Fig. 9.1
Progressive multiple sclerosis nomenclature. Progressive MS nomenclature according to the current criteria [2]
Prior to the 2013 MS disease course revision, the phenotype of a patient with primary progressive disease course, who concurrently experiences relapses, was classified as progressive relapsing MS (PRMS) [5]. However, according to current nomenclature, descriptors for disease activity (relapses or MRI activity) and progression (clinical worsening or progression of brain atrophy) are appended to primary and secondary progressive disease courses (Fig. 9.1) [2].
Pathological and imaging studies suggest that relapsing and progressive MS are a single disease entity with distinct clinical phenotypes [4, 6]. However, in contrast to RRMS, the mechanisms underlying progressive MS are poorly understood, and therapeutic options available in RRMS are usually not effective. As a consequence, therapeutic options in progressive MS are limited to fairly unspecific immunosuppressive agents, such as azathioprine, mitoxantrone, or cyclophosphamide, which all carry the risk of serious side effects [7–9], and symptomatic treatments. When a certain disability landmark or a progressive course has been reached, the disease tends to progress relentlessly and largely independently of the preceding course and relapse number and severity [10, 11]. This is presumably related to the fact that the efficiency of remyelination declines with increasing age and disease duration [12, 13]. In progressive MS, neurodegeneration is thought to occur independently of the initial inflammatory response [4], although inflammation is present at all MS stages [14]. Neuropathological studies suggest that inflammatory processes in progressive MS brains at least partially evolve independently of damage to the blood-brain barrier, which may explain why potent anti-inflammatory disease-modifying drugs given in the periphery are inefficacious in progressive MS [4]. A key feature of progressive MS is pronounced cortical demyelination including cortical lesions and, more broadly, diffuse and widespread damage to the normal-appearing white and gray matter. Several mechanisms underlying disease progression have been proposed, including axonal demise in focal white matter lesions and loss of remyelination, which may cause ongoing accrual of neurological disability when functional compensation is exhausted. Microglial activation, altered axonal ion homeostasis, mitochondrial injury, oxidative stress, and iron accumulation are—although not unique to progressive MS—considered relevant contributing factors to irreversible tissue damage [4, 12, 15].
Optical Coherence Tomography in Progressive Multiple Sclerosis
An overview of current optical coherence tomography (OCT) measurement protocols used in progressive multiple sclerosis is given in Fig. 9.2. The peripapillary retinal nerve fiber layer (RNFL or the more specific abbreviation pRNFL) is the most established parameter and features in almost all studies to date. Measurement of total macular volume (TMV) is less common and has been recently superseded by intraretinal layer segmentation in macular volume scans.
Fig. 9.2
Optical coherence tomography measurements. Common optical coherence tomography protocols and derived parameters useful in diagnosing and monitoring patients with progressive MS
Investigation of progressive MS using OCT is far rarer than in relapsing-remitting MS [16]. The few studies that include OCT findings specifically in progressive MS have had cohorts of such a few patients each and have used different generations of OCT technology (time domain and spectral domain OCT, whose measurements are not directly comparable) [17, 18]. Some studies (e.g., [19]) combine relapsing-remitting and progressive MS patients in one analysis and are therefore not discussed here in detail. An overview of relevant studies, including key findings, is given in Table 9.1 [20–32]. The key findings of all studies are summarized below.
First author | Year | OCT | PPMS | SPMS | Key findinga | Ref. |
|---|---|---|---|---|---|---|
Pulicken | 2007 | TD | 12 | 16 | This study did not differentiate between eyes with and without previous optic neuritis but included this information as covariate RNFL thickness in eyes from SPMS (81.8 ± 15.6 μm) and PPMS patients (88.9 ± 13.3 μm) was significantly lower than in HC (102.7 ± 11.5 μm) and showed a marked decrease compared to RRMS patients (94.4 ± 14.6 μm) TMV was not different between HC (6.6 ± 0.5 mm3), RRMS (6.5 ± 0.5 mm3), and PPMS patients (6.5 ± 0.6 mm3). SPMS patients showed decreased TMV (6.2 ± 0.4 mm3) | [20] |
Henderson | 2008 | TD | 23 | 27 | This study specifically investigated eyes without previous optic neuritis In comparison to HC (98.8 ± 10.5 μm), RNFL thickness from SPMS patients’ eyes (88.4 ± 10.9 μm) was significantly lower and RNFL thickness from PPMS patients’ eyes nonsignificantly lower (93.9 ± 13.9 μm) The same was true for TMV with HC (6.81 ± 0.31 mm3), SPMS (6.46 ± 0.41 mm3), and PPMS (6.64 ± 0.42 mm3) | [21] |
Costello | 2009 2010 | TD TD | 0 9 | 7 13 | This study separated between eyes with and without previous MSON In eyes without history of MSON, RNFL thickness was reduced in PPMS (94.3 ± 8.3 μm), RRMS (99.6 ± 14.3 μm), and SPMS eyes (84.7 ± 11.7 μm), compared to CIS eyes (105.7 ± 12.3 μm) | [22] [23] |
Siepman | 2010 | TD | 29 | (34)b | This study found no difference in RNFL thickness in eyes of PPMS patients with eyes of (data not published) | [24] |
Serbecic | 2010 2014 | SD SD | 0 0 | 17 17 | SPMS patients with or without previous MSON showed significantly reduced RNFL thickness compared to healthy controls. In patients with previous optic neuritis, even greater RNFL reduction was found | [25] [26] |
Saidha | 2011 | SD | 16 | 20 | GCL + IPL was significantly thinner in RRMS patients (71.6 ± 9.8 μm), SPMS (66.4 ± 10.2 μm), and PPMS (74.1 ± 7.1 μm) than in healthy controls (81.8 ± 6.3 mm). GCL + IPL thickness was most decreased in SPMS. GCL + IPL thickness correlated significantly with EDSS, high-contrast, 2.5 % low-contrast, and 1.25 % low-contrast letter acuity in MS. A subset of patients showed thinning of the outer retinal layers | [27] |
Albrecht | 2012 | SD | 12 | 41 | PPMS and SPMS patients showed significant thinning of peripapillary RNFL and GCL + IPL in both patients with and without previous MSON. The INL was only reduced in PPMS in comparison to HC in both patients with and without previous optic neuritis | [28] |
Gelfand | 2012 | SD | 33 | 60 | This study focused on CIS and compared damage to later diseases stages Retinal axonal loss was increasingly prominent in more advanced disease stages with proportionally greater thinning in eyes previously affected by optic neuritis. In the absence of clinically evident optic neuritis, RNFL thinning was similar between progressive MS subtypes | [29] |
Oberwahrenbrock | 2012 | SD | 41 | 65 | RNFL thickness was reduced in SPMS eyes compared to RRMS eyes, and TMV was reduced in SPMS and PPMS eyes compared to RRMS eyes, regardless of MSON history. Independent of MS subtype, more pronounced RNFL thinning and TMV reduction were found in eyes with previous MSON | [30] |
Balk | 2014 | SD | 29 | 61 | PPMS patients showed more intact inner retinal layers (RNFL to INL) compared to relapsing onset MS patients. Only in MS eyes without previous MSON did patients with typical MS show more severe thinning of the inner retinal layers compared to patients with a benign disease course, even after an average disease course of 20 years |
Retinal Nerve Fiber Layer Thickness and Total Macular Volume
Scans of patients with progressive MS show reduced RNFL thickness in the peripapillary ring compared to healthy controls and also relapsing-remitting MS patients. An overview plot from [30] is given in Fig. 9.3, and a sample report is shown in Fig. 9.4.
Fig. 9.3
RNFL and TMV in progressive MS. Peripapillary RNFL and TMV from patients with relapsing-remitting and progressive MS (Adapted from Oberwahrenbrock et al. [30]). Eyes with a previous history of MSON on the left, eyes without history of MSON (NON) on the right
Fig. 9.4
OCT imaging in secondary progressive MS. Shown are sample findings from an eye from an SPMS patient with a history of optic neuritis. (a) Normal scanning laser ophthalmoscopy image showing the peripapillary ring scan area. (b) Peripapillary OCT ring scan showing reduced RNFL thickness (red lines). Note that the coincidental vitreous detachment is of no pathologic relevance. (c) Height profile in comparison to normative data in the nasal (NAS), inferior (INF), temporal (TMP), and superior (SUP) areas of the ring scan. Colors indicate RNFL thickness within the 95th percentile (green), between the 95th and 99th percentile (yellow), below the 99th percentile (red), and with regard to thicker RNFL higher than 1st percentile (purple) and between the 1st and 5th percentile (blue). (d) Profile data from c visualized in a typical sectorial circle with color indicators derived from c. On the left, a detailed view on the temporal-superior (TS), nasal-superior (NS), nasal (N), nasal-inferior (NI), temporal-inferior (TI), and temporal (T) sectors. Additionally, the figure shows average RNFL thickness (G) and RNFL thickness in the papillomacular bundle (PMB) as well as the N/T ratio. The right-hand image focuses on superior, nasal, inferior, and temporal quadrants exclusively. The temporally accented RNFL thickness reduction is typical for eyes after optic neuritis both in relapsing-remitting and secondary progressive MS. The nasal sectors are also affected, but here thickness reduction is often mild and is within normal physiology, as is the case for this patient
Two potential explanations for the pronounced RNFL thinning in progressive patients exist: first, these patients may show more pronounced loss based on a more severe or also different disease pathology than relapsing-remitting patients [27]; and second, the investigated patients may simply have experienced longer disease duration, giving time for a greater damage accumulation [29, 30]. Data from studies published to date are not sufficient to answer this question. An additional confounder is a patient history of MS-associated optic neuritis (MSON). It is universally accepted that MSON additionally damages the retina, quantified by increased RNFL thinning, and such episodes may often be subclinical or unrecognized, leading to an accumulation of damage the longer the disease lasts. Nonetheless, it is conspicuous that PPMS patients, who by definition do not suffer from relapsing MSON, show a similar RNFL reduction as SPMS patients without previous optic neuritis, suggesting that non-relapse-associated neuro-axonal degeneration in the retina and optic nerve also occurs in other MS disease courses.
Current data does not allow any solid conclusions regarding the spatial distribution of RNFL reduction in progressive MS. MSON-associated damage leads to pronounced effect of the temporal quadrant in relapsing-remitting MS [33, 34], but whether this is also the case in progressive MS patients without previous MSON has not been investigated sufficiently. Likewise, the few applicable longitudinal studies to date do not show how RNFL reduction develops over time (see later).
Data on total macular volume (TMV) or thickness changes is scarce. Only a few studies have investigated TMV together with RNFL, because TMV is generally considered less specific than RNFL as it measures the whole retinal thickness instead of solely the main region of interest. [35] Published data supports this notion with similar but less specific findings in comparison to RNFL (see Fig. 9.4 for an example).
Intraretinal Layers
Since the introduction of spectral domain OCT, different intraretinal layer thicknesses can be derived from macular volume scans. This allows the potential investigation of distinct pathologies in the retina of patients with MS, which affect other layers than the RNFL. Evidence for intraretinal changes in MS is shown in histopathology studies, in which, for example, neuronal loss in the inner nuclear layer has been reported [36]. So far, the few studies applying intraretinal segmentation have detected changes—as expected—mainly in the ganglion cell layer (GCL) and inner plexiform (IPL) thickness (often combined as ganglion cell and inner plexiform layer [GCIPL] for increased reliability). Data for outer retinal layers is less consistent. Of interest is the inner nuclear layer (INL), for which both thickening and thinning have been reported. One study suggested that INL thickness increases with disease severity [37]. Another study showed that an increased INL thickness correlates with worsened brain atrophy, specifically in progressive MS. However, several studies also showed INL thinning in progressive MS (e.g., [28]), and it is currently unclear exactly how INL thinning and thickening occur in relation to MSON, disease duration, and disease severity.
Microcystic Macular Edema, and Retrograde Maculopathy
One form of INL thickening is microcystic macular edema (MME), initially described in less than 10 % of MS patients [38]. MME can also occur in progressive MS, as the example in Fig. 9.5 shows. However, MME is not specific to MS and has since been reported in several different ocular pathologies [39]. It is now established that MME is associated with acute optic nerve damage [40] and most likely reflects unspecific reactive processes in the inner nuclear layer to acute ganglion cell degeneration, as also discussed in the chapter by Mathias Abegg in this book [41]. The terms retrograde maculopathy or macular microcystoids have been suggested as more appropriate than MMO for this OCT sign [42, 43].
Fig. 9.5
Microcystic macular edema can occur in eyes from patients with MS, including progressive MS. On the left, a scanning laser ophthalmoscopy image shows typical darker areas around the macula with accentuation of the optic nerve head-facing side. The green line indicates the B-scan position on the right. On the right a B-scan of the affected area shows few cystoid structures, marked with yellow arrows, in the inner nuclear layer
Primary Macular Phenotype
On the other hand, Saidha et al. have reported macular thinning spanning all intraretinal layers of a subgroup of MS patients with comparably intact RNFL [44]. The study showed that this macular thinning predominant (MTP) phenotype occurred more frequently in progressive MS patients than in relapsing-remitting MS patients and could represent an extreme form of a primary macular pathology in MS patients. The MTP phenotype was potentially recently confirmed in a different US cohort [45]. However, its exact characteristics and significance are currently unclear. We and others (personal communication) have not been able to identify any patients showing this phenotype, and this potentially interesting finding requires further investigation [46].
Association of OCT Findings with MRI Measures of Brain Damage
Several studies have shown an association of retinal damage as measured by OCT with brain atrophy (brain parenchymal fraction [BPF], gray and white matter volume) on magnetic resonance imaging (MRI) (Fig. 9.6) [37, 40, 47–52]. However, only a few of these studies described or investigated patients with progressive MS separately. A key finding in a study of 61 MS patients by Sepulcre et al., comprising 5 SPMS, 6 PPMS, and 29 healthy controls [19], showed significant correlation of whole gray matter and whole white matter volumes with average RNFL thickness in MS patients; however, separated analyses for the few progressive patients were not provided. Gordon-Lipkin et al. were the first to show that lower RNFL thicknesses were associated with reduced BPF and cerebrospinal fluid (CSF) volume in a cohort of 40 MS patients, but not in 15 healthy controls [48]. The MS cohort comprised 20 RRMS, 15 SPMS, and 5 PPMS patients; however, OCT results (RNFL, TMV) were only given for the MS group as a whole, instead of per subgroup. Subgroup analyses on correlation between OCT measurements and brain atrophy were only run on RRMS and SPMS patients and revealed that RNFL thickness was significantly related to BPF and CSF volume in RRMS, but not SPMS. The authors discussed two possible explanations: (1) a possible basement effect in progressive patients, in which either RNFL or brain volume bottom out with minimal further decline, or (2) primary involvement of the spinal cord, but less cerebral involvement in SPMS. Both these intriguing hypotheses will require longitudinal studies. However, using OCT as an outcome tool in trials with potentially neuroprotective agents in patients with progressive disease carries an important caveat: when substantial retinal loss has already occurred at the time of study inclusion, it may be too late to detect slowing of further tissue loss by experimental treatment versus placebo or active comparator when measuring RNFL or TMV.
Fig. 9.6
OCT and brain atrophy. Retinal layer thickness correlates with brain atrophy and also disease severity in progressive MS. Shown are 2 cases: one patient with low disease activity and low gray matter (GM) atrophy on the left, and one patient with high disease activity and severe GM atrophy on the right. (a) T1 MRI scans from these patients showing a periventricular slice. (b) Inner nuclear layer (INL) changes. Some patients with high disease activity show increased INL thickness, which might correspond to higher neuroinflammatory activity in these patients [37, 40]. INL can also appear unchanged or thinned in severely affected patients, and the relevance, if any, of either occurrence still needs to be determined. Factors leading to either development still need to be determined. (c) Ganglion cell and inner plexiform layer (GCIPL) thickness correlates with brain and GM atrophy similarly to retinal nerve fiber layer thickness (RNFL). Neuronal loss in the brain coincides with neuronal loss in the ganglion cell complex (GCC), consisting of inner plexiform, ganglion cell, and retinal nerve fiber layers. Retinal ganglion cell dendrites reside in the inner plexiform layer, cell bodies in the ganglion cell layer, and projecting axons in the retinal nerve fiber layer. However, neurodegeneration does not seem to spread beyond the INL [47]
Another cross-sectional study on the relationship between retinal neuro-axonal measures and brain volume measurements comprised 84 MS patients (58, relapsing-remitting disease course; 18, secondary progressive; 8, primary progressive) [52]. SPMS and PPMS patients were older than RRMS patients (mean 58.3 and 55.0, respectively, vs. 37.4 years) and had longer disease duration (mean 21.7 and 15.8, respectively, vs. 7.5 years), whereas the proportion of eyes with a history of optic neuritis was comparable between RRMS and SPMS patients (26 % and 28 %, respectively). In contrast to Gordon-Lipkin et al., this study used advanced spectral domain OCT technology, which enables segmentation of individual intraretinal layers (see previous). Intracranial volume was significantly positively associated with the combined measure (GCIPL) of ganglion cell layer (GCL) and inner plexiform layer (IPL) in both healthy controls and the entire MS cohort. Inner nuclear layer (INL) thickness was inversely associated with the volume of the normal-appearing white matter (NAWM) in the entire MS cohort, and peripapillary RNFL (pRNFL) thickness positively correlated with cortical gray matter volume in RRMS. Subgroup analyses revealed a positive association of outer nuclear layer (ONL) thickness with cortical gray matter (GM) volume in SPMS patients and in PPMS patients, positive correlations of ONL thickness with brainstem volume and of pRNFL thickness with NAWM and cortical GM volume. However, the significance of these findings—as the authors acknowledge—is limited by the low number of patients in the progressive disease course groups and the high number of statistical tests without correction for multiple comparisons, giving rise to the possibility that the identified correlations occurred by chance alone.
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