Is the number of patients with motor neuron disease increasing?

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09-01-2018

Is the number of patients

with motor neuron

disease increasing?

AN EPIDEMIOLOGICAL STUDY OF THE MND- TEAM PATIENTS DURING 5 YEARS

AV: ALEXANDRA SUNDELIN HANDLEDARE: INGELA NYGREN

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Motorneuronsjukdomar (MNS) är en grupp neurodegenerativa sjukdomar där amyotrofisk lateral skleros (ALS) utgör den stora majoriteten av fallen. ALS innebär en progressiv förlust av motorisk funktion (svaghet i armar och ben), svårigheter med tal och sväljning, och till slut drabbas även andningsfunktionen vilket oftast är det som leder till döden. Det årliga insjuknandet beräknas vara 2-4 per 100000 invånare, och överlevnaden är vanligtvis 3-5 år. Ca 5-10 % av fallen är ärftliga och resterande är sporadiska. Det finns inget bot och ingen etablerad orsak till sjukdomen.

För att undersöka om antalet patienter med motorneuronsjukdomar har ökat gjordes en journalstudie av de patienter som var inskrivna i MNS-teamet på Akademiska sjukhuset åren 2012-2016.

Samtidigt inhämtades information om ålder, kön, tidigare sjukdomar, överlevnad, debut, rökning, arbete och ärftlighet för att kunna beskriva gruppen i relation till resten av befolkningen. Resultaten visar att såväl det årliga insjuknandet som förekomsten har ökat i Uppsala län, i Dalarnas län ligger siffrorna ungefär på samma nivå som de gjort i tidigare studier. Detta indikerar att en ökning har skett. Övriga resultat visar att det är något fler män än kvinnor, medelåldern är 65 år och

medelöverlevnaden är 2,6 år. Gruppen har färre andra sjukdomar än befolkningen i stort, något fler rökare än resten av befolkningen, och många som arbetar med fysiskt krävande arbeten. Detta stämmer väl överens med hur den här gruppen brukar beskrivas i annan forskning, och således tycks detta vara en representativ grupp.

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4 Background

Motor neuron disease

Motor neuron disease (MND) is a group of neurodegenerative diseases affecting the motor neurons.

The most common is amyotrophic lateral sclerosis (ALS) which affects both upper and lower motor neurons. It’s characterized by deteriorating motor function, atrophy of the muscles, blurred speech, dysphagia, and eventually deterioration of breathing function which usually is the cause of death.

The survival is usually 3-5 years, although some patients live considerably longer. Younger and previously healthy individuals usually survive longer. It can happen to people all ages, but the incidence rate increases after the age of 40 until about 75 when it decreases again. It is slightly more common among men. Primary lateral sclerosis (PLS) only affects the upper motor neurons and has a slower progression. Progressive spinal muscular atrophy (PSMA) is a sporadic condition with a slow progression only affecting the lower motor neurons. Spinal muscular atrophy (SMA) is divided into four groups, all of them caused by genetic defects. Most of them manifest shortly after birth or during childhood, SMA type IV is usually the version that may manifest in adulthood and is less severe than type I and II. It does not shorten the life expectancy of the affected. Kennedy’s syndrome is also caused by a genetic defect, a mutation in the androgenic receptor located on the X- chromosome, which means that it’s a condition only affecting men while women may be carriers.

The progression is very slow, the symptoms may be very mild for many years, and the progression of the disease doesn’t shorten the life of the affected. (Ansved and Solders; Ropper et al., 2014;

Solders, 2018)

Genetics

Since the clear majority of the MND-population have ALS, the main focus will be to describe this condition in greater detail. About 90-95 % of the ALS cases are sporadic, and the remaining cases hereditary. The most common mutation is a hexanucleotide repeat expansion on C9orf72, which is sometimes found in sporadic cases as well. Another established mutation is that of the SOD1-gene, which like C9orf72 might be found among sporadic cases as well. With emerging new techniques for genetic sequencing and mapping, efforts have been made trying to elucidate further genetic clues behind the disease. In a genome-wide association study an additional gene associated to ALS was found, two associated loci, and it was also estimated that there is a single-nucleotide

polymorphism-heritability in some of the cases (van Rheenen et al., 2016). The underlying genetics are complex, much like the rest of the events leading up to the emerging neurodegeneration. Many theories about the underlying causes have emerged during the years based on observed associations, and the most likely answer is that several of these mechanisms are involved in the pathogenesis.

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5 Comorbidities

Many researchers have proposed an autoimmune basis from observed associations to autoimmune disease. Myasthenia gravis has been observed as a pre-existing condition in a much higher

frequency than expected based on the prevalence of both conditions and the likelihood of them occurring in the same patient (de Pasqua et al., 2017; Turner et al., 2013). There is also evidence that previous use of chemotherapy is less common in ALS-patients than controls (Kuczmarski et al., 2017). It has also been suggested that previous cancers is less common among ALS-patients,

although that might be true studies investigating whether cancer reduces the risk of developing ALS has failed to show a significant association (Fois et al., 2010; Freedman et al., 2013).

Psychiatric disorders prior to the debut is more common compared to the general population (Turner et al., 2016). Frontotemporal dementia (FTD) is genetically linked to ALS through familial TDP-53-mutations where some family members might develop FTD and other family members develop ALS. The most common genetic cause of familial clustering of FTD and ALS is the C9orf72 repeat expansion, where both diseases might develop or either one of them separately. ALS patients often display an emotional instability and other behavioural changes similar but milder than those presented in someone who suffers from FTD. Similarly, FTD patients often develop mild motor neuron symptoms even in the absence of actual MND. An increased prevalence of psychiatric illness in family members of patients with C9orf72 expansion has also been noted (Burrell et al., 2016). Frontotemporal dementia might be misdiagnosed as bipolar disorder or schizophrenia, and this may account for some cases with those psychiatric

comorbidities. It is hypothesized that a shared genetic vulnerability explains some of the cases as well. Depression has also been found to be more common prior to the debut of MND. The

psychiatric illnesses might represent a common denominator or if in close proximity to MND-debut it might represent psychiatric manifestations of MND. Changes in the cortical architecture prior to symptoms might also account for the higher frequency of depression prior to developing loss of motor function (Turner et al., 2016).

Despite evidence that is sometimes inconclusive regarding the associations of different conditions to ALS, there is one thing that has been evident through all studies about comorbidities and pre-existing illness, the ALS population is less inflicted with chronic illness than the general population (Hollinger et al., 2016; Mitchell et al., 2015). For instance, cardiovascular disorders, very common among the general population as we age, has been proven to have a lower prevalence than in the general population in large scale studies (Hollinger et al., 2016; Mitchell et al., 2015;

Sutedja et al., 2011; Turner et al., 2012). Hyperlipidaemia on the other hand is subject to conflicting results regarding prevalence and impact on progression (Mitchell et al., 2015; Seelen et al., 2014).

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Some studies indicate higher prevalence of hyperlipidaemia among MND-patients, some indicate lower prevalence, while others find no difference. Although higher prevalence is usually the case.

The main issue regarding hyperlipidaemia that has been debated previously is whether it has a positive impact on the prognosis. It was proposed that hyperlipidaemia served as a protective factor and increased survival in ALS-patients, but studies to confirm this hypothesis have reached

conflicting conclusions on the subject. The idea of protection from hyperlipidaemia has mostly been abandoned, and instead it is believed that hyperlipidaemia might be the product of increased

metabolic demands due to the disease (Chiò et al., 2009; Dupuis et al., 2008; Rafiq et al., 2015).

Lifestyle, occupation and environment

A lean physique and higher physical activity level has been associated with ALS for a long time, this is to some extent based on anecdotal information from clinicians, but it has scientific support as well. A common characteristic for the ALS-populations is lower body mass index than the general population, as well as more physical activity. The higher physical activity is generally included in work (Beghi et al., 2010), but there is also evidence supporting a possible association to

professional athleticism. For instance, surprisingly many cases have been found among Italian football players (Chiò et al., 2005). Microtraumas from preforming sports has been disproven as the underlying cause of this association. Previous traumas is debated as a risk factor and subject to conflicting results (Beghi et al., 2010; Pupillo et al., 2012). In addition to this, military service has been proven to be associated with higher risk of ALS (Tai et al., 2017). In contrast to the generally healthier lifestyle of the ALS-population, smoking is usually slightly more common and has an established association (Alonso et al., 2010; Armon, 2009), but is not causal.

Environmental factors have also been associated, such as exposure to pesticides and heavy metals (Andrew et al., 2017). An association with farming has been found, where pesticides is the most likely damaging component (Kab et al., 2017). The amino acid BMAA (β-N-methylamino-L- alanine), a product of the cyanobacteria, has been associated with the outbreak of a disease very similar to ALS in Guam following World War II (Chernoff et al., 2017). The incidence of this disease has decreased drastically when the dietary products containing high amounts of BMAA was abandoned. This has been studied in other parts of the world as an environmental contribution to the pathogenesis. Algae is another source of BMAA from the cyanobacteria and people living in

proximity to the ocean might be exposed to it. A recent phase I study in the United states tried counteracting the effects of the exposure in ALS-patients using L-serine-supplements (Bradley et al., 2017), whether this is an eligible treatment remains to be seen.

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7 Incidence and Prevalence

One study investigated the incidence of ALS in Sweden from 1991 to 2005 and found an increase in incidence from 2.32 per 100 000 to 2.98 (Fang et al., 2009). This was the last published study found on incidence in Sweden. Since the general impression among clinicians is that there has been a further increase in incidence new studies are warranted to confirm this. A study investigating the incidence in Europe was performed for the years 1998-1999 including Ireland, United Kingdom and Italy. The incidence was 2.16 per 100000, with only minor variations between the included

countries (Logroscino et al., 2010). The incidence and prevalence in Japan 2009-2010 was 2.2 and 9.9 per 100000 (Doi et al., 2014). In Norway during 2009-2015 the prevalence was 7.6 per 100000 (Nakken et al., 2017). In the United states the prevalence was 5 per 100000 in year 2013 (Mehta et al., 2016).

Treatment

Assuming there has been an increase, the need for new treatments is growing. Riluzole is the only established treatment for ALS, it provides neuroprotection through inhibition of glutamatergic processes. It may prolong survival for a couple of months and delay onset of respiratory failure.

Since Riluzole was approved in 1995 there has been no new treatments established, and not for lack of trying. Big efforts have been made trying a great number of compounds as treatments for ALS with disappointing results (Petrov et al., 2017). For a while it was believed that Lithium (a mood stabiliser) had neuroprotective properties beneficial for ALS-patients, this has unfortunately been disproven among many other suggested treatment options (Chiò and Mora, 2013). Edaravone is a free radical scavenger that reduces oxidative stress and has recently been in the pipeline for new treatment options. It has unfortunately only shown positive results in a limited subgroup of the ALS-population and also has the disadvantage of being administered intravenously (Abe et al., 2017; Hardiman and van den Berg, 2017). It has been approved by the FDA, but further studies are needed to determine how the treatment can be used in clinical practice to benefit the patients, or at least some of them. Masitinib, a tyrosine kinase inhibitor, is an oral treatment targeted for a larger part of the ALS-population. It has been tried as a treatment combined with Riluzole in a large phase III trial of which the results have not yet been published. Previous results have shown promise, and it’s possible that Masitinib might be the first oral treatment to accompany Riluzole (Khalid et al., 2017).

Hypothesis and conditions for the study

The MND-team at Akademiska sjukhuset Uppsala, consists of neurologist, nurse, physiotherapist, occupational therapist, counsellor, speech therapist and nutritionist, attending to different aspects of

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the needs the patients develop as the disease progresses. When diagnosed with a motor neuron disease the patients receive further care from the collective efforts of the MND-team.

The primary aim of the study is to investigate if the incidence has increased, and at the same time explore the MND-patients’ history and describe them as a group regarding age, gender, comorbidities, mortality, occupation, smoking habits, onset (spinal/bulbar), and family history of MND. Clinicians have noticed an increase in patients that cannot be explained solely by the growing population and increased lifespan. The hypothesis is that the incidence has increased. The increase is probably not big enough to reflect possible changes in the characteristics of the affected.

If an increase can be attributed to a specific subgroup, it is unlikely to be reflected in the results of this study.

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9 Methods

The data was collected by reviewing the medical records of all patients with a diagnostic code (G12.2, G12.9) for a motor neuron disease during the years 2012 to 2016 at Akademiska sjukhuset, Uppsala. This includes all MND-patients in Uppsala county and Dalarna county, some patients from neighbouring counties and consultations for second opinions. The total number of patients was initially 177, 2 patients were excluded, one because of a misdiagnosis and the other because that patient was only admitted for an unrelated procedure and did not receive other health care in this region. All MNDs were included, ALS, PLS, Kennedy’s, SMA. PLS, Kennedy’s and SMA were not included when calculating incidence, prevalence and mortality, because the progression of these conditions is slower. The definition of ALS was according to the El Escorial criteria, the incidence and prevalence rates are calculated from the patients meeting them. Notes from all involved health care personnel was used as source of information.

For the calculation of incidence and prevalence for Uppsala and Dalarna county,

population statistics for each year was collected from SCB (swedish central agency for statistics).

For comparison to the general population regarding comorbidities and smoking habits statistics from Folkhälsomyndigheten (public health agency) was collected. Additionally, statistics about the use of prescription medication for hyperlipidaemia was collected from Socialstyrelsen (the Swedish medical board).

The results are presented with descriptive statistics. No ethical permission was needed for this study since it’s a student research project and because it’s an observational retrospective study.

Permission to review the medical records was granted from the director of the neurology department.

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10 Results

General characteristics

A total of 175 patients were included, 100 men and 75 women. 152 of the patients had ALS according to the El Escorial criteria. The mean age was 65 for both men and women, the youngest patient was 19 and the oldest 88. The onset was spinal for 53 % of the patients and bulbar for 47 %.

Bulbar onset was more common in women. About 6 % of the patients had a family history of MND.

The average time to diagnosis was 2.2 years (range 1 month to 21 years), the longest times being exclusive to the patients with Kennedy’s syndrome (table 1).

Table 1. General characteristics of the studied population

Total number of patients 175

ALS according to El Escorial 152

PLS 11

Kennedy’s syndrome 8

SMA 4

Spinal onset 53 %

Bulbar onset 47 %

Men 100 (57 %)

Women 75 (43 %)

Age 19-88 (mean 65)

Survival 4 m – 15 y 7 m (mean 2,6 y)

Time to diagnosis 1 m – 21 y (mean 2,2 y)

Incidence and prevalence

Among the residents of Uppsala county, the incidence of ALS has increased compared to previous national average, with the highest incidence in year 2013, 4.34, and the lowest in year 2015, 1.98.

The average incidence during the years 2012-2016 is 3.66. For Dalarna county however, the incidence is slightly lower, with the exception of the highest incidence in year 2013, 3.61, the lowest incidence was in year 2014, 1.79. The average incidence during the years 2012-2016 2.57.

The prevalence increases from 9.06 in year 2012 to 12.73 in year 2016 in Uppsala county. In

Dalarna county the prevalence increases from 5.42 in year 2012 to 7.38 in year 2016, with a peak of 7.57 year 2013.

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Figure 1. The incidence and prevalence for each year from 2012 to 2016 for Uppsala and Dalarna county respectively.

Comorbidities, lifestyle and occupation

Table 2. Acquired illness prior to MND-diagnosis Health problems prior to

diagnosis

%

No chronic illness 22

Minor chronic illness 23

Other neurological disorders 7

Autoimmune disorders 11

Psychiatric conditions 11

Cardiovascular disorders (incl. hypertension) 43

Malignancy 10

Diabetes 13

Hyperlipidaemia 14

3,8 4,34

4,01

1,98

4,15 9,06

10,42

12,04

10,45

12,73

2,17

3,61

1,79

2,49 2,81

5,42

7,57 7,17 7,47 7,38

2012 2013 2014 2015 2016

Uppsala incidence Uppsala prevalence Dalarna incidence Dalarna prevalence

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Table 3. Differences in characteristics between men and women

Men Women

Mean age 65 65

Onset Spinal 60 %, Bulbar 40% Spinal 44 %, Bulbar 56 %

Smoking 18 % 25 %

No chronic illness 17 % 24 %

Survival 2,5 years 2,8 years

Comorbidities are shown in table 2. Prior to MND-diagnosis 22 % had no chronic illness, 23 % only had a minor chronic illness (such as asthma, allergies, migraine) prior to diagnosis. It was more common among the women with no chronic illness prior to diagnosis (table 3). 11 % suffered from psychiatric disorders (including psychiatric disorders treated by primary care physicians such as depression and anxiety). The biggest group was cardiovascular disorders, which 43 % of the patients suffered from.

When looking at lifestyle choices it was found that 51 % had never smoked, 25 % had quit smoking, and 21 % were still smoking at the time of diagnosis. More female smokers were found than male (table 3). Of the 175 patients 73 were still alive at the time the study was performed. The mean survival time for the deceased patients was 2.6 years (range 4 months to 15 years 7 months).

Women had a slightly longer survival (2.8 years) than men (2.5 years).

Occupations are displayed in table 4. The biggest occupation group was

farming/industrial/construction, 23 % of the patients, 22% worked in health and child care. 30 % had a physically demanding occupation. 19 % of the patients had a degree from a higher education.

Table 4. Former and present occupations of the studied population Occupation (former or present) %

Health and child care 22

Farming or industrial/construction work 23

Service 11

Office 19

Transportation 6

Physically demanding work 30

Higher education 19

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13 Discussion

Incidence, prevalence and mortality

Increased incidence was found in Uppsala county, but not in Dalarna where it remained around the same level or slightly lower compared to previous findings for national statistics. The incidence had a peak in the year 2013 for both counties. The results for Uppsala county supports the hypothesis that the ALS incidence has increased, the increasing prevalence gives further support. The

increasing prevalence could however have other explanations, for instance longer survival. There is no evidence in the results of this study of increased time of survival. In fact, the mean survival time for the deceased patients was slightly lower. However, one should keep in mind that the survival time for the patients still living might be higher, and the time frame for this study is too short for conclusions regarding survival. Because of the available and frequently used treatments for nutritional and non-invasive breathing support it would be reasonable to assume that the true survival is somewhat longer. One should also keep in mind while analysing the mortality rate for the patients in this study that the frequency of bulbar onset was much higher than expected, and bulbar onset is associated with shorter survival. Bulbar onset was more frequent among the female patients, but they had slightly longer survival than that for the men. The mean age was the same for both men and women, 65, which is slightly higher than in most studies, but within normal range.

The mean age is usually lower among the male patients. Higher age is also a possible explanation for slightly shorter survival.

The incidence in Dalarna county was about the same or slightly lower compared to previous national average. This could be explained by a possible difference in the population, such as lower quota of people in the age group with the highest incidence. Another possible explanation is that there were people that were never referred to the MND-team in Uppsala, either because the diagnosis was not considered or the affected refrained from seeking medical attention for their condition. Another possibility is that the five years included in this study has an unusually low incidence for the area, or the residents have different genetic and environmental conditions making them less vulnerable for MND than the national average would suggest. Since MND is unusual one person would make a statistical difference in a population of this size, and practical events such as if a person is diagnosed in December one year or in January the next might influence the results.

Comorbidities

The most frequent comorbidity was cardiovascular disorders including hypertension, 43 % of the patients. More than 50 % of the general population over 65 years has hypertension and about 18 % of the general population has another cardiovascular disorder. The number of patients with this

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comorbidity seems low considering that most of them are seniors where hypertension alone is more common in the general population. The lower than expected occurrence of cardiovascular disorders is in line with findings in other studies, and it has been suggested that cardiovascular disorders decreases the risk of developing MND (Sutedja et al., 2011; Turner et al., 2012). In fact, it has been suggested that either other illnesses are protective against MND, or that MND is protective against other illnesses (Hollinger et al., 2016; Mitchell et al., 2015). About 33 % of the general population is expected to develop a malignancy sometime during their lifetime, among the patients in this study only 10 % had a history of malignancy or an ongoing condition. Since the incidence of

malignancies increases with age it stands to reason that at least some of the patients would have developed a malignancy if they had lived longer. In previous studies evidence pointing to

chemotherapy decreasing the risk of MND has been found (Kuczmarski et al., 2017), this is also a possible explanation for the low occurrence of malignancy.

Among other neurological disorders 4 cases of myasthenia gravis was found, this is interesting since others have hypothesised that there is a connection between MND and this other rare condition (de Pasqua et al., 2017; Turner et al., 2013). To prove such a relationship

multinational studies would be needed to examine a much larger number of patients. Regarding the number of patients with hyperlipidaemia it’s difficult to make an assessment as to its importance, since the definition of this condition and when it’s clinically significant is debated. There is no scientific consensus about whether the condition is more or less common among MND-patients or if it has any impact on the disease (Chiò et al., 2009; Dupuis et al., 2008; Hollinger et al., 2016;

Körner et al., 2013; Mitchell et al., 2015; Rafiq et al., 2015; Seelen et al., 2014). Because of the inconsistent findings regarding this comorbidity it is reasonable to assume that the occurrence of hyperlipidaemia does not have a strong impact on the development of MND. However, it is still possible that it could be linked to the disease as a part of the pathophysiological changes. The patients with hyperlipidaemia that was identified in this study are those with the diagnosis in their medical records and/or receiving treatment, the actual biochemical status was not investigated as part of the study which means that there is no way of assessing how many are affected by the condition. 9.5 % of the general population are receiving treatment for hyperlipidaemia, while 14 % of the patients in this study had this comorbidity. This might mean that this MND-population have a slightly higher prevalence of hyperlipidaemia, but it could also have other explanations. A possible explanation is higher awareness regarding health in this patient group, and they may be more inclined to ask for screening regarding common conditions such as hyperlipidaemia.

It has been suggested that there is a connection in the genetics between certain psychiatric disorders and MND (Burrell et al., 2016), and that frontotemporal dementia prior to MND diagnosis might be misdiagnosed as schizophrenia or bipolar disorder. Depression in proximity to the debut of

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MND symptoms might be due to changes in cerebral architecture (Turner et al., 2016). The results of this study do not support higher prevalence of psychiatric disorders among MND patients, in fact the occurrence is slightly lower than that for the general population. Depression might be more common than the results indicate. It might not be recorded as a separate diagnosis or acknowledged as a symptom before MND debut.

Lifestyle, occupation and environment

When comparing the number of smokers to the general population, more smokers were found among the patients than in the general population and less never smokers among the patients than in the general population. This is in accordance with the current standpoint where smoking is

considered an established risk factor for MND (Alonso et al., 2010; Armon, 2009). The female patients had a higher percentage of smokers, which is also an established fact in the general

population in Sweden. The information about the smoking habits of the patients in this study is not elaborate enough for further speculation about the relationship between MND and smoking, although it is sufficient to support the notion that such a relationship exists.

A large proportion of the patients had a physically active occupation, and many of them had chosen a health-conscious lifestyle. It has been suggested many times that there is a relationship between such a lifestyle and MND, and the results of this study is certainly in favour of that theory.

Many studies indicate that there is a relationship between physical activity and MND, but the nature of this relationship remains open for speculation (Beghi et al., 2010). Another large group was farmers/construction/industrial workers where exposure to toxins may be an issue. This is yet another subject that has been researched in previous studies (Andrew et al., 2017; Kab et al., 2017).

This study would support a relationship between hazardous occupations and MND. Then again many of these occupations are also physically demanding which makes it harder to reach a conclusion regarding the existence and nature of a relationship to MND.

Strengths, limitations and the future

Five years is a relatively short time frame, which limits the possibilities to assess the changes in incidence and prevalence, a longer time frame would have been preferable for this purpose. As to the other data collected all MND-patients treated at Akademiska sjukhuset during this timeframe are included, which means that the results really do represent this population. Reviewing patient history files, with its disadvantages, is nonetheless an effective way to gather information about a larger number of patients. Although the information sometimes lacks desired details, this type of study reduces the risk of bias. If there is any kind of bias, it’s not because of the design of the study.

The comparison of the results is not with a matched control group, the comparison is only meant to

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put the results into perspective. No definite conclusions should be drawn from these results. The overall results are consistent with previous findings, the prevalence of other illness being lower than in the general population, the smoking habits, and the frequency of family history of MND. The mean age of onset is also within the expected range. This means that it’s reasonable to assume that this is a representative MND-population. Because of the way the data was collected, by reviewing medical records available at Akademiska sjukhuset, it is possible that the medical histories are incomplete. Patients might have failed to mention previous medical treatments received elsewhere, that might have influenced the results of this study.

Similar studies for the rest of Sweden’s regions would be interesting for comparison between different areas nationally but also for international comparison. In the pursuit of answers regarding rare conditions such as MND evidence is hard to come by, which makes it important to mention possibilities. The facts that can merely make up for modest speculation in this study may prove to be valuable in a larger context.

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Is the number of patients with motor neuron disease increasing?