Steve Brown

Brian Squire

Mike Lewis

THE IMPACT OF INCLUSIVE AND FRAGMENTED OPERATIONS STRATEGIES ON OPERATIONS PERFORMANCE

Keywords:

établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

This paper examines the relationship between the process and content of operations strategy within firms and plant performance in a range of operations parameters. Further, the paper examines the explicit links between business mainstream and operations strategies within firms by exploring the strategy formulation process and possible links between this relationship and subsequent operations performance. Although there is a substantial body of work that explores the links between operations strategy (OS) and a range of performance outcomes (Tunälv 1992[START_REF] Kathuria | Aligning work force management practices with competitive priorities and process technology: a conceptual examination[END_REF], Deveraj et al. 2004, Rhee and Mehra 2006) there is more ambiguity is in establishing links between how OS is formulated and operational performance. There is an OS process literature (e.g. [START_REF] Skinner | Manufacturing -the missing link in corporate strategy[END_REF][START_REF] Skinner | Manufacturing strategy: The story of its evolution[END_REF][START_REF] Hill | Manufacturing Strategy[END_REF][START_REF] Platts | Manufacturing audit in the process of strategy formulation[END_REF][START_REF] Mills | A framework for the design of manufacturing strategy process[END_REF][START_REF] Menda | The manufacturing strategy formulation process: linking multifunctional viewpoints[END_REF][START_REF] Brown | Manufacturing strategy, manufacturing seniority and plant performance in quality[END_REF][START_REF] Barnes | Research methods for the empirical investigation of the process of formation of operations strategy[END_REF], 2002[START_REF] Slack | Product customisation and manufacturing strategy[END_REF] but it remains a minority research interest [START_REF] Dangayach | Manufacturing strategy: literature review and some issues[END_REF] and one that is predominantly conceptual [START_REF] Anderson | The process of manufacturing strategy[END_REF][START_REF] Brown | Linking manufacturing strategy to the strategy mainstream: the case for strategic resonance[END_REF] or "follow[s] Skinner's prescriptive intent" [START_REF] Barnes | The complexities of the manufacturing strategy formation process in practice[END_REF]: ). In sum, empirical investigations of the link between how organisations formulate operations strategy -both in terms of process and content -and subsequent operations performance represent a significant research opportunity, which we explore in this paper.

Finding links between strategy formulation and 'success' remains one of the 'holy grails' [START_REF] Golden | Towards a definition of flexibility: in search of the Holy Grail?[END_REF]Powell 2000, Kaplan and[START_REF] Kaplan | Measuring the strategic readiness of intangible assets[END_REF] within the strategy literature. We do not seek to provide a panacea but believe that this paper will provoke interest and potential for further research on the links between strategic operations planning and performance.

Clearly, to assume that there will be a linear relationship between strategy formulation and consequent success is suspect [START_REF] Mintzberg | Strategy safari: A guided tour through the wilds of strategic management Financial Times Books London[END_REF]. However, to assume also that a set of dynamic capabilities [START_REF] Teece | Dynamic capabilities and strategic management[END_REF] will be in place purely 'by chance' both within the firm and with partners within complex networks is also a problematic proposition [START_REF] Brown | Linking manufacturing strategy to the strategy mainstream: the case for strategic resonance[END_REF]. This paper does not pretend to provide specific links between generic strategy formulation and subsequent performance but does purport to find links between particular types of strategic formulation and performance. This paper is constructed as follows. In the next section we discuss some of the key issues within the literature related to operations strategy. Following this we develop the conceptual framework and examine specific links between operations strategy and strategy mainstream literature and explore some of the inherent weaknesses in the two, interlinking bodies of literature. We then present our primary research, including methodology; subsequently, we discuss the analysis and discussion; next, we acknowledge the limitations of the research. Finally, we offer conclusions and suggest possibilities for future research as well as implications for managers from our findings. It is now forty years since [START_REF] Skinner | Manufacturing -the missing link in corporate strategy[END_REF] seminal contribution to the literature on operations strategy and although operations strategy research has matured (e.g. Swink and Way 1995[START_REF] Vickery | Production competence and business strategy: do they affect business performance[END_REF][START_REF] Verma | Statistical power in operations management research[END_REF] it remains, typically, conceptually subservient to the broader strategy field (Akkermans and Von Aken 1992[START_REF] Brown | Manufacturing the future -strategic resonance for enlightened manufacturing[END_REF][START_REF] Brown | Linking manufacturing strategy to the strategy mainstream: the case for strategic resonance[END_REF]. The importance of the operations function on a strategic levelspecifically manufacturing operations -can be traced back to [START_REF] Skinner | Manufacturing -the missing link in corporate strategy[END_REF]. This was the first time that the competitive potential of the operations capabilities of the firm -and the attendant need to link these to the firm's strategic decision levels -was first explored. [START_REF] Skinner | The focused factory[END_REF] developed some of his thinking with the concept of the focused factory, again linked to how the firm could compete via its in-house capabilities. Further major insights were forthcoming throughout the 1980s from both the USA and UK (for example [START_REF] Hayes | Strategic planning: Forward in reverse?[END_REF]Wheelwright 1984, Hill 1985). Researchers began by exploring OS as a series of big 'tradeoff' decisions [START_REF] Skinner | The focused factory[END_REF], Wheelright 1984) but more recently it has been presented as an incremental process of cumulative capability development (Ferdows andDeMeyer 1990, Rosenzweig andRoth 2004).

Operations Strategy.

Operations strategy literature has often been contextualised within manufacturing paradigms and a summary of how the firm's operations were linked to specific modern manufacturing terms was provided by Brown and Cousins (1994:306) shown here in Figure 1:

Please insert figure 1 about here

Over time the impact of operations strategy has developed beyond the realm of operations management into wider aspects of business strategy [START_REF] Anderson | The process of manufacturing strategy[END_REF][START_REF] Meredith | A longitudinal study of the role of manufacturing technology in business strategy[END_REF][START_REF] Ward | Business strategies and manufacturing decisions: An empirical examination of linkages[END_REF], influencing areas as diverse as: The selection of new process technologies [START_REF] Honeycutt | The impact of flexible manufacturing on competitive strategy[END_REF][START_REF] Schroeder | Linking competitive strategy and manufacturing process technology[END_REF][START_REF] Wathen | Manufacturing strategy in business units[END_REF][START_REF] Gagnon | Resource-based competition and the new operations strategy[END_REF][START_REF] Beach | Manufacturing operations and strategic flexibility: Survey and cases[END_REF][START_REF] Das | Process innovativeness in technology services organizations: Roles of differentiation strategy, operational autonomy and risk-taking propensity[END_REF]. It has been noted that a key element of accruing capabilities in flexibility comes from the utilisation of process technology where, again, the role of manufacturing/operations strategy can be pivotal [START_REF] Kathuria | Aligning work force management practices with competitive priorities and process technology: a conceptual examination[END_REF].

2. New product development [START_REF] Voss | Managing new product design and development: An Anglo-German study[END_REF]Spring & Dalrymple 2000).

3.

Human resource management [START_REF] Bates | The crucial interrelationship between manufacturing strategy and organizational culture[END_REF][START_REF] Youndt | Human resource management, manufacturing strategy, and firm performance[END_REF]Paiva et al. 2008).

Tunälv (1992) found that firms with a formulated operations strategy achieve higher business performance than firms without such a strategy, with respect to return on sales.

Papke-Shields and Malhotra ( 2001) extended this research by explicitly testing the alignment between business and manufacturing strategies and firm performance. [START_REF] Sun | The alignment between manufacturing and business strategies: Its influence on business performance[END_REF] examined the relationships between alignment, business performance and manufacturing performance. They found that alignment has a positive, although not linear, relationship with four subjective measure of business performance. [START_REF] Joshi | Alignment of strategic priorities and performance: An integration of operations and strategic management performance[END_REF] provided interesting insights into strategic alignment within the firm and operations performance.

However, as important as Skinner's and other contributions have been, there are problems with their application to the current competitive arena. First, the focus on firmspecific capabilities now needs to be broadened into discussions on capabilities outside the domain of one firm and needs to be seen instead within more complex networks or supply chains. This is highly relevant to the primary research of this paper, which is the assembly of personal computers where strategy is not merely a firm-specific process but must also be seen as an inter-firm engagement within sets of organizations. Thus, firm-specific capabilities, although very important, also need to be seen within a wider context of sets of capabilities [START_REF] Kouvelis | Supply chain management research and production and operations management: review, trends, and opportunities[END_REF][START_REF] Boyer | Extending the supply chain: Integrating operations and marketing in the online grocery industry[END_REF]2006;[START_REF] Buhman | Interdisciplinary and interorganizational research: establishing the science of enterprise networks[END_REF][START_REF] Holcomb | Toward a model of strategic outsourcing[END_REF][START_REF] Rudberg | Global operations strategy: Coordinating manufacturing networks[END_REF].

Second, operations strategy has often been written as an entity within itself, aside of the strategy/business mainstream. Consequently, its impact has been questioned [START_REF] Brown | Linking manufacturing strategy to the strategy mainstream: the case for strategic resonance[END_REF]. This is not intended to be a pejorative assertion; indeed the opposite is true with this paper, which is motivated by an observed lack of alignment between operations strategy and mainstream strategy research. After all, even if one questions traditional hierarchies where the strategic role of operations is limited to supporting corporate and market(ing) decisions, it is self-evident that operations strategy concepts must at least be cognizant of mainstream strategic management concerns [START_REF] Wheelwright | Competing through development capability in a manufacturing-based organization[END_REF].

There are areas where the connections are impressive. Consider how, for instance, operations strategy research contrasting 'outside → in' (Hill 1985, Platts and[START_REF] Platts | Manufacturing audit in the process of strategy formulation[END_REF] and 'inside → out' models [START_REF] Hayes | Strategic planning: Forward in reverse?[END_REF], Cleveland et al. 1989, Vickery 1991[START_REF] Dröge | Sources and outcomes of competitive advantage: An exploratory study in the furniture industry[END_REF], Mills et al. 2005) echoes and develops debates about market-led 1 or resource-based 2 views on strategic fit [START_REF] Miles | Designing strategic human resources systems[END_REF], Hosskisson et al. 1999[START_REF] Johnson | Exploring Corporate Strategy[END_REF]. Although some research disputes the validity of the original 'sandcone' model (Flynn and Flynn 2004), this notion of leveraged capability has increasingly become the OS orthodoxy, reinforced by the incorporation of resource-based theory (RBT) from within strategic management [START_REF] Hayes | Strategic planning: Forward in reverse?[END_REF], Cleveland et al. 1989, Vickery 1991[START_REF] Dröge | Sources and outcomes of competitive advantage: An exploratory study in the furniture industry[END_REF], Amundson 1998, Mills et al. 2005, Paiva et al. 2008).

1 Posits competitive changes within markets should determine market strategy -including entry and exit decisions [START_REF] Haspeslagh | Portfolio planning: uses and limits[END_REF][START_REF] Hax | The use of the industry attractiveness-business strength matrix in strategic planning[END_REF][START_REF] Hax | The concept of strategy and the strategy formation process[END_REF], 1991[START_REF] Boeker | Competition in a multi-market environment: the case of market exit[END_REF].

Typified by the Structure-Conduct-Performance (SCP) paradigm [START_REF] Porter | Competitive strategy[END_REF], 1985[START_REF] Thomas | From I-O economics S-C-P paradigm through strategic groups to competence-based competition: reflections on the puzzle of competitive strategy (industrial-organizational; structure-conduct-performance)[END_REF]).

2 Posits advantages sustainable because of strategic resources [START_REF] Rumelt | Towards a strategic theory of the firm[END_REF][START_REF] Barney | Organizational culture: can it be a source of sustained competitive advantage?[END_REF], 1991, At the same time, however, significant disconnects persist -in particular in the area of strategy processes -and we will argue in this paper that these conceptual gaps are detrimental to the development of the operations strategy sub-field.

The last decade has seen strategy become much more interested in 'strategy as practice' (e.g. [START_REF] Pettigrew | The character and significance of strategy process research[END_REF][START_REF] Barry | Strategy retold: Toward a narrative view of strategic discourse[END_REF][START_REF] Oakes | Business planning as pedagogy: Language and control in a changing institutional field[END_REF][START_REF] Hendry | Strategic decision-making, discourse, and strategy as social practice[END_REF][START_REF] Whittington | Strategy as practice[END_REF], 2001) in part driven by a pragmatic return to practitioner priorities (i.e. 'how to do strategy'). There is also the issue that faced with global competitive pressures, returns to traditional macro assets (e.g. returns to scale, barriers to entry) are diminishing and alternative rents can be generated by leveraging those micro-assets enabled, to a large degree, by the strategising process itself [START_REF] Johnson | Exploring Corporate Strategy[END_REF].

Corresponding interest in the 'practice of operation strategy,' however, remains minimal (Anderson et al. 1989[START_REF] Minor | A review of empirical manufacturing strategy studies[END_REF][START_REF] Dangayach | Manufacturing strategy: literature review and some issues[END_REF][START_REF] Barnes | Research methods for the empirical investigation of the process of formation of operations strategy[END_REF], 2002). This is despite the operation management field's avowedly practitioner-centric nature and research suggesting firms with formulated operations (manufacturing) strategies achieve higher business performance (return on sales) than firms without (Tunälv 1992) and a positive performance impact associated with alignment between business and operations strategies [START_REF] Papke-Shields | Assessing the impact of the manufacturing/operations executive's role on business performance through strategic alignment[END_REF][START_REF] Sun | The alignment between manufacturing and business strategies: Its influence on business performance[END_REF][START_REF] Joshi | Alignment of strategic priorities and performance: An integration of operations and strategic management performance[END_REF]).

Paradoxically, it may be that the adoption of an incremental RBT-type logic, where relevant "operating decisions are made thousands of times per day by virtually every individual in the organization" (Boyer and McDermott 1999: 290) and where firms maximise the strategic contribution of their operations by following the correct sequence of improvement options (Schmenner and Swink 1998), may serve to diminish the apparent relevance of the strategy formulation process. In our literature search it became apparent that there are gaps in the literature including the specific links between strategy mainstream and operations strategy; and the links between these two entities and performance at plant level. It is these areas that we shall examine in the primary research. Following the literature review that we undertook, the decision was taken to focus our research on the pivotal question of whether there is any demonstrable relationship between the nature of the operations strategy, including its process and content, and operational performance. In doing so, the aim was to provide a clear motivation for subsequent research (i.e. 'we should worry about process because it impacts performance!').

Conceptual Framework

Bearing in mind that it is the independent variable for the study, it is essential to build a model of the OS process. Both pragmatic and empirical OS models reinforce the notion that OS process is primarily a matter of alignment. For example, consider the first two steps of the [START_REF] Hill | Manufacturing Strategy[END_REF][START_REF] Hill | Manufacturing Strategy[END_REF] framework:

1. Align with corporate objectives. More generally, it is held as axiomatic that strategic fit between OS and competitive strategy is critical to organizational effectiveness [START_REF] Hill | Manufacturing Strategy[END_REF], Williams et al 1995, Smith and Reece 1999). Empirical studies appear to confirm a positive impact on firm performance resulting from an alignment between business and operations strategies (Papke-Shields and Malhotra 2001, [START_REF] Sun | The alignment between manufacturing and business strategies: Its influence on business performance[END_REF][START_REF] Joshi | Alignment of strategic priorities and performance: An integration of operations and strategic management performance[END_REF], Rhee and Mehra 2006, Karim 2007).

2. Align with other functional (marketing) strategies. Empirical work has explored the operational performance benefits of cross-functional (e.g. marketing-manufacturing) congruence and consensus (Ward et al. 1994[START_REF] Bozarth | The impact of market requirements focus and manufacturing characteristics focus on plant[END_REF][START_REF] Boyer | Strategic consensus in operations strategy[END_REF], Hausman et al. 2002).

In a recent study, Paiva et al. ( 2008) explored these processes of alignment using an RBT framework and concluded that these 'integrated' activities (i.e. being involved in corporate strategy, involved in cross-functional teams, etc.) are also crucial in generating strategically valuable knowledge assets. Correspondingly, our data collected a number of measures related to the alignment between business and operations level strategies and the breadth of involvement of operations executives in a range of strategic activities (e.g. product mix, supply chain, NPD, etc.). Given that a number of OS studies have used perceptual measures of performance (e.g. [START_REF] Papke-Shields | Assessing the impact of the manufacturing/operations executive's role on business performance through strategic alignment[END_REF][START_REF] Sun | The alignment between manufacturing and business strategies: Its influence on business performance[END_REF][START_REF] Joshi | Alignment of strategic priorities and performance: An integration of operations and strategic management performance[END_REF] this study drew on the academic literature focused on plant-level performance parameters (e.g. [START_REF] Womack | The machine that changed the world[END_REF][START_REF] Oliver | The European auto components industry: Manufacturing performance and practice[END_REF][START_REF] Brown | The contribution of manufacturing strategy involvement and alignment to world class manufacturing performance[END_REF] to identify a number of measurable performance variables. As we shall see, an exploratory piece of work, scores against these metrics will then be used to cluster firms into two broad groups: one designated strategically inclusive, the other, strategically fragmented.

We describe our methodology below but we can state here that we used a combination of a vast literature survey on topics of business strategy and operations strategy coupled with academic literature that focused on plant parameters. As a result of this we examined [START_REF] Papke-Shields | Assessing the impact of the manufacturing/operations executive's role on business performance through strategic alignment[END_REF][START_REF] Sun | The alignment between manufacturing and business strategies: Its influence on business performance[END_REF][START_REF] Joshi | Alignment of strategic priorities and performance: An integration of operations and strategic management performance[END_REF], this study is based on objective measures. It is accepted that perceptual measures may be used when objective measures are not relevant or available [START_REF] Dess | Measuring organizational performance in the absence of objective measures: The case of the privately-held firm and conglomerate business unit[END_REF]. However, the firms in our sample were both willing and able to share objective measures, with the caveat that confidentiality needed to be maintained.

Business performance is primarily measured at two levels: the domain of financial performance or the domain of operational performance [START_REF] Venkatraman | Measurement of business performance in strategy research: A comparison of approaches[END_REF]. It was considered that the domain of operational performance was more appropriate

given that the study examined business unit level strategy. This may help fill a further gap in the literature because: "…when alignment [between operations and business strategy] has been studied, its impact on the manufacturing unit's performance has rarely been examined" (Joshi et al, 2003, p355).

The hypothesised relationships were tested through 15 longitudinal case studies of operations within assembly plants in the personal computing industry. We undertook the research in two stages. In the first stage we explored the strategy process, in particular, how plants devised strategy (both business and operations levels) and the role of operations personnel in the process. This first data set was collected in 2005. In the second stage we [START_REF] Womack | The machine that changed the world[END_REF][START_REF] Oliver | The European auto components industry: Manufacturing performance and practice[END_REF]. This data set was collected in late 2007 to early 2008. The time lag between stages one and two was deliberate and was designed to capture the lag between strategy and outcomes.

We chose the single product sector, personal computers, for both theoretical and methodological reasons. Theoretically, the PC industry offers a good opportunity to study the strategy-performance relationship due to changes from mass production to mass customisation and from vertical integration to networked contract manufacturing [START_REF] Brown | Manufacturing the future -strategic resonance for enlightened manufacturing[END_REF]. The development of capabilities to survive in this new environment does not come about by chance but must be developed and accumulated over time [START_REF] Brown | The strategy-capabilities link in mass customization[END_REF]. Methodologically, the use of a single industry setting minimises the influence of contextual variables, an approach well supported in the strategy literature (e.g. [START_REF] Dowell | Entry timing, exploration, and firm survival in the early U.S. bicycle industry[END_REF][START_REF] Lavie | Alliance portfolios and firm performance: A study of value creation and appropriation in the U.S. software industry[END_REF].

We examined three plants in the USA; seven within Europe; one in Singapore; two in Malaysia and two in Taiwan. All but 2 of the plants (one in Europe and one in the US) were operating units under the leadership of a separate headquarters function and all maintained an in-house manufacturing and/or assembly capability. The plants were selected on for the following reasons:

1. Access: We have developed relationships with these plants and gained their trust over a number of years and access is an import factor for researchers. Thus the plants' willingness to share date on an ongoing basis allowed us to gain rich sources of data for this research. For our part, we have honoured their requirement for the names of the Companies themselves to remain anonymous -although each plant was willing for us to share data.

2. Plant size: We wanted to ensure consistency across plants and so the sizes of the plants were within a set range (750-1000 personnel). Not surprisingly, there were occasions where either downsizing or increase in headcount took place over time but the commonality of the size across the plants was an important factor in this research. Indeed, one of the plants from Malaysia, which had shown interest, was rejected because of its size.

3. Core Processes: Part of the business strategy of the firms included in this research was to retain the core of manufacturing and assembly processes in house and since the unit of analysis of this research was at the plant level in each case, this was an important deciding factor in the choice of plants used within the research All data were collected through semi-formal questionnaires administered to senior level managers whose positions within the hierarchy of the firms were consistent across the plants.

In each case we interviewed the most senior level contact available within the specific function, typically respondents such as manufacturing directors, finance directors or the Chief Operating Officer. The range of respondents varied from three to six per plant and the typical (median) length of the interviews was 60 minutes.

Measurement of the independent variable

The independent variable for this study was the operations strategy process. Data was collected on ten measures related to the breadth of involvement of operations executives in the strategy process and the alignment between business and operations level strategies.

It is well established that strategic planning often fails when the process excludes functional or departmental managers [START_REF] Mintzberg | The Rise and Fall of Strategic Planning[END_REF]. Participation has been found to create greater awareness and buy-in to organisation objectives [START_REF] Wooldridge | The strategy process, middle management involvement, and organizational performance[END_REF][START_REF] Ketokivi | Strategic planning as an integrative device[END_REF]. Moreover, involvement of functional personnel is more likely to create strategic alignment between functional and business-level strategies (Papke-Shields and Malhotra, 2001). In order to ascertain the extent of alignment between operations strategy (as a functional-level strategy) and business level strategy, we asked respondents to • Senior operations personnel are actively involved in the business strategy process and not employed purely as plant technical specialists.

• There are explicit, plant-specific, operations strategies in place.

• These strategies feed into, and form part of, business strategy.

• There is cohesion in content and timing between business and manufacturing strategies.

The involvement of operations personnel also helps to ensure that the full range of operations issues is considered in the strategic planning process. We therefore asked respondents to gauge their involvement across a range of operations issues including supply chain management, process technology, capacity, product mix, facilities and NPD. This was measured by asking respondents to indicate their level of involvement on the following six Likert-scale items (1 = No involvement to 5 = Strong involvement):

• Supply chain. Strategic decision-making in the nature and shape of the supply chaininvolving the degree of vertical integration as well as buyer-supplier relations for the plant.

• Process technology. Strategic process technology investment -including the degree of, and rationale behind, investment in new process technology for plants.

• Capacity. Strategic capacity decisions -including involvement in decisions on adding to, downsizing, or even divesting entire plants.

• Product mix. Determining levels of production of existing products and models of the plant's current product portfolio.

• Facilities. Strategic growth initiatives including new facilities/location decisions.

• NPD. Strategic NPD in both existing and new markets. The unidimensionality of these ten items was tested using a principal components analysis with varimax rotation using SPSS version 14.0. Although we have a small sample size, there is evidence to suggest that this can be compensated if item loadings are greater that 0.80 [START_REF] Maccallum | Sample size in factor analysis[END_REF]. As shown in Table 1 all items load onto a single factor and have loadings of greater than 0.842 and the majority are above 0.90. The reliability of this factor was α = 0.98, which together with the results of the factor analysis is suggestive of strong construct validity.

Measurement of the dependent variable

Data were collected on nine objective measures of manufacturing performance from all 15 plants. Although performance can be measured at various levels of the organisation, such as financial performance (e.g. Germain et al, 2008) or project performance (e.g. Oke et al, 2008), manufacturing performance was considered more appropriate to test the effect of operations strategy at the plant level. An attribute of this research design is the use of objective performance data rather than perceptual measures. While it is accepted that perceptual measures may be used when objective measures are not relevant or available [START_REF] Dess | Measuring organizational performance in the absence of objective measures: The case of the privately-held firm and conglomerate business unit[END_REF], the firms in our sample were both willing and able to share objective measures, with the caveat that confidentiality needed to be maintained.

As there is no single agreed set of measures of manufacturing performance, we undertook a vast literature search to identify and select the most commonly used objective measures. The result was a set of measures that reflects the multiple dimensions of operations performance, including quality, inventory, supply chain management, and new product development [START_REF] Hayes | Restoring Our Competitive Edge[END_REF][START_REF] Schonberger | World Class Manufacturing: The Lessons of Simplicity Applied[END_REF][START_REF] Womack | The machine that changed the world[END_REF][START_REF] New | World-class manufacturing versus strategic trade-offs[END_REF][START_REF] Oliver | The European auto components industry: Manufacturing performance and practice[END_REF][START_REF] Flynn | World-class manufacturing: An investigation of Hayes and Wheelwright's foundation[END_REF][START_REF] Brown | Manufacturing the future -strategic resonance for enlightened manufacturing[END_REF]. Following [START_REF] Ketokivi | Manufacturing practices, strategic fit and performance A routine-based view[END_REF], this study employs a multi-dimensional approach to performance • Percentage of failure at final inspection (PERF_1)

• Percentage of operations employees involved in QCs or CI activities (PERF_2)

• Annual number of suggestions per employee (PERF_3)

• Class A inventory WIP levels (hours) (PERF_4)

• Finished goods inventory (hours) (PERF_5)

• Inventory turns (yearly) (PERF_6)

• Percentage of class A suppliers having contracts lasting more than 3 years (PERF_7)

• Number of suppliers accounting for over 80% of purchases (PERF_8)

• Innovation time of new product development (NPD) (months) (PERF_9)

Another benefit of this research design is that it prevents common methods variance.

The use of perceptual measures for the independent variable and objective measures for the dependent variable preclude 'artifactual' relationships caused by the use of a common method [START_REF] Podsakoff | Self-reports in organizational research: Problems and prospects[END_REF].

Analysis

Table 1 present the descriptive statistics for the variables used in this study.

[Please insert A two-step cluster analysis was used to group the firms. The first step was a hierarchical agglomerative technique (Ward's minimum variance cluster method), used to distinguish outliers and to determine an appropriate number of clusters to be carried forward to step two. We used hierarchical cluster analysis followed by an independent samples t-test (see below) to analyse the data due to relatively small sample size. Both these techniques are suitable for sample sizes equivalent to ours (e.g. Brown and Melamed, 1993;[START_REF] Hair | Multivariate data analysis[END_REF]. Using the agglomeration schedule it was noted that no single member clusters were present, therefore it was assumed no outliers existed. We recognise that determining the number of clusters can be somewhat subjective and in response, we adopted the procedure suggested by [START_REF] Hair | Multivariate data analysis[END_REF]. The number of clusters was selected using changes in the agglomeration coefficient. Small coefficients indicate fairly homogenous clusters, whereas, large coefficients or a large percentage change in the coefficient indicates heterogeneous clusters. The agglomeration coefficient shows a large percentage increase in going from two clusters to a single cluster (627%). This may be contrasted with the much smaller percentage changes in going from three to two clusters (27%) and four to three clusters (26%).

Step two consisted of an iterative partitioning (SPSS Quick Cluster) cluster analysis.

The cluster centroids from the hierarchical analysis were used as initial seed points for the final clusters. The cluster centres were slightly adjusted when compared to step one, however no change was observed in the group members. Table 1 shows the final cluster centres for the two groups. Examination of the two clusters shows that cluster two has higher values for all of the associated variables. Furthermore, it appears that all variables were highly significant in distinguishing the two clusters.

[Please insert To check the stability of the cluster solution we applied an alternative method and compared the results [START_REF] Hair | Multivariate data analysis[END_REF]. A second non-hierarchical analysis was performed allowing SPSS to randomly select the initial seed points. The results were comparable between the techniques validating the solution shown in table 1.

To check the predictive validity of the final solution we focused on a variable that has a theoretically based relationship to the ten clustering variables, but was not included in the cluster solution. We asked whether operations personnel were in place at senior management levels of the firm. It would appear this variable is closely related to the original ten variables, but could not be included in the cluster analysis because ordinal variables are not supported by distance measures (here we used squared Euclidean distance). If a significant difference exists for this variable we can conclude that the two clusters display predictive validity. We conducted an independent samples t-test on the two clusters. The test indicated that the cluster means are significantly different (see table 2), showing that cluster two was significantly more likely to have manufacturing personnel in place at senior management levels than cluster one. This further validates the solution shown in table 1.

[Please insert table 3 about here]

Interpretation of clusters

Two clusters were identified with evidence of both stability and predictive validity. The interpretation stage involves assigning each cluster a name or label that accurately describes the nature of that cluster [START_REF] Hair | Multivariate data analysis[END_REF].

The first group of plants (cluster 1), those expressing themselves as unconcerned with the process of formulating either business or manufacturing strategy, are termed strategically fragmented. We used this term because these plants' characteristics clearly represent the chief concerns from [START_REF] Skinner | Manufacturing -the missing link in corporate strategy[END_REF] to the present day within the operations strategy literature. The main concerns include the absence of operations personnel at strategic levels of the firm together with lack of involvement in the strategic direction of the firm and the consequent lack of operations strategies that link with wider, business-level strategies. This cluster represents six plants or 40% of the sampled population. Plants with strategically fragmented strategy processes display low scores on all variables (cluster means between 1.14 and 2.43, on a five point Likert scale).

The second group of plants (cluster 2), those appearing concerned with the process of formulating both business and/or manufacturing strategy, are termed strategically inclusive.

This cluster represents nine plants or 60% of the sampled population. Plants display high scores on all variables (cluster means between 4.56 and 5.00, on a five point Likert scale).

Specifically, operations personnel are more likely to be involved in the business strategy planning process and key business level decision-making processes. Furthermore, plants are likely to have explicit manufacturing strategies, which feed into, and form part of, business strategy.

Findings and Discussion

The hypotheses were tested using an independent samples t-test. Table 4 indicates significant differences between the two groups for all dimensions of performance. We will discuss each of the hypotheses in turn.

[Please insert table 4 about here]

Hypothesis One On average 90% of the Class A suppliers of inclusive plants enjoy contracts of longer than 3 years, compared to just 30% of fragmented plant suppliers. We followed this study with some informal interviews with each of the plants. Of interest were the criteria used by the plants to select suppliers. Whereas strategically fragmented plants always emphasised price as the number one criterion, strategically inclusive were far more interested in quality where price could sometimes rank third or fourth on the list of prioritised criteria. As we stated in the Introduction, we are not attempting to provide the 'holy grail' in terms of links between strategy and subsequent performance. However, from our data there are strong links between a particular type of operations strategy, which we have termed strategically inclusive and plant performance. The key findings that emerge are:

Hypothesis

First, from our data, strategically inclusive plants outperformed the strategically fragmented plants in all of the operations parameters that we examined. Thus the notion of the 'focused factory' [START_REF] Skinner | The focused factory[END_REF], which formed part of the early work on operations strategy literature, seems to be weakened by modern-day high-performing plants that are able to perform a range of capabilities simultaneously. In short, strategically inclusive plants appear to accumulate exceptional operations capabilities over time. One possible question that we did not examine was the process of accumulating such capabilities in terms of a sequence and whether this is consistent across all pants -this may be of potential research interest (cf. Ferdows and De Meyer, 1990).

Second, the scope and range of responsibilities of senior-level operations staff was a key feature of strategically inclusive plants. Although senior-level operations presence was noted in both strategically inclusive and strategically fragmented firms, their roles differed.

In strategically fragmented firms the senior-level operations staff were engaged in managing day-to-day, operational and technical tasks -as important as these are, of course. However, in strategically inclusive plants, senior-level operations staff were involved in wider, businesslevel aspects of the firm. This again resonates with earlier citations that we made that mentioned the potential for operations strategy to impact areas including. • The selection of new process technologies [START_REF] Honeycutt | The impact of flexible manufacturing on competitive strategy[END_REF][START_REF] Schroeder | Linking competitive strategy and manufacturing process technology[END_REF][START_REF] Wathen | Manufacturing strategy in business units[END_REF][START_REF] Gagnon | Resource-based competition and the new operations strategy[END_REF][START_REF] Beach | Manufacturing operations and strategic flexibility: Survey and cases[END_REF][START_REF] Das | Process innovativeness in technology services organizations: Roles of differentiation strategy, operational autonomy and risk-taking propensity[END_REF].

• New product development [START_REF] Voss | Managing new product design and development: An Anglo-German study[END_REF]Spring & Dalrymple 2000).

• Human resource management [START_REF] Bates | The crucial interrelationship between manufacturing strategy and organizational culture[END_REF][START_REF] Youndt | Human resource management, manufacturing strategy, and firm performance[END_REF]Paiva et al. 2008).

However, in these and many other citations, no evidence was forthcoming in terms of empirical data, which this paper now offers.

Third, the role and importance of operations strategy was another important issue here.

Although we made distinctions between the process and content of strategy, it would appear that strategically inclusive plants are those where the content of the strategy is much wider than in strategically fragmented firms. This is possibly governed by the process, whereby, as we have just noted, senior-level operations staff are engaged in a range of business issues of the firm and not employed for technical knowledge and experience only. The role of operations strategy within strategically inclusive plants acted as a bridge between operations strategy and plant-specific activities. Operations strategy in strategically inclusive plants also linked together business strategy and operational capabilities. In the world-class plants, operations strategy was integrated within the wider business strategy, with the operations and business strategies being synchronised in time. This supports earlier work by [START_REF] Voss | Differences in manufacturing strategy decisions between Japanese and Western manufacturing plants: the role of strategic time orientation[END_REF] on the importance of time horizons within operations strategy. It also resonates with work by Das (1990) on the importance of time horizons within mainstream strategy processes.

Limitations of the Research

Before highlighting the key conclusions derived from the analysis of the research, it is important to reflect upon the work's limitations. Our study has several limitations. First, the Second, the focus on only one industry has clear advantages but it inevitably raises questions of generalizability and transferability. Future research could take a multiple-source data collection approach in order to deal with this issue.

Third, this was an exploratory study and although well-established metrics were used, we only explored four operations performance parameters (quality, inventory, supplier management and innovation). Future research could examine a rage of other important operations performance measures including flexibility, delivery, cost, customisation or variety. Some of the measures used to examine the four capabilities could be expanded. In particular, supplier management measures could examine in more depth the nature of the relationships as well as their duration.

Fourth, we have described what has happened -namely, that there appears to be links between the process of strategy and subsequent performance. What we have not done is to analyse in depth why such links exist and, again, this provides opportunities for future research where more in-depth, firm-specific, profiling could be undertaken via further longitudinal case studies.

Conclusions and Future Research Directions.

Whilst we accept that our study has limitations, it has also exhibited some interesting and important findings, namely that the process and content of operations strategy tends to have an impact on operations performance in a range of key parameters. There can be no doubt that the current competitive arena, which includes Lean Production, Mass and integral to accruing and developing such capabilities are two ingredients that form the core of an inclusive strategy formulation process: the role of senior-level operations personnel and the nature and scope of the operations strategy, which has to be explicitly linked to the business strategy of the firm. Specifically, in spite of the changes to manufacturing practices, we suggest that the process of formulating and implementing strategy has not kept pace with such changes over time. A more detailed focus on the formulation process thus makes an important contribution to the strategy process within volatile competitive conditions.

The paper offers implications for both academic researchers and practitioners alike. We have outlined some of the opportunities for researchers above and in particular we stress the need for better cohesion and dialogue between operations strategy and business mainstream literature. Although the two bodies of literature are not mutually exclusive, at present the links between the two and the co-dependence of each in a range of overlapping areas need to be explored in depth.

For practitioners, particularly within industries that seek to outsource operations activities in the name of cost reductions, there are major implications. The key issue is that senior level personnel need to ensure that there are specific operations and business strategies in place and that the capabilities of the firm are accumulated, developed and safeguarded over time. [START_REF] Pine | Making mass customization work[END_REF] Reflecting the need for high volume combined with recognition of cutomers' (or 'consumers') specific wishes Flexible Specialisation Piore and Sable (1984) This concept relates to the manufacturing strategy of firms (especially small firms) to focus on parts of the value-adding process and collaboration within networks to produce whole products. Lean Production & Lean Supply [START_REF] Womack | The machine that changed the world[END_REF][START_REF] Lamming | Beyond Partnership Prentice Hall[END_REF] This concept was developed from the massively successful Toyota Production System (TPS), which focused on the removal of all forms of waste from the production transformation system. Agile Manufacturing [START_REF] Kidd | Agile manufacturing -forging new frontiers[END_REF] This concept emphasises the need for an organisation to be able to switch frequently from one market-driven objective to another. Strategic Manufacturing [START_REF] Hill | Manufacturing Strategy[END_REF][START_REF] Brown | Strategic manufacturing for competitive advantage[END_REF]2000) Here the authors emphasise the need for the Operations capabilities to be framed in a strategic context and brought to the fore. The authors offer templates to positioning Operations capability and strategy.

F

F

  operations performance in terms of four factors: quality, inventory, supplier management, and innovation. Using questionnaire and interview data from a study of the personal computer industry, preliminary evidence of differential operational performance (e.g. defect and inventory levels, speed of NPI, etc.) associated with what are classified as either 'inclusive' or 'fragmented' operations strategy processes can be highlighted. This leads us to the following four hypotheses: H1: Strategically inclusive plants will have superior quality performance when compared to strategically fragmented plants H2: Strategically inclusive plants have superior inventory performance when compared to strategically fragmented plants H3: Strategically inclusive plants have superior supplier performance when compared to strategically fragmented plants Our research explored the relationship between the content and process of operations strategy (including elements of supply), and plant performance. Whereas a number of previous studies have used perceptual measures of performance (e.g. Papke-Shields and

  plant-level performance data across nine areas critical to the operations function (e.g.

  of agreement on the following four Likert-scale items (1 = Strongly disagree to 5 = Strongly agree):

  some of the problems associated with composite performance indexes. The nine measures of performance were:

  strategically inclusive plants have superior quality performance when compared to strategically fragmented plants. Although neither group was able to demonstrate quality capabilities of "zero defects", strategically inclusive plants significantly outperform their strategically fragmented rivals. The two groups differed significantly in terms of the number of employees in QCs and CI activities (t = 14.77, p<0.001), the annual number of suggestions per employee (t = 8.75, p<0.001) and the percentage of failure at final inspection (t = -13.68, p<0.001).Although neither group is near to the ideal of zero defects the strategically inclusive plants are certainly a great deal closer. The results indicate they involve over four times the number of employees in QCs and CI activities compared to strategically fragmented plants and receive over double the number of suggestions per employee each year. This is reflected in the percentage failure at final inspection of 1.39% in the inclusive plants and 4.75% in the fragmented plants. Although it is not possible to draw a direct line of causation between the two, it is possible to say that strategic inclusiveness appears to contribute to lowering the percentage of failure at final inspection.Hypothesis TwoH2 predicted that strategically inclusive plants have superior inventory performance when compared to strategically fragmented plants. In support, we found that strategically inclusive plants carry fewer inventories and have higher inventory turns than strategically fragmented plants. The two groups differed significantly in terms of hours of Class A WIP inventory (t = -8.69, p<0.001), hours of Finished Goods Inventory (t = -9.31, p<0.001), and inventory turns (t = 5.30, p<0.001).Contrasting the manifest variables is telling. The range of "Class A" components' work-in process for strategically inclusive plants ranged from a minimum of 2 hours to a hours; in the strategically fragmented plants this ranged between 24 and 42 hours. Similarly, finished goods inventory ranged from a minimum of 2 hours to a maximum of 12 hours in the strategically inclusive plants, and between 24 and 36 hours in the strategically fragmented plants.Hypothesis ThreeH3 predicted that strategically inclusive plants have superior supplier performance when compared to strategically fragmented plants. In support, we found that strategically inclusive plants have a larger percentage of suppliers with long-term contracts and a more consolidated supply base than strategically fragmented plants. The two groups differed significantly in terms of percentage of class A suppliers having contracts lasting more than 3 years (t = 10.38, p<0.001) and the number of suppliers accounting for over 80% of purchases (t = -5.58, p<0.001).

  FourH4 predicted that strategically inclusive plants have a faster new product development process when compared to strategically fragmented plants. In support, we found that the two groups differed significantly on the lead-time of new product development (t = -11.20, In fact, new product development time is over twice as fast in strategically inclusive plants.

  Manufacturing, places huge demands upon operations capabilities

table 1

 1

	about here]

table 2 about here]

	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	O n l
	y
	16

  size is one factor that is immediately obvious. Although our statistical methods are appropriate to test the hypotheses that we have proposed here, the statistics are sensitive to sample size. Thus, a larger sample size would be desirable to obtain more stable findings and so this provides opportunities for further research.

	relatively small sample
	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	O n l
	y
	22

Operations Strategy and the links to manufacturing paradigms Paradigm Author Description Mass Customisation

	Figure 1:
	o r F o r F o r F o r F o r F o r F o r F o r F o r
	P P P P P P P P P
	e e e e e e e e e
	e r e r e r e r e r e r e r e r e r
	R R R R R R R R R
	e e e e e e e e e
	v i e v i e v i e v i e v i e v i e v i e v i e v i e
	w w w w w w w w w
	O n l O n l O n l O n l O n l O n l O n l O n l O n l
	y y y y y y y y y
	32

Table 1 : Descriptive statistics

 1

	Variable	Mean	S.D.	1	2	3	4	5	6	7	8	9	10
	1. PERF_1	2.74	1.76	1.00
	2. PERF_2	57.67 34.22	-0.94	1.00
	3. PERF_3	16.47	7.43	-0.93	0.93	1.00
	4. PERF_4	16.40 13.21	0.87	-0.91	-0.84	1.00
	5. PERF_5	15.33 10.57	0.95	-0.91	-0.88	0.88	1.00
	6. PERF_6	66.33 31.76	-0.91	0.89	0.83	-0.87	-0.91	1.00
	7. PERF_7	41.93 26.85	-0.81	0.84	0.80	-0.84	-0.88	0.77	1.00
	8. PERF_8	108.80 22.01	0.78	-0.76	-0.70	0.89	0.79	-0.84	-0.69 1.00
	9. PERF_9	23.33 10.65	0.94	-0.91	-0.89	0.89	0.93	-0.93	-0.87 0.85	1.00
	10.	3.4	1.42	-0.27	0.20	0.26	-0.03	-0.25	0.06	0.21 0.10	-0.15 1.00
	OPERATIONS STRATEGY	r o
			P
			e
				e r
					R
					e
						v i e
							w
								O n l
									y

Table 2 : Two cluster solution of non-hierarchical cluster analysis

 2

		Cluster 1 (n=6)	Cluster 2 (n = 9)
	Factor	Mean	SD	Mean	SD	F
	Active involvement in strategy	1.71	.49	4.56	1.01	46.112***
	Explicit, plant level strategies	1.86	.38	4.78	.44	194.895***
	Integration into business strategy	1.14	.38	4.67	.50	239.575***
	Cohesion in content & timing	1.86	.69	4.56	.53	79.023***
	Active involvement in supply chain	2.43	.53	4.89	.33	128.182***
	Active involvement in technology	1.86	.38	4.56	.53	130.348***
	investment
	Active involvement in capacity	2.00	.58	4.67	.50	98.000***
	decisions
	Active involvement in production	2.14	1.22	4.56	.53	28.963***
	levels
	Active involvement in growth	2.14	1.07	5.00	.00	65.625***
	initiatives
	Active involvement in NPD	2.29	1.11	4.67	.50	33.144***

*** Significant at p<0.001

Table 3 : predictive validity of final solution (equal variances assumed)

 3

		Cluster 1 (n = 6)	Cluster 2 (n = 9)
	Factor	Mean	SD	Mean	SD	t
	Senior ops	1.11	.33	1.86	.38	-4.192***
	personnel
	*** Significant at p<0.001

Table 4 : Operations performance of strategically inclusive and dissonant clusters

 4

			Strategically	Strategically
	Factor	Hypothesis	fragmented	inclusive
			(Cluster 1) n = 6	(Cluster 2) n = 9	t
			Mean	SD	Mean	SD
	% of failure	H1	4.75	.62	1.39	.34	-13.68***
	Involvement in QC	H1	18.33	7.53	83.89	8.94	14.77***
	& CI
	Suggestions per	H1	8.33	2.42	21.89	3.22	8.75***
	employee
	Class A inventory	H2	30.83	6.88	6.78	3.90	-8.69***
	WIP
	Finished goods	H2	27.00	5.02	7.56	3.13	-9.31***
	inventory
	Inventory turns	H2	15.66	4.97	59.44	19.60	5.30***
	Long term suppliers	H3	30.83	15.30	90.00	6.61	10.38***
	Number of suppliers	H3	130.67	12.37	94.22	12.41	-5.58***
	Innovation time of	H4	35.33	3.27	15.33	3.46	-11.20***
	NPD

http://mc.manuscriptcentral.com/tprs Email: ijpr@lboro.ac.ukInternational Journal of Production Research


MD Colette Donaghy
email: donaghy1a@hotmail.com

MBBS Matthew J Thurtell

MD PhD Erik P Pioro

MD J Mark Gibson

MD R John Leigh

Eye Movements in Amyotrophic Lateral Sclerosis and its Mimics: A Review with Illustrative Cases

Keywords: Saccades, smooth pursuit; saccadic intrusions, nystagmus

Abnormal eye movements are increasingly recognized in patients with amyotrophic lateral sclerosis (ALS) and, when they occur, may provide insights into the pattern and pathogenesis of the disease process. In patients with disorders that mimic ALS, abnormal eye movements may point to the correct diagnosis. In both of these circumstances, systematic examination of eye movements and interpretation of the findings with reference to modern concepts of their neural substrate will aid diagnosis and suggest pathogenesis. Here, we highlight key points with illustrative case histories and eye movement records.

INTRODUCTION

Classical teaching is that eye movements are spared in amyotrophic lateral sclerosis (ALS), except in those patients whose lives are prolonged by artificial ventilation. [START_REF] Mizutani | Development of ophthalmoplegia in amyotrophic lateral sclerosis during use of respirators[END_REF] Over the past twenty years, however, a number of reports have indicated that patients with ALS may show a range of eye movement disorders similar to those encountered in other degenerative and hereditary neurological diseases. [START_REF] Abel | Effects of stimulus velocity and acceleration on smooth pursuit in motor neuron disease[END_REF][START_REF] Averbuch-Heller | Slow vertical saccades in motor neuron disease: correlation of structure and function[END_REF][START_REF] Donaghy | Ocular fixation instabilities in Motor Neurone Disease: a marker of frontal lobe dysfunction[END_REF][START_REF] Donaghy | Slow saccades in bulbar-onset Motor Neurone Disease[END_REF][START_REF] Evdokimidis | Frontal lobe dysfunction in amyotrophic lateral sclerosis[END_REF][START_REF] Gizzi | Ocular motor function in motor neuron disease[END_REF][START_REF] Marti-Fabregas | Oculomotor abnormalities in motor neuron disease[END_REF][START_REF] Ohki | Ocular abnormalities in amyotrophic lateral sclerosis[END_REF][START_REF] Okuda | Motor neuron disease with slow eye movements and vertical gaze palsy[END_REF][START_REF] Palmowski | Eye movement in amyotrophic lateral sclerosis: a longitudinal study[END_REF][START_REF] Shaunak | Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment[END_REF][START_REF] Ushio | Atypical motor neuron disease with supranuclear vertical gaze palsy and slow saccades[END_REF][START_REF] Leveille | Eye movements in amyotrophic lateral sclerosis[END_REF][START_REF] Kobayashi | Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity[END_REF][START_REF] Jacobs | An eye movement disorder in amyotrophic lateral sclerosis[END_REF] These reports raise several questions. Do abnormal eye movements provide any insights into the pathogenesis of the disease process in those patients who show them? Which diagnoses should the clinician consider when confronted with an apparent "ALS patient" who has abnormal eye movements? Can eye movement abnormalities provide clues to accurate diagnosis of disorders that mimic ALS? What eye movement abnormalities are consistent with a diagnosis of ALS? Much is now known about the neurobiology of eye movements, making them widely used as diagnostic and research tools. Salient features of the properties and neural substrate of the functional classes of eye movement are summarized in Table 1 of supplementary material and Figure 1 as a background to this review; the reader is referred to current texts for more details. [17 18] We will then discuss, in turn, disorders of saccades, smooth pursuit, ocular fixation, and ophthalmoplegia in ALS. We also discuss how an advance in molecular pathology techniques, namely TAR DNA-binding protein-43 (TDP-43) staining, [START_REF] Arai | TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis[END_REF] may provide insight into a progressive supranuclear palsy (PSP) variant of ALS. Finally, we discuss how eye movements may help with accurate diagnosis of disorders that mimic ALS.

Case histories are presented to illustrate these points.

SACCADE ABNORMALITIES IN ALS

A saccade is a rapid eye movement that brings the image of an object of interest onto the fovea, for clearest vision. Several types of saccade can be tested at the bedside and measured in the laboratory, including visually-guided saccades, memory-guided saccades, and antisaccades; we will discuss abnormalities of each of these, in turn.

Disturbance of Visually-Guided ("Reflexive") Saccades in ALS

The peak velocity of saccades is a function of their amplitude; large saccades in humans may exceed 500 degrees/second. The pulse of innervation driving the eye muscles is generated by burst neurons in the brainstem reticular formation (Figure 1B). The paramedian pontine reticular formation (PPRF) houses burst neurons for horizontal saccades, whereas the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) in the midbrain houses burst neurons for vertical and torsional saccades (Figure 1B). Between saccades, burst neurons are inhibited by omnipause neurons in the nucleus raphe interpositus in the pons. Prior to the onset of a saccade, omnipause neurons cease discharging, allowing the burst neurons to fire. Current views are that lesions of either the burst or omnipause neurons could cause slowed saccades. [START_REF] Leigh | The neurology of eye movements[END_REF] Saccades made reflexively to novel visual stimuli were thought to be normal in patients with ALS. However, Donaghy and colleagues found that reflexive saccades were slower in bulbar-onset compared with spinal-onset ALS. [START_REF] Donaghy | Slow saccades in bulbar-onset Motor Neurone Disease[END_REF] A number of older studies have also reported slow saccades. Leveille et al described slow reflexive saccades in two of ten ALS patients with rapidly-progressive disease. [START_REF] Leveille | Eye movements in amyotrophic lateral sclerosis[END_REF] Similarly, Ohki et al found that four of nine ALS patients showed slower reflexive saccades compared with age-matched controls. [START_REF] Ohki | Ocular abnormalities in amyotrophic lateral sclerosis[END_REF] It is therefore likely that slow saccades in ALS patients are indicative of brainstem pathology.

Is there a Progressive Supranuclear Palsy (PSP) Variant of ALS?

Supranuclear gaze palsies with slow saccades have been reported in ALS patients, often in association with cognitive impairment or bulbar-onset disease. [3 10 13 15] Averbuch-Heller and colleagues reported slow vertical saccades in two ALS patients with bulbar symptoms; post mortem examination in one demonstrated neuronal cell loss in the riMLF and substantia nigra, with relative preservation of the ocular motor nuclei. [START_REF] Averbuch-Heller | Slow vertical saccades in motor neuron disease: correlation of structure and function[END_REF] We recently studied a similar patient, as described in the text box.

A recent neuropathological study of a patient with an ALS-Plus syndrome resembling PSP found TDP-43 positive inclusions in a pattern consistent with ALS. [START_REF] Mccluskey | Amyotrophic lateral sclerosis-plus syndrome with TAR DNA-binding protein-43 pathology[END_REF] The authors described a 66-year-old man with progressive bulbar palsy and limb weakness. He demonstrated extrapyramidal signs, as well as slow vertical and horizontal saccades A 70-year-old man presented with progressive bulbar dysfunction and decreased mobility. Examination revealed slowed vertical and, to a lesser extent, horizontal saccades, with a reduced vertical range of movement. He was severely dysarthric, with a flaccid palate, frontal release signs, brisk jaw jerk and facial reflexes, slowed tongue movements, but no tongue atrophy or fasciculations. Legs were moderately spastic and weak proximally, more severely on the right, but without fasciculations or atrophy. Stretch reflexes were pathologically brisk in bilateral upper and lower limbs with extensor plantar responses. Axial tone was slightly increased with moderate postural imbalance and retropulsion. MRI of his brain showed scattered non-specific punctate white matter changes and mild generalized atrophy but no midbrain atrophy. Electromyography of right limb muscles revealed only mild chronic neurogenic changes and MRI of cervical and lumbar spines showed minimal degenerative disc disease. Combined upper and lower motor neuron dysfunction only at the bulbar level and upper motor neuron dysfunction at cervical and lumbar levels was consistent with an El Escorial diagnosis of possible ALS. Eye movement recordings, using the magnetic search coil technique, confirmed marked slowing of vertical saccades, with mild slowing of horizontal saccades (Figure 2), similar to that encountered in patients with PSP. [START_REF] Leigh | The neurology of eye movements[END_REF] with supranuclear gaze palsy. Neuropathological findings included corticospinal tract degeneration and loss of anterior horn motor neurons. TDP-43 positive inclusions were found in anterior horn cells, motor cortex, midbrain, hypoglossal nucleus, globus pallidus, caudate, putamen, hippocampus, and substantia nigra. Although the inclusions were found in the midbrain, the authors did not mention involvement of the riMLF.

PSP is known to be a tauopathy, and is defined pathologically by an accumulation of tau protein and neuropil threads in the pallidum, subthalamic nucleus, red nucleus, substantia nigra, pontine tegmentum, striatum, oculomotor nucleus, medulla, and dentate nucleus. [START_REF] Williams | Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges[END_REF] Although not proven, it is likely that the supranuclear vertical gaze palsy of PSP arises due to involvement of burst neurons in the riMLF. [START_REF] Leigh | The neurology of eye movements[END_REF] TDP-43 has recently been found to be a major component of the ubiquinated inclusions characteristic of frontotemporal lobar dementia (FTLD) and sporadic ALS, [START_REF] Arai | TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis[END_REF] and so one might ask why, with such differing pathologies, there are clinical similarities in the ocular motor phenotypes of PSP and ALS? Firstly, neurodegenerative disorders associated with extrapyramidal disease can be seen in association with both tau and alpha-synuclein pathology, highlighting that one phenotype does not necessarily indicate a particular pathology. Secondly, with the discovery of TDP-43 as the major disease protein in ALS, we now have a clearer idea about the extent of pathology in ALS. In a neuropathological study of TDP-43 in 31 ALS patients, Geser et al found that the basal ganglia and substantia nigra were the regions most frequently involved outside of the motor system; the midbrain and pons, which house the burst neurons for saccades, are also involved in about 50% of cases. [START_REF] Geser | Evidence of multisystem disorder in wholebrain map of pathological TDP-43 in amyotrophic lateral sclerosis[END_REF] We propose that slow saccades can be part of the clinical profile of bulbar-onset ALS and that they indicate involvement of the brainstem reticular formation that houses the neural machinery for generating saccades (Figure 1B). In a proportion of such cases, the pathology may be extensive enough to produce supranuclear gaze palsy, with or without extrapyramidal features, thus presenting as a PSP-variant of ALS. Unpublished work by one of the authors (CD) comparing eye movements in 8 patients with PSP and 14 patients with bulbar-onset ALS found that there were many similarities, with both having slowed reflexive saccades and an increased frequency of saccadic intrusions (SIs) during attempted fixation, although the abnormalities were more marked in the PSP group. Clinicians should therefore be aware of the potential for misdiagnosis due to overlap between the clinical and eye movement abnormalities in these conditions.

Disturbance of Volitional Saccades in ALS

Although the clinical examination of eye movements may be normal in ALS, laboratory evaluation of the cognitive control of saccades, especially testing of memory-guided saccades and antisaccades, has provided important insights. Memory-guided saccades are made towards a visual target that has been flashed at a peripheral location some time (typically several seconds) previously. Antisaccades are made to the imagined mirror image of a visually-presented target; for example, when a target is flashed at a location 10 degrees to the left of centre, the subject is required to generate a saccade to an imagined location 10 degrees to the right of centre. Both "short-term" memory-guided saccades (where the remembered target was shown seconds before) and antisaccades are abnormal in ALS patients. ALS patients make accurate memory-guided saccades, but with increased latency (reaction time). [START_REF] Shaunak | Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment[END_REF] In the antisaccade task, ALS patients generate saccades that are both inaccurate and made at increased latency. [5 12] One study separated antisaccade errors into type 1 (subject looks incorrectly towards the target and does not self-correct) and type 2 (subject looks incorrectly towards the target, but self-corrects), and found that only type 1 errors were increased in ALS patients. [START_REF] Donaghy | Slow saccades in bulbar-onset Motor Neurone Disease[END_REF] Furthermore, a positive correlation was found between type 1 errors and both the Stroop test (a neuropsychological test of attention and frontal lobe function) and the ALSFRSr (amyotrophic lateral sclerosis functional rating scale revised), including its bulbar subscore.

Thus, ALS patients have increased errors during the antisaccade task, as well as increased latency of antisaccades and "short-term" memory-guided saccades. How can these findings be explained? Both the frontal eye fields (FEF) and dorsolateral prefrontal cortex (DLPC), shown in Figure 1A, contribute to the programming of antisaccades, but in different ways. On one hand, the right hemisphere DLPC is activated during antisaccades, [START_REF] Ford | Neural processes associated with antisaccade task performance investigated with event-related FMRI[END_REF] and patients with DLPC lesions have an increased percentage of errors in the antisaccade task. [START_REF] Leigh | The neurology of eye movements[END_REF] On the other hand, patients with FEF lesions have a normal percentage of errors on the antisaccade task, but make their antisaccades at increased latency. Overall, it appears that the increased antisaccade type 1 errors and latencies encountered in ALS are due to involvement of both DLPC and FEF. It is also possible to propose a hypothesis to account for generation of memory-guided saccades, since functional imaging studies suggest that DLPC contributes to spatial memory for up to about 20 seconds. [START_REF] Leigh | The neurology of eye movements[END_REF] In summary, abnormalities in the cognitive control of saccades in ALS patients indicate frontal lobe involvement, which fits well with the ever enlarging literature from neuroimaging and neuropsychological studies of frontal lobe impairment in patients with ALS, even in those without clinical evidence of dementia. [START_REF] Abrahams | Frontal lobe dysfunction in amyotrophic lateral sclerosis. A PET study[END_REF][START_REF] Kew | The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study[END_REF][START_REF] Ringholz | Prevalence and patterns of cognitive impairment in sporadic ALS[END_REF] Based on neuropsychological studies, up to 50% of non-demented ALS patients have frontal lobe impairment, [START_REF] Ringholz | Prevalence and patterns of cognitive impairment in sporadic ALS[END_REF] although these studies come from ALS-clinic-based populations and may be biased. Traditionally, it had been thought that 3-5% of ALS patients have an associated FTLD, [START_REF] Neary | Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)[END_REF] although recent evidence suggests a clinicopathological disease spectrum with overlap between ALS and FTLD. [START_REF] Geser | Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies[END_REF]

SMOOTH PURSUIT ABNORMALITIES IN ALS

Smooth pursuit eye movements evolved to permit foveation of moving targets. It is possible to measure both the onset and maintenance of smooth pursuit. The onset of smooth pursuit is usually measured using step-ramp stimuli, in which the target steps to one side and then moves smoothly in the opposite direction.

Step-ramp stimuli aim to position the image of the moving target close to the fovea of the retina at the time when the eye first starts to move; thus, they allow for the reaction time to onset of smooth pursuit and promote generation of smooth pursuit without superimposed saccades.

Maintenance of smooth pursuit is often studied using small visual targets that move in predictable triangular or sinusoidal waveforms. The maintenance of smooth pursuit is usually expressed as velocity gain, the ratio of pursuit eye velocity to stimulus velocity. A more indirect method to assess pursuit gain is to look for catch-up saccades, which are generated to place the fovea back on target if pursuit is inadequate.

Using a predictable, triangular stimulus waveform, Donaghy and colleagues found a reduced velocity gain in 44 ALS patients compared to controls, as well as a reduced proportion of time spent in smooth pursuit. [START_REF] Donaghy | Slow saccades in bulbar-onset Motor Neurone Disease[END_REF] An example of impaired smooth pursuit is shown in Figure 1B of the supplementary material. Three further studies using triangular and sinusoidal waveforms also found reduced velocity gain in ALS patients compared with controls.[2 8 14] A further study found that smooth pursuit was impaired and largely replaced by catch-up saccades in 11 out of 18 ALS patients. [START_REF] Jacobs | An eye movement disorder in amyotrophic lateral sclerosis[END_REF] In contrast, Shaunak and colleagues assessed 17 ALS patients with a triangular waveform stimulus and found that pursuit velocity gain was normal. [START_REF] Shaunak | Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment[END_REF] However, Gizzi and colleagues found reduced smooth pursuit velocity gain only in ALS patients with parkinsonian features, and concluded that pursuit was normal in classical sporadic ALS. [START_REF] Gizzi | Ocular motor function in motor neuron disease[END_REF] Thus, most, but not all, studies have reported abnormalities of smooth pursuit gain in ALS patients. How can these findings be explained? Smooth pursuit is controlled by cerebro-ponto-cerebellar pathways; the cortical areas involved include parts of the temporal and parietal lobes, as well as the FEF.

Posterior cortical areas involved in smooth pursuit project to the cerebellum via the dorsolateral pontine nuclei (DLPN), whereas the FEF projects via nucleus reticularis tegmenti pontis (NRTP). Neurons from the dorsal vermis and flocculus/paraflocculus of the cerebellum are thought to project to the ocular motor nuclei of the brainstem via the cerebellar fastigial nuclei, vestibular nuclei, and y-group nuclei of the brainstem. [START_REF] Leigh | The neurology of eye movements[END_REF] Smooth pursuit gain is reduced in normal elderly subjects, as well as in patients with parkinsonian disorders, FTLD, Alzheimer's disease, cerebellar disorders, and metabolic disturbances, such as hepatic encephalopathy. [START_REF] Leigh | The neurology of eye movements[END_REF] Impaired smooth pursuit is also due to certain medication or drug intoxications, and is therefore not diagnostically specific. [START_REF] Leigh | The neurology of eye movements[END_REF] Nonetheless, electrophysiological and microstimulation studies of the pursuit region of the FEF indicate a role for the FEF in the setting of gain. [START_REF] Leigh | The neurology of eye movements[END_REF] Thus, reduced smooth pursuit velocity gain in ALS patients could arise from involvement of the frontal lobes and, more specifically, the FEF.

OCULAR FIXATION ABNORMALITIES IN ALS

Saccadic Intrusions

Saccadic intrusions (SIs) consist of involuntary saccades that disrupt fixation. SIs are evident on clinical examination, especially during ophthalmoscopy. Measurements have demonstrated several types of SI, including square-wave jerks, single saccadic pulses, double saccadic pulses, and monophasic and biphasic square-wave jerks, which are most common. [START_REF] Leigh | The neurology of eye movements[END_REF] Examples of SIs are shown in Figure 1A of the supplementary material. SIs can occur in normal subjects. However, saccadic oscillations without an intersaccadic interval, such as flutter and opsoclonus, do not occur in healthy subjects. [START_REF] Leigh | The neurology of eye movements[END_REF] Palmowski et al first described fixation abnormalities in seven of eight ALS patients. [START_REF] Palmowski | Eye movement in amyotrophic lateral sclerosis: a longitudinal study[END_REF] Shaunak and colleagues noted an increased frequency of square-wave jerks in ALS patients compared to controls, but they did not measure other SIs. [START_REF] Shaunak | Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment[END_REF] Donaghy and colleagues formally examined fixation in ALS and not only demonstrated an increased SI amplitude in ALS patients compared to controls, but also showed a correlation between SI amplitude, verbal fluency, and Stroop test scores (measures sensitive to frontal lobe dysfunction). [START_REF] Donaghy | Ocular fixation instabilities in Motor Neurone Disease: a marker of frontal lobe dysfunction[END_REF] Thus, fixation abnormalities may be due, at least in part, to impairment of the frontal lobes or their projections to the superior colliculus.

The neural substrate of fixation comprises both cortical and brainstem components. In monkey, numerous studies have demonstrated that FEF is important for suppressing saccades, as well as initiating them. [START_REF] Leigh | The neurology of eye movements[END_REF] Functional imaging studies suggest that the frontal lobes have a role in sustaining steady fixation in humans, with a positron emission tomography study finding activation clusters in the FEF and intraparietal sulci bilaterally when subjects fixated on a central target, but not when they simply kept their eyes open in darkness. [START_REF] Petit | PET study of the human foveal fixation system[END_REF] In the brainstem, electrophysiological and pharmacological inactivation studies in monkey suggest that the rostral pole of the superior colliculus is important in sustaining steady fixation. [START_REF] Leigh | The neurology of eye movements[END_REF] The superior colliculus receives inputs from cortical areas concerned with eye movements; projections from the FEF are both direct and via the basal ganglia. Other inputs are from the mesencephalic reticular formation and cerebellar fastigial nucleus. [START_REF] Leigh | The neurology of eye movements[END_REF] In one monkey, irrepressible saccades resulted from an infarct involving the rostral pole of the superior colliculus, adjacent reticular formation, and periaqueductal gray. [START_REF] Leigh | The neurology of eye movements[END_REF] Pharmacological inactivation of the mesencephalic reticular formation has produced square-wave jerks in monkeys. Similarly, pharmacological inactivation of the rostral pole of the superior colliculus in a monkey reduced suppression of saccades. [START_REF] Leigh | The neurology of eye movements[END_REF] Square-wave jerks are prominent in PSP and pallidotomy has been found to increase square wave-jerks in patients with Parkinson's disease, [START_REF] Leigh | The neurology of eye movements[END_REF] suggesting a role for the basal ganglia in producing SIs. Square-wave jerks have also been reported in cerebellar disorders, such as in some spinocerebellar ataxias. [START_REF] Leigh | The neurology of eye movements[END_REF] In summary, the most consistent abnormality of fixation in ALS is increased SI amplitude. [START_REF] Donaghy | Slow saccades in bulbar-onset Motor Neurone Disease[END_REF] SIs show the same relationship between amplitude, peak velocity, and duration as do voluntary saccades, and are therefore thought to be generated by the same brainstem machinery. While increases in SI amplitude could arise due to dysfunction within these pathways, correlations between SI amplitude and measures of frontal lobe dysfunction suggest that SIs could arise due to involvement of frontalcollicular pathways.

Nystagmus

A second cause for disruption of steady fixation is nystagmus, which is a repetitive toand-fro movement of the eyes that is initiated by a slow phase. It occurs when there is a disturbance within any of the mechanisms that have evolved to hold gaze steady (see Supplementary Table 1). [START_REF] Leigh | The neurology of eye movements[END_REF] One such mechanism is the vestibulo-ocular reflex, which generates eye movements that compensate for head movements, and another is the gaze-holding mechanism, which holds the eyes in an eccentric position against the elastic restoring forces of the orbital tissues and depends on a neural network (the "neural integrator") within the brainstem and cerebellum. Lastly, pathology affecting the afferent visual system, from the eye to posterior cortex and its pontine-cerebellar projections, can also cause nystagmus. In this case, nystagmus can result from an impaired ability to correct for retinal image drift or disruption of the visual inputs that allow eye movement calibration according to visual demands. Nystagmus is rarely reported in ALS, although there are two reported cases of ALS, confirmed post-mortem, with nystagmus. [START_REF] Kushner | Nystagmus in motor neuron disease: clinicopathological study of two cases[END_REF] One of these had gaze-evoked nystagmus, followed later by supranuclear palsy of horizontal gaze and upgaze, while the other had gaze-evoked nystagmus with a normal range of eye movements. Gaze-evoked nystagmus often occurs with brainstem or cerebellar disease, [START_REF] Leigh | The neurology of eye movements[END_REF] although the ensuing supranuclear gaze paresis in the first patient suggests involvement of the midbrain and pons. Post mortem examination in one of the patients revealed two small carcinoid tumours in the terminal ileum, raising the question of whether the nystagmus could have been a feature of a paraneoplastic syndrome rather than the patient's ALS.

Thakore and colleagues described three patients with downbeat nystagmus (Figure 1A, supplementary material) and a predominantly lower motor neuron syndrome, with wrist and finger extensor weakness and evidence of anterior horn cell disease. [START_REF] Thakore | Motor neuronopathy with dropped hands and downbeat nystagmus: a distinctive disorder? A case report[END_REF] Cerebellar atrophy was noted on imaging in one patient, who had initially presented with balance and gait difficulties. It is possible that these patients had a distinct syndrome, although their electrophysiology was consistent with ALS. In summary, nystagmus is not a common finding in ALS; when it occurs, it may present an opportunity to investigate the pathophysiology of the disorder, but could also suggest an ALS mimic (discussed in the last section).

OPHTHALMOPLEGIA

Case reports of ALS patients with external ophthalmoplegia are uncommon, and mainly concern patients whose life has been prolonged by long-term ventilation. [START_REF] Mizutani | Development of ophthalmoplegia in amyotrophic lateral sclerosis during use of respirators[END_REF] In some reports, involvement of the ocular motor nuclei has been noted on post mortem examination. [START_REF] Harvey | Amyotrophic lateral sclerosis with ophthalmoplegia. A clinicopathologic study[END_REF] Kaminski and colleagues reviewed the evidence for sparing of ocular motor neurons in ALS.[51] When comparing ocular motor with spinal motor neurons, there are differences in glutamate neurotransmitter activity, calcium-binding protein, androgen receptor expression, and their dependence on trophic factors. However, no single theory satisfactorily explains why ocular motor neurons are relatively spared in ALS. It is possible that patients who develop external ophthalmoplegia represent the extreme end of the disease spectrum, where the process has extended to involve the ocular motor nuclei of the brainstem.

SUMMARY OF EYE MOVEMENT ABNORMALITIES IN ALS

Much like the continuum of cognitive disturbance proposed in the ALS literature, [START_REF] Geser | Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies[END_REF] eye movement abnormalities probably form a spectrum, with normal eye movements at one end of the spectrum and supranuclear gaze palsies and, rarely, ophthalmoplegia at the other. Many patients with sporadic ALS have increased latency of antisaccades, with increased antisaccade errors, reduced smooth pursuit velocity gain, and increased saccadic intrusion amplitude. Current evidence suggests that these abnormalities arise due to frontal lobe involvement. In those patients with advanced or bulbar-onset disease, however, it is likely that more extensive pathological changes in the brainstem give rise to slowed saccades with or without supranuclear gaze palsy. In these instances, ocular motor abnormalities may mimic those of PSP, with more marked involvement of vertical saccades and relative sparing of horizontal saccades. Many of these ALS patients have other ocular motor signs suggestive of PSP, such as SI, increased antisaccade errors, and decreased smooth pursuit gain.[5 8 12 14] Nonetheless, with the advent of sensitive molecular pathological markers, such as TDP-43, future clinicopathological studies are likely to identify the neural substrate of atypical eye movement and clinical findings in ALS and, in doing so, further our understanding of the clinical spectrum of this disorder.

EYE MOVEMENT ABNORMALITIES IN ALS MIMICS

The syndromes that most commonly mimic ALS -benign fasciculation syndrome, cervical spondylitic myelopathy, multifocal motor neuropathy, and inclusion body myositis -are not known to cause eye movement abnormalities. However, a range of other motor neuron disorders can produce an ALS-like picture, with associated eye movement abnormalities (Table 1). Palsies of the oculomotor (III), trochlear (IV), and abducens (VI) cranial nerves (CN) should suggest disease in the subarachnoid space, cavernous sinuses, orbit, or posterior nasopharynx. Rare hereditary progressive bulbar syndromes, such as Brown-Vialetto-Van Laere [33] and Fazio-Londe [START_REF] Gulati | Progressive bulbur paralysis (Fazio-Londe disease)[END_REF] syndromes, can also produce CN III, IV, and VI palsies. Although hearing loss is suggestive of these syndromes, it is unknown if vestibular dysfunction occurs in affected patients.

Parkinsonian syndromes, especially PSP, may present like ALS, with prominent bulbar dysfunction and decreased mobility. PSP patients are known to have a distinctive eye movement disorder: slowing of vertical saccades, along with increased frequency of saccadic intrusions (square wave jerks). [START_REF] Leigh | The neurology of eye movements[END_REF] However, the potential for diagnostic difficulty exists when taking into consideration the case reports describing slow saccades with or without supranuclear gaze palsy in ALS patients with or without a bulbar onset.[3 10 13 15] Kennedy's disease (KD), also known as spinal-bulbar muscular atrophy, is an Xlinked degenerative condition of lower motor neurons causing late-onset muscular atrophy, with fasciculations of the face and tongue. KD can mimic ALS, but differs from sporadic ALS with absence of pyramidal involvement and a slowly-progressive course.

Unpublished work by one of the authors (CD) has found normal fixation, saccades, and smooth pursuit in four patients with KD. Reflexive saccades, however, were found to be slowed in one KD patient we have studied (Figure 2 supplementary material). [START_REF] Thurtell | Abnormal eye movements in Kennedy disease[END_REF] Bulbar myasthenia gravis (MG) can occasionally be mistaken for ALS. MG can present with fluctuating ptosis, reduced range of eye movements that does not conform to specific ocular motor nerves, or even complete ophthalmoplegia. Finding a reduced range of eye movement with preservation of small, fast saccades ("quiver movements") is highly suggestive of MG. [START_REF] Leigh | The neurology of eye movements[END_REF] Although rare, late-onset Tay-Sach's disease (LOTS), a lysosomal storage disorder due to inactivity of the enzyme hexosaminidase A, can also mimic ALS, but typically gives rise to interrupted or multi-step saccades, which have not been reported to occur in ALS. [START_REF] Leigh | The neurology of eye movements[END_REF] The spinocerebellar ataxias (SCAs) are a constantly enlarging group of inherited multi-system disorders that can present with cerebellar, pyramidal, and extrapyramidal dysfunction. SCA-3 (Machado-Joseph disease) can present with an ALS-like picture and therefore should be considered in the differential diagnosis of ALS. While approximately 56% of SCA-3 patients have ophthalmoplegia, other ocular motor findings, such as saccadic hypermetria and gaze-evoked nystagmus, are suggestive of cerebellar disease. [START_REF] Riess | SCA3: neurological features, pathogenesis and animal models[END_REF] SCA-3 is also known to cause reduced gain of the vestibulo-ocular reflex. [START_REF] Leigh | The neurology of eye movements[END_REF]

CONCLUSIONS

We can now challenge the widely held view that eye movements are normal in ALS. As we have shown, a range of eye movement abnormalities can occur in ALS and have provided insights into the distribution and nature of the disease process. Eye movements have the potential to help identify ALS mimics in patients who are misdiagnosed due to the inherent difficulty in diagnosing ALS. Eye movements, which are easy to record and for which a neural substrate is well established, provide us with a powerful behavioral tool to investigate the workings of the brain in ALS. Measurement of eye movement abnormalities in future longitudinal studies seems likely to provide further insights into the nature of this stubborn and malign disease. 6. Chronic progressive external ophthalmoplegia due to mitochondrial myopathy [START_REF] Leigh | The neurology of eye movements[END_REF] Vestibular-Ocular Reflex:

Reduced Gain SCA-3 (Machado-Joseph Disease) [START_REF] Leigh | The neurology of eye movements[END_REF] Guamanian ALS [START_REF] Lepore | Supranuclear disturbances of ocular motility in Lytico-Bodig[END_REF] Ocular fixation:

1. Saccadic Intrusions A) Increased frequency B) Increased amplitude 2. Unspecified nystagmus PSP, MSA [START_REF] Leigh | The neurology of eye movements[END_REF] ALS [START_REF] Donaghy | Ocular fixation instabilities in Motor Neurone Disease: a marker of frontal lobe dysfunction[END_REF], PSP [START_REF] Leigh | The neurology of eye movements[END_REF] Polio [START_REF] Murray | Ocular abnormalities in poliomyelitis and their pathogenesis[END_REF] 3. Downbeat nystagmus 4. Periodic alternating and centripetal nystagmus MSA [START_REF] Leigh | The neurology of eye movements[END_REF] CJD [START_REF] Leigh | The neurology of eye movements[END_REF] Saccades:

1. Slow reflexive saccades Kennedy's Disease [START_REF] Thurtell | Abnormal eye movements in Kennedy disease[END_REF] ALS [5 6 12], PSP [START_REF] Leigh | The neurology of eye movements[END_REF] Frontal lobe pathology co-existent with cervical/lumbar root disease

Frontal lobe pathology co-existent with cervical/lumbar root disease ALS [6 12] ALS [5 9 14], PSP* [START_REF] Leigh | The neurology of eye movements[END_REF] PSP [START_REF] Leigh | The neurology of eye movements[END_REF] Saccadic dysmetria:

1. Hypometria SCA-3 (Machado-Joseph Disease) [START_REF] Leigh | The neurology of eye movements[END_REF] MG [START_REF] Leigh | The neurology of eye movements[END_REF] Smooth Pursuit:

1. Reduced velocity gain 2. Broken by saccades ALS [2 5 8], PSP [START_REF] Leigh | The neurology of eye movements[END_REF] ALS [START_REF] Jacobs | An eye movement disorder in amyotrophic lateral sclerosis[END_REF], HSP (SPG30 mutation) [START_REF] Klebe | Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3[END_REF] Multi-system HIV infection [START_REF] Leigh | The neurology of eye movements[END_REF] Guamanian ALS [START_REF] Lepore | Supranuclear disturbances of ocular motility in Lytico-Bodig[END_REF] *Most particularly noted in vertical saccades LOTS, Late-Onset Tay-Sach's disease; PSP, Progressive Supranuclear Palsy; MSA, Multiple System Atrophy; CBGD, Corticobasal Ganglionic Degeneration; SCA, Spinocerebellar Ataxia; MG, Myasthenia Gravis; CJD, Creutzfeldt-Jakob Disease; HSP, Hereditary Spastic Paraplegia.

Figure 1 :

 1 FIGURE LEGEND:

Figure 2 :

 2 Figure 2: Saccadic abnormalities in a 70-year-old man with bulbar-onset ALS. Eye

Table 1 : ALS and its mimics, categorised according to eye movement findings Eye movement findings ALS or its mimic

 1

	No known abnormality	Benign fasciculation syndrome
		Cervical Spondylitic Myelopathy
		Hyperparathyroidism
		Inclusion Body Myositis
		Multifocal Motor Neuropathy
	Ocular misalignment and	1. Cranial Nerve Palsies:
	limited range of movement	Skull base and posterior nasopharyngeal
		lesions, Sjogren's syndrome [18], Fazio-
		Londe [34], Brown-Vialetto-Van Leare
		syndrome [33], Polio [37]
		2. Neuromuscular junction disease: MG
		3. Restrictive Ophthalmopathy:
		Thyroid-associated (Graves') orbitopathy
		/Hyperthyroidism
		4. Ophthalmoplegia: SCA 3 (Machado-
		Joseph Disease) [36]
		5. Unspecified restricted vertical and
		horizontal ocular motility: Lead [38]

ACKNOWLEDGEMENTS

Supported by NIH grant EY06717, Department of Veterans Affairs, and Evenor Armington Fund (Dr. Leigh). The funding sources had no role in the writing of this review.

COPYRIGHT

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Group and co-owners or contracting owning societies (where pusblished by the BMJ Group on their behalf), and its Licensees to permit this article (if accepted) to be published in the Journal of Neurology, Neurosurgery and Psychiatry and any other BMJ Group products and to exploit all subsidiary rights, as set out in our licence (http://jnnp .bmjjournals.com/ifora/licence.pdf).

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

AUTHORS CONTRIBUTIONS

All authors were involved in writing the manuscript. In addition, Colette Donaghy performed the literature search, Matthew Thurtell and John Leigh recorded eye movements for the patients highlighted in the case reports and assembled the figures, and Erik Pioro identified patients for the case studies.