlated well with its anticonvulsant effect in several animal models. This suggests that the anticonvulsant effect of CBD is due to the parent compound and not its metabolites [27].
\nIn summary, CBD was shown to display broad spectrum anticonvulsant activity in a wide range of animal models of epilepsy including generalized seizures caused by electroshock and GABA inhibiting drugs and focal seizures induced by placement of toxic metals on the cortex. It however had no effect on models of generalized absence seizures [38]. CBD also blocked kindling of a second epileptic focus [36]. Even at high doses it failed to cause any behavioral or cognitive side effects in test animals. This would suggest that CBD is a potent anticonvulsant with limited cognitive side effects, making it an attractive potential anticonvulsant in the pediatric population [33, 37].
\nIn addition, Δ9-THC and CBD several other cannabinoids have been evaluated for the potential anticonvulsant activity. These include ∆9-tetrahydrocannibivarin (∆9-THCV) and cannabidivarin (CBDV) which have been shown to have anticonvulsant effects. ∆9-THCV is a non-psychoactive cannabinoid that acts as a CB1R antagonist. In a Mg2+ depleted solution ∆9-THCV decreased the amplitude and duration of abnormal neuronal burst activity. ∆9-THCV potentiated the effects on neuronal bursting of both phenobarbital and valproic acid. In a PTZ rat model ∆9-THCV did not decrease the severity or duration of seizures or seizure mortality. However significantly fewer rats exposed to PTZ that were treated with ∆9-THCV displayed seizures compared to those that were given PTZ alone [39]. Like CBD, CBDV is believed to exert its effects via CB1R independent mechanisms and has limited neurotoxicity [40]. CBDV has been shown to decrease the amplitude and duration of abnormal bursting in mouse and rat hippocampal slices in in both Mg2+ depleted solution and solution to which 4-aminopyridine (4-AP) has been added. CBDV also significantly decreased the number of seizures seen in in vitro MES and audiogenic seizure models in mice and PTZ induced seizures in rats. Unlike CBD, CBDV also prolonged the latency of seizure induction in a dose dependent manner. Administration of CBDV had no effect on motor performance in mice regardless of the ode administered [41]. The terpenes, which are another class of compounds found in cannabis, also possess a wide range of pharmacological activity on the mammalian nervous system at very low concentrations. Individually, these terpenes have not been assessed in patients with epilepsy [42, 43].
\nThe combinatorial effect of the chemical components of cannabis has been postulated wherein cannabis whole plant extracts may benefit from ‘entourage’ effects to yield greater effectiveness than treatment with a purified cannabinoid [42, 44]. This is supported by preclinical studies. In the
The use of cannabis as a treatment for a variety of ailments in eastern and Mediterranean cultures over the last several millennium has been well documented [47]. The first description of the use of cannabis to treat seizures came from Dr. W. O’Shaugnessy who while working in India reported its successful use to treat seizures in an infant [48]. Following this, cannabis extracts became widely used throughout Europe and North America as an accepted treatment for epilepsy [49]. Following prohibition and with the introduction of other anticonvulsants, cannabis fell out of use as a treatment for epilepsy in western cultures.
\nDuring the mid-twentieth century, several reports on the effect of recreational cannabis consumption surfaced with contrasting effects. Several case reports described patients having decreased seizure frequency following the consumption of cannabis [50]. Cannabis consumption was also shown to be protective against first unprovoked seizures. In adult males who smoked cannabis in the last 90 days, the odds of having a first unprovoked seizure was 0.38 compared to adult males who never consumed cannabis [51]. Conversely, a patient with a history of epilepsy who had been seizure free for several months on medication was reported to have had an exacerbation of seizures following the consumption of cannabis [52].
\nIn 1978, Mechoulam et al. reported their double blinded placebo-controlled study of CBD used as an add-on therapy in patients with refractory focal onset seizures. Of the four patients who took CBD two were seizure free for the 3 months of the study while another had partial improvement. None of the five patients who took placebo had any improvement in their seizures [53]. Cunha et al. reported the results of their study investigating the potential of CBD in patients with refractory temporal lobe epilepsy. In the first phase of the study, healthy adult volunteers were randomized to receive either placebo or CBD at 3 mg/kg/day for 30 days. Of 8 volunteers receiving CBD, 2 reported somnolence otherwise no adverse effects were reported. In the second phase, 15 adult patients with drug-resistant temporal lobe epilepsy were randomized to receive either placebo or CBD (up to 300 mg/day) for a period of 18 weeks in a double-blinded manner. Four of 8 patients dosed with CBD had complete improvement while three had partial improvement. No adverse effects were noted in patients given CBD [54].
\nTwo further studies showed no significant difference in seizure reduction with the addition of CBD as an adjunctive therapy. However, in one study patients were given CBD at a dose of 300 mg/day and their plasma CBD levels were maintained at 20–30 ng/ml. Subsequently one participant who had no difference in their seizure frequency was placed on CBD at a higher dose of up to 1200 mg/day. CBD plasma levels were higher averaging 150 ng/ml. This patient had a significant decrease in their seizure frequency suggesting that higher doses of CBD (and higher plasma levels) were required for seizure control [55].
\nIn recent years there has been a public perception that cannabis is a potent, natural, and safe alternative therapy for epilepsy. This has driven the demand for and use of cannabis and its derived products to treat epilepsy especially in those patients whose seizures are medically intractable. Coupled with the media exposure showing examples of the apparent miraculous effects of CBD oil in select epileptic patients, treating physicians have struggled to balance the patient demand for cannabis products and the need for studies to determine their, efficacy, dosing, side-effect profile, and indication. To that end, there have been multiple studies, predominantly in children, looking into these clinical questions. Unfortunately, the overwhelming majority of these studies have been retrospective, unblinded, and uncontrolled resulting in their being hampered by various forms of bias and potential placebo effect. Despite the plethora of published research on this topic, questions still remain on the use of cannabis in epilepsy.
\nIn this section, we will review the limitations of the studies, the studies using artisanal and CBD enriched cannabis herbal extracts (CHE), the studies using highly purified pharmaceutical grade CBD, and a meta-analysis of the CBD studies.
\nThe widespread use of cannabis and the effect of bias are highlighted in various published surveys. McLachlan performed a survey in London, Ontario, Canada, in which more than 60% of patients declared that cannabis was effective for their seizures and stress levels [56]. Ladina et al. reported a case series of 18 patients who all found medicinal cannabis very helpful for seizure control and improvement of mood disorder [57]. By contrast, Press had reported a significant discrepancy in reported responder rate between preexisting Colorado residents and those who moved to Colorado to obtain cannabis to treat their child’s epilepsy (22 vs. 47%) suggesting there is a significant perception bias among these children’s caregivers as to the therapeutic benefits of cannabis [58]. Physician bias may also play a role as a recent survey by Mathern showed contrasting opinions about CBD between neurologists and the general public. In his study, a minority of epileptologists and general neurologists said that there were sufficient data safety (34%) and efficacy data (28%) and only 48% would advise using medical cannabis and only in severe cases of epilepsy. Conversely, nearly all patients and the general public responded that there was sufficient safety (96%) and efficacy (95%) data, and 98% would recommend cannabis in cases with severe epilepsy [59].
\nGiven the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with “illicit” cannabis extracts, the majority of extract samples used by the families contained low concentrations of cannabidiol, while Δ9-THC was present in nearly every sample [60]. These findings highlighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of published studies included serum CBD levels.
\nTo date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None involved artisanal CBD or the CBD oil extracts.
\nWhile keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing seizures and improving quality of life.
\nTzadok reported out of 74 children being treated with a 20% CBD and 1% Δ9-THC CHE, 89% reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].
\nSimilarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and clobazam group [62].
\nMcCoy et al. performed a prospective open label study using a 2:100 Δ9-THC:CBD CHE in 20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements in quality of life measures and spike index on electroencephalogram (EEG). Adverse events during the titration period included somnolence, anorexia and diarrhea [63].
\nThe Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent with a single batch of 1:20 Δ9-THC:CBD CHE used for all study participants. Concentrations of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum Δ9-THC concentrations remained lower than what would be expected to cause intoxication even at the maximum dose of oil extract. None of the participants displayed any evidence of Δ9-THC intoxication clinically throughout the study. Preliminary data suggests that an effective and well-tolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ9-THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].
\nWith the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias remained, better clinical studies had been performed.
\nDevinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7) [66].
\nFrom this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life (QOL). Interestingly, these differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure reducing effects [67].
\nDevinsky et al. later performed a double blind, placebo-controlled trial in patients with Dravet syndrome including 120 children and young adults using Epidiolex with a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD, as compared with a decrease from 14.9 (baseline) to 14.1 with placebo (adjusted median difference between cannabidiol vs. placebo was −22.8% points [CI], −41.1 to −5.4; p = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93–4.30; p = 0.08). This study shows an overall benefit of CBD over placebo but also a large placebo effect in the control group [68].
\nAnother trial that assessed the efficacy of Epidiolex in reducing atonic seizures in patients with Lennox-Gastaut syndrome. In this double blind, placebo-controlled trial, a total of 225 patients were enrolled, 76 patients were assigned to a treatment group (20 mg/kg/day CBD) and 76 to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 41.9% in the treatment group vs. 21.8% in the placebo group. As with the other studies assessing Epidiolex, the most common adverse events among the patients in the treatment groups were somnolence, decreased appetite, and diarrhea [69].
\nA recent systematic review assessed the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug resistant epilepsy with outcome measures including 50% seizure reduction, complete seizure freedom, improved QOL. A total of 36 studies were identified including 6 randomized controlled trials and 30 observational studies. Overall CBD at a dose of 20 mg/kg/day was more effective than placebo in reducing seizure frequency by 50% (Relative Risk 1.74: 1.24–2.43). For one patient to achieve a 50% reduction in seizures the number of patient needed to treat was 8. In pooled data of 17 of the observational studies CBD at 20 mg/kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures (95% CI: 39.0–58.1%) while pooled data from 14 observational studies showed 8.5% of patients became seizure free (95% CI: 3.8–14.5%). Quality of life improved in 55.8% of patients (95% CI: 40.5–70.6%) while serious adverse events related to treatment with CBD was very low at 2.2% of patients (95% CI: 0.0–7.9%). From this data, the authors concluded that pharmaceutical grade CBD may reduce seizure frequency but other randomized controlled trials examining a more diverse group of epilepsy syndromes and other cannabinoids was needed [70].
\nTo date, the evidence to support the use of cannabis in adults is minimal. STAR 1 is a phase 2A, randomized, double blind, placebo-controlled study that evaluated the safety and efficacy of synthetic transdermal CBD in adult patients with focal epilepsy. In this study 174 patients were randomized to receive either 195 mg CBD, 390 mg CBD or placebo via a transdermal patch. Patients who completed the 12-week study were able to continue into the 24-month open-label extension STAR 2 study (n = 171). In as of yet published data from these trials there was an increase in efficacy of transdermal CBD over 18 months. Median percentage change in seizure rates was −25% at 3 months, −40% at 6 months, −48% at 9 months, −52% at 12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were seen [71].
\nIn comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol’s responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic (“drop attack”) seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73].
\nOf note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This apparent superiority of a CHE containing Δ9-THC would be in keeping with the proposed entourage effect in which the various cannabinoids can act synergistically with one another [42, 44].
\nThe cannabinoids found in cannabis appear to offer a unique pharmacological mode of action in the treatment of epilepsy. This, combined with the apparent low risk of serious side effects, makes cannabis and an attractive potential option for patients with treatment resistant epilepsy.
\nCurrently, there is a large public perception that cannabis products are superior to and safer than conventional anti-epileptic medications especially in treating patients with Dravet syndrome and other pediatric onset epileptic encephalopathies. Based on interpretation of the available data, the authors feel that cannabis based therapies show promise in the treatment of children with treatment resistant epilepsies. While the studies to date assessing cannabis based therapies for the treatment of epilepsy have been encouraging, they should be interpreted with caution. At this time, the long-term adverse effects, the indicated epilepsy and seizure types suitable for treatment with cannabis, the dosing of CBD and other cannabinoids, remain unknown. Also, there is minimal data regarding the pharmacokinetics of the cannabinoids especially in children and when used in patients with multiple concomitant medications. Moreover, the existing studies are limited with the majority of them being retrospective and subject to bias, possible placebo effect, and other limitations.
\nAs such, further studies assessing the safety and efficacy of cannabis based therapies in both adults and children are urgently needed. The authors recommend that these studies start with well-designed dose finding studies that include age stratified pharmacokinetic analysis followed by larger scale clinical trials. When faced with physicians that are reluctant to authorize cannabis based products due to a lack of high quality safety and efficacy data, parents who are desperate to help their children are then forced to turn to unregulated suppliers of cannabis. This puts their children at risk of harm and themselves in legal jeopardy.
\nPurpose statement: This chapter explores the role of cannabis-based therapies in the treatment of children and adults with epilepsy.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. 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