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MND risk factors: an epidemiological study in the North West of England
JOURNAL OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
MND risk factors: an epidemiological study in the North West of England J.D. Mitchell a, R.B. Davies b,,, A. A1-Hamad ~' Department of Neurology, b Centre]brApplied Statistics. Lancaster c Department of Geography, d Department ~)1"Neurology,
b, A.C.
Gatrell e, G. Batterby
Royal Preston Hospital, Preston, UK Uniz,ersity, Fylde College, Lancaster LA1 4YF, UK Lancaster Unil'ersity, Lancaster, UK Royal Preston Hospital, Preston, UK
Accepted 21 February 1995
1. Introduction
About one in 50000 people world wide develop motor neurone disease each year (International Alliance of A L S / M N D Associations) and approximately o n e in a thousand deaths in England and Wales are caused by this inevitably fatal neurological disease (Buckley et al., 1983). However, in spite of an extensive literature on the probable causes of MND, there is no c o n s e n s u s on the risk factors let alone any understanding of its aetiology. The disease is more prevalent in men than in women but there is no other unequivocal empirical evidence on the social, environmental, and other factors which may effect the occurrence or progress of the disease. In this paper we report new results on M N D risk factors from a case control study of the epidemiology of the disease in the North West of England. We also compare the identified risk factors with the factors which appear to influence the progress of the disease from onset to death.
area of residence (District Health Authority). The first control was a healthy individual not suffering from any known disease. The other control was suffering from another, non-degenerative, neurological disease. A research nursing sister visited each patient and control and completed a detailed life profile questionnaire, covering demographic, residence, work, medical and life-style histories. The results in this p a p e r are confined to the M N D patients and healthy controls.
3. G e n d e r and age of onset
The sex ratio ( m a l e / f e m a l e ) is 1.51 confirming that the male population is substantially more at risk than the female population. Ages at onset are summarised in Fig. 1. There is a clear peak in onset for females in the age range 60-70 while the highest risk period for males appears to cover a broader age range from 50 to 70. Overall, the mean age of onset for women (64 years) is higher than that for males (61 years).
2. The study 4. Relative risk analysis
The study was based at the neurology department of the Royal Preston Hospital. 128 patients from a population approaching 1.8 million in Lancashire and South Cumbria (UK) presented with M N D over the 5-year period 1989 to 1993, inclusive and participated in the study. Two case controls were selected for each patient, matched for sex, year of birth ( + 4 years) and
* Corresponding author. Tel.: (+ 44-1524)593064; Fax: (+ 44-1524) 592681. (~022-510X/95/$09.50 © 1995 Elsevier Science B.V. All rights resepeed SSDI 0022-5 1 0 X ( 9 5 ) 0 0 0 6 6 - 6
Using the interview data from the patients and healthy controls, relative risks were estimated for a wide range of possible M N D risk factors. These factors included family structure variables; immunisation history; medical history (including broken bones or fractures); travel abroad; smoking and alcohol consumption; occupational exposure to chemicals, solvents, etc.; diet; contact with animals; and residential history. The factors which were found to be statistically significant are summarised in Table 1. Half of these
ZD. Mitchell et al. /Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
62
5. Rate of progression of the disease
50 n Female [3 M a l e 40
30
4
i
20 I
_10 ~
i
l.,dL 20-<30
30 <40
40-<50
59-<60
60 <70
lli. 70 <80
80 <90
Age at onset
Fig. 1. G e n d e r and age of onset for M N D patients.
factors are related to medical history. The proportLon of M N D patients who recall having been vaccinated against polio, either by injection or orally, is little over half the proportion for the healthy controls. Similarly, significantly fewer M N D patients recall having had rubella or chickenpox (varicella). This may indicate that M N D patients are more likely to have these illnesses very early in life as overall reporting is far lower than aggregate incidence in the population suggests. The relatively high rate of thyroid disorders in the M N D patients is of interest in relation to previous work on thyroid related hormones (Guiloff, 1995) (Fig. 2). Occupational exposure to fumes and dust proved to be highly significant (p-value =0.004), leaving little doubt that this reflects, either directly or indirectly, a genuine risk factor although we are not aware that any similar relationship has been reported before. Other environmental effects were found to be non significant. Finally, the relative risk analysis identified an unexpected family composition effect: being first born or an only child appears to reduce substantially the risk of MND. As for the rubella and chickenpox results, one possible explanation is that the underlying risk factor is illness in early childhood. First born and only children would therefore have reduced risk of M N D because they had less pre-school exposure to infectious disease.
As M N D involves a progressive weakness of the motor system it is possible that risk factors reflect aetiological mechanisms which accelerate this deterioration rather than cause or trigger it. An analysis of survival times from onset to death was undertaken to investigate this hypothesis. Technically, this analysis was based on a log-logistic regression model for survival times (see, for example, Aitken et al. (1989)). The survival times for those patients still alive at the end of the study were treated as right censored, a routine operation in survival analysis. In the analyses of the previous section, gender and age effects were controlled by the case-control matching. In this section, gender and age are included explicitly in the analysis which proceeded in two stages. At the first stage, gender and age were analysed in exactly the same way as the variables which had proved to be significant M N D risk factors; the effect of each on survival times was estimated by including it separately as the sole explanatory variable in a log-logistic regression analysis. At the second stage, variables significant at stage 1 were reanalysed with age included as a control variable in each regression. Gender was not used as a control variable as it proved to be far from significant in the stage 1 analysis. The results are summarised in Table 2. Age at onset is highly significant. If this variable were a surrogate for the rate of progression of the disease, later onset would be associated with longer survival times. However, the results suggest the reverse relationship with a circa 20% reduction in survival time estimated for an increase of 10 years in the age of onset. We would speculate that this effect is too pronounced to be attributable to a greater vulnerability of older patients to infection during the final stages of the disease. The other results are similarly difficult to explain. Two of the medical history risk factors are significantly related to survival and are consistent with the 'accelerating deterioration' hypothesis: These are oral vaccination against polio and having chickenpox (with circa 50 and 60% increase in survival time, respectively).
Table 1 Significant relative risk factors Risk factors
Relative risk estimate
95% confidence interval
Vaccinated against polio (injection) Vaccinated against polio (oral) Had german measles (rubella) Had chickenpox (varicella) Had thyroid disorder Exposed to fumes and dust First in family An only child
0.52 0.54 0.52 0.53 3.02 2.46 0.46 0.33
0.28-0.96 0.32 0.90 0.28-0.94 0.30-0.94 1.05-8.66 1.47-4.09 0.27-0.77 0.15-0.72
63
J.D. Mitchell et al. /Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
(A) Have you been vaccinated against polio (injection)?
(B) Have you been vaccinated against polio (oral)?
6O
f40 20 20
B Healthy controls • MND patients Yes
No
E3Healthy controls • MND patients
Don't know
Yes
(C) Have you ever had German measles (rubella)?
No
Don't know
(D) Have you ever had chickenpox (varicella)?
70
70
60
60
50
50
7
E 40
8
o
a_ 30
&30 i
20
20
[3 Healthy conlrols • MND patients
10 0 Yes
No
0
" "
Don't know
"
No
Yes
(E) Have you ever had thyroid disorder? 120
[] Healthy controls • MND patienls
i....
t0~: 'iiiiil Ji:iiii Don't know
(F) Have you been exposed to fumes or dust?
-
70
[
-
- -
/
6O
100 I
5O
~E4O
~5o
8
g_
40 2O
K Healthy controls • MND ~3atients
10
0 Yes
NO
Yes
(G) Were you an only child'? 100
--
80
"
......
Don't kr,ow
m
NO
El Healthy controls • MND patients
Don't know
(H) Were you the first born in the family? 80
~ -
6 0 `¸
6O~ c
®
04O 40
2O [] Healthy controls
[] Healthy coelrols • MND patients Yes
No
• MND patients Yes
Fig. 2. Relative risk analysis: raw data.
No
64
J.D. Mitchell et al. /Journal of the Neurological Sciences 129 (SuppL ) (1995) 61-64
Table 2 Survival analysis results Risk factor
Age at onset Gender (female) Vaccinated against polio (injection) Vaccinated against polio (oral) Had german measles (rubella) Had chickenpox (varicella) Thyroid disorder Exposed to fumes and dust Only child
Individually
Controlling for age at onset
Significance level (p)
Estimated multiplicative effect on survival time
< 0.001 0.8 0.75 0.02 0.09 0.008 0.9 0.8 0.3
0.79 ~ 1.(14 0.93 1.52 1.43 1.61 0.99 0.96 0.75
Significancelevel (p)
Estimated multiplicative effect on survival time
0.10 0.18 0.04
1.34 1.31 1.43
a For each 10 years of age at onset. However, vaccination against polio by injection is not significant a n d n e i t h e r are rubella or thyroid disorder. Moreover, only chickenpox r e m a i n s significant at the c o n v e n t i o n a l 5% level after controlling for age. Finally, we f o u n d no evidence that survival time is affected by o c c u p a t i o n a l exposure to fumes and dust or birth o r d e r and, although they are less p r o n e to the disease, there is no evidence that w o m e n tend to survive longer t h a n m e n after onset of symptoms.
6. Concluding comments This epidemiological study has g e n e r a t e d a complex p a t t e r n of results. It raises some f u r t h e r difficult questions r e g a r d i n g viral illness a n d susceptibility to M N D . T h e r e is also evidence of an e n v i r o n m e n t a l association a n d we f o u n d that M N D appears to be less p r e v a l e n t a m o n g s t the first b o r n a n d only children. Exposure to illness in early life may be a c o m m o n factor u n d e r l y i n g the results for family composition, rubella, a n d chickenpox. But, in contrast to rubella a n d family composition, chickenpox was also f o u n d to be significantly
related to survival time after onset. M N D p a t i e n t s have lower r e p o r t e d incidence of chickenpox a n d those who did claim to have had chickenpox survived on average longer after onset. This was the only risk factor which also a p p e a r s to affect survival times after controlling for age.
Acknowledgements W e are grateful to the M o t o r N e u r o n Disease Association a n d its M a n c h e s t e r Branch for their g e n e r o u s support for this study.
References Buckley, J. el al. (1983) Motor neuron disease in England and Wales: 1959-1979. J. Neurol. Neurosurg. Psychiat, 46: 197-205. Aitken, M. et al. (1989) Statistical Modelling in GLIM, Oxford University Press, Oxford, 1989. Guiloff, R.J. (1995) Clinical pharmacology of motor neurons. In: Leigh, P.N. and Swash, M. (Eds.), Motor Neuron Disease, Biology and Management, Springer-Verlag, London, pp. 345-373.
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
MND risk factors: an epidemiological study in the North West of England J.D. Mitchell a, R.B. Davies b,,, A. A1-Hamad ~' Department of Neurology, b Centre]brApplied Statistics. Lancaster c Department of Geography, d Department ~)1"Neurology,
b, A.C.
Gatrell e, G. Batterby
Royal Preston Hospital, Preston, UK Uniz,ersity, Fylde College, Lancaster LA1 4YF, UK Lancaster Unil'ersity, Lancaster, UK Royal Preston Hospital, Preston, UK
Accepted 21 February 1995
1. Introduction
About one in 50000 people world wide develop motor neurone disease each year (International Alliance of A L S / M N D Associations) and approximately o n e in a thousand deaths in England and Wales are caused by this inevitably fatal neurological disease (Buckley et al., 1983). However, in spite of an extensive literature on the probable causes of MND, there is no c o n s e n s u s on the risk factors let alone any understanding of its aetiology. The disease is more prevalent in men than in women but there is no other unequivocal empirical evidence on the social, environmental, and other factors which may effect the occurrence or progress of the disease. In this paper we report new results on M N D risk factors from a case control study of the epidemiology of the disease in the North West of England. We also compare the identified risk factors with the factors which appear to influence the progress of the disease from onset to death.
area of residence (District Health Authority). The first control was a healthy individual not suffering from any known disease. The other control was suffering from another, non-degenerative, neurological disease. A research nursing sister visited each patient and control and completed a detailed life profile questionnaire, covering demographic, residence, work, medical and life-style histories. The results in this p a p e r are confined to the M N D patients and healthy controls.
3. G e n d e r and age of onset
The sex ratio ( m a l e / f e m a l e ) is 1.51 confirming that the male population is substantially more at risk than the female population. Ages at onset are summarised in Fig. 1. There is a clear peak in onset for females in the age range 60-70 while the highest risk period for males appears to cover a broader age range from 50 to 70. Overall, the mean age of onset for women (64 years) is higher than that for males (61 years).
2. The study 4. Relative risk analysis
The study was based at the neurology department of the Royal Preston Hospital. 128 patients from a population approaching 1.8 million in Lancashire and South Cumbria (UK) presented with M N D over the 5-year period 1989 to 1993, inclusive and participated in the study. Two case controls were selected for each patient, matched for sex, year of birth ( + 4 years) and
* Corresponding author. Tel.: (+ 44-1524)593064; Fax: (+ 44-1524) 592681. (~022-510X/95/$09.50 © 1995 Elsevier Science B.V. All rights resepeed SSDI 0022-5 1 0 X ( 9 5 ) 0 0 0 6 6 - 6
Using the interview data from the patients and healthy controls, relative risks were estimated for a wide range of possible M N D risk factors. These factors included family structure variables; immunisation history; medical history (including broken bones or fractures); travel abroad; smoking and alcohol consumption; occupational exposure to chemicals, solvents, etc.; diet; contact with animals; and residential history. The factors which were found to be statistically significant are summarised in Table 1. Half of these
ZD. Mitchell et al. /Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
62
5. Rate of progression of the disease
50 n Female [3 M a l e 40
30
4
i
20 I
_10 ~
i
l.,dL 20-<30
30 <40
40-<50
59-<60
60 <70
lli. 70 <80
80 <90
Age at onset
Fig. 1. G e n d e r and age of onset for M N D patients.
factors are related to medical history. The proportLon of M N D patients who recall having been vaccinated against polio, either by injection or orally, is little over half the proportion for the healthy controls. Similarly, significantly fewer M N D patients recall having had rubella or chickenpox (varicella). This may indicate that M N D patients are more likely to have these illnesses very early in life as overall reporting is far lower than aggregate incidence in the population suggests. The relatively high rate of thyroid disorders in the M N D patients is of interest in relation to previous work on thyroid related hormones (Guiloff, 1995) (Fig. 2). Occupational exposure to fumes and dust proved to be highly significant (p-value =0.004), leaving little doubt that this reflects, either directly or indirectly, a genuine risk factor although we are not aware that any similar relationship has been reported before. Other environmental effects were found to be non significant. Finally, the relative risk analysis identified an unexpected family composition effect: being first born or an only child appears to reduce substantially the risk of MND. As for the rubella and chickenpox results, one possible explanation is that the underlying risk factor is illness in early childhood. First born and only children would therefore have reduced risk of M N D because they had less pre-school exposure to infectious disease.
As M N D involves a progressive weakness of the motor system it is possible that risk factors reflect aetiological mechanisms which accelerate this deterioration rather than cause or trigger it. An analysis of survival times from onset to death was undertaken to investigate this hypothesis. Technically, this analysis was based on a log-logistic regression model for survival times (see, for example, Aitken et al. (1989)). The survival times for those patients still alive at the end of the study were treated as right censored, a routine operation in survival analysis. In the analyses of the previous section, gender and age effects were controlled by the case-control matching. In this section, gender and age are included explicitly in the analysis which proceeded in two stages. At the first stage, gender and age were analysed in exactly the same way as the variables which had proved to be significant M N D risk factors; the effect of each on survival times was estimated by including it separately as the sole explanatory variable in a log-logistic regression analysis. At the second stage, variables significant at stage 1 were reanalysed with age included as a control variable in each regression. Gender was not used as a control variable as it proved to be far from significant in the stage 1 analysis. The results are summarised in Table 2. Age at onset is highly significant. If this variable were a surrogate for the rate of progression of the disease, later onset would be associated with longer survival times. However, the results suggest the reverse relationship with a circa 20% reduction in survival time estimated for an increase of 10 years in the age of onset. We would speculate that this effect is too pronounced to be attributable to a greater vulnerability of older patients to infection during the final stages of the disease. The other results are similarly difficult to explain. Two of the medical history risk factors are significantly related to survival and are consistent with the 'accelerating deterioration' hypothesis: These are oral vaccination against polio and having chickenpox (with circa 50 and 60% increase in survival time, respectively).
Table 1 Significant relative risk factors Risk factors
Relative risk estimate
95% confidence interval
Vaccinated against polio (injection) Vaccinated against polio (oral) Had german measles (rubella) Had chickenpox (varicella) Had thyroid disorder Exposed to fumes and dust First in family An only child
0.52 0.54 0.52 0.53 3.02 2.46 0.46 0.33
0.28-0.96 0.32 0.90 0.28-0.94 0.30-0.94 1.05-8.66 1.47-4.09 0.27-0.77 0.15-0.72
63
J.D. Mitchell et al. /Journal of the Neurological Sciences 129 (Suppl.) (1995) 61-64
(A) Have you been vaccinated against polio (injection)?
(B) Have you been vaccinated against polio (oral)?
6O
f40 20 20
B Healthy controls • MND patients Yes
No
E3Healthy controls • MND patients
Don't know
Yes
(C) Have you ever had German measles (rubella)?
No
Don't know
(D) Have you ever had chickenpox (varicella)?
70
70
60
60
50
50
7
E 40
8
o
a_ 30
&30 i
20
20
[3 Healthy conlrols • MND patients
10 0 Yes
No
0
" "
Don't know
"
No
Yes
(E) Have you ever had thyroid disorder? 120
[] Healthy controls • MND patienls
i....
t0~: 'iiiiil Ji:iiii Don't know
(F) Have you been exposed to fumes or dust?
-
70
[
-
- -
/
6O
100 I
5O
~E4O
~5o
8
g_
40 2O
K Healthy controls • MND ~3atients
10
0 Yes
NO
Yes
(G) Were you an only child'? 100
--
80
"
......
Don't kr,ow
m
NO
El Healthy controls • MND patients
Don't know
(H) Were you the first born in the family? 80
~ -
6 0 `¸
6O~ c
®
04O 40
2O [] Healthy controls
[] Healthy coelrols • MND patients Yes
No
• MND patients Yes
Fig. 2. Relative risk analysis: raw data.
No
64
J.D. Mitchell et al. /Journal of the Neurological Sciences 129 (SuppL ) (1995) 61-64
Table 2 Survival analysis results Risk factor
Age at onset Gender (female) Vaccinated against polio (injection) Vaccinated against polio (oral) Had german measles (rubella) Had chickenpox (varicella) Thyroid disorder Exposed to fumes and dust Only child
Individually
Controlling for age at onset
Significance level (p)
Estimated multiplicative effect on survival time
< 0.001 0.8 0.75 0.02 0.09 0.008 0.9 0.8 0.3
0.79 ~ 1.(14 0.93 1.52 1.43 1.61 0.99 0.96 0.75
Significancelevel (p)
Estimated multiplicative effect on survival time
0.10 0.18 0.04
1.34 1.31 1.43
a For each 10 years of age at onset. However, vaccination against polio by injection is not significant a n d n e i t h e r are rubella or thyroid disorder. Moreover, only chickenpox r e m a i n s significant at the c o n v e n t i o n a l 5% level after controlling for age. Finally, we f o u n d no evidence that survival time is affected by o c c u p a t i o n a l exposure to fumes and dust or birth o r d e r and, although they are less p r o n e to the disease, there is no evidence that w o m e n tend to survive longer t h a n m e n after onset of symptoms.
6. Concluding comments This epidemiological study has g e n e r a t e d a complex p a t t e r n of results. It raises some f u r t h e r difficult questions r e g a r d i n g viral illness a n d susceptibility to M N D . T h e r e is also evidence of an e n v i r o n m e n t a l association a n d we f o u n d that M N D appears to be less p r e v a l e n t a m o n g s t the first b o r n a n d only children. Exposure to illness in early life may be a c o m m o n factor u n d e r l y i n g the results for family composition, rubella, a n d chickenpox. But, in contrast to rubella a n d family composition, chickenpox was also f o u n d to be significantly
related to survival time after onset. M N D p a t i e n t s have lower r e p o r t e d incidence of chickenpox a n d those who did claim to have had chickenpox survived on average longer after onset. This was the only risk factor which also a p p e a r s to affect survival times after controlling for age.
Acknowledgements W e are grateful to the M o t o r N e u r o n Disease Association a n d its M a n c h e s t e r Branch for their g e n e r o u s support for this study.
References Buckley, J. el al. (1983) Motor neuron disease in England and Wales: 1959-1979. J. Neurol. Neurosurg. Psychiat, 46: 197-205. Aitken, M. et al. (1989) Statistical Modelling in GLIM, Oxford University Press, Oxford, 1989. Guiloff, R.J. (1995) Clinical pharmacology of motor neurons. In: Leigh, P.N. and Swash, M. (Eds.), Motor Neuron Disease, Biology and Management, Springer-Verlag, London, pp. 345-373.