Shinshu M ed J, 64⑸ :239 〜246, 2016

Increasing Incidence and Age at Onset of Amyotrophic Lateral
Sclerosis in Nagano Prefecture, Japan
Chinatsu KOBAYASHI , Daigo MIYAZAKI , Tomomi KINOSHITA
Akiyo HINENO and Akinori NAKAMURA
1) Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine
2) Intractable Disease Care Center, Shinshu University Hospital

Background :A recent increase in the incidence of amyotrophic lateral sclerosis (ALS)has been reported inseveral countries. A similar trend was suspected for Nagano prefecture in Japan. Thus, we retrospectively
examined the incidence of ALS and the characteristics of ALS patients at Shinshu University Hospital.
Methods:From hospital clinical records,we identiﬁed and enrolled 199 patients with ALS diagnosed based on
the El Escorial criteria during the period 1985‑2014.The 30‑year period was divided into six terms of 5 years
each. The incidence of ALS, sex ratio, subtype (limb‑ or bulbar‑onset ALS), and age at onset (＜65 or65years)were investigated separately for each term.
Results:The incidence of ALS signiﬁcantly increased in the two most recent terms (2005‑2009 and 2010‑2014)
overall, and in both men and women. A signiﬁcant diﬀerence in mean age at onset was observed in the twomost recent terms as compared with the ﬁrst term (1984‑1989).The increase in age at onset was particularly
notable in the women with bulbar‑onset ALS. No signiﬁcant change was found in the proportion of ALS
patients who were residents of the M atsumoto medical service area as compared with those from other areas.
Conclusion : We conﬁrmed that the incidence of ALS in Nagano prefecture has been recently increasing.
Furthermore, the ratio of patients with older‑onset ALS has recently increased because of the chronologicalincrease in age at onset of ALS patients. Shinshu Med J 64 : 239 ―246, 2016
(Received for publication February 18, 2016;accepted in revised form June 10, 2016)
Key words:amyotrophic lateral sclerosis, incidence, Japan, population aging, onset

Introduction

prognosis and quality of life,probably reﬂecting thediﬀerent mechanisms causing the disease . The

Amyotrophic lateral sclerosis (ALS) is the mostinvolvement of bulbar and respiratory muscles iscommon and well‑recognized form of motor neuron

characterized by dysarthria, choking, ineﬀective

disease.It is characterized bythe progressive degen-cough,dyspnea,and progressive respiratory failure,eration and subsequent loss of upper and lower

which generally lead to death within 3 to 5 years of

motor neurons,which lead to weakness and paraly-

disease onset . The estimated incidence has been

sis of the upper and lower limbs,and facial,bulbar,

reported to be around 1‑2 cases per 100,000 inhabit-truncal,and respiratory muscles .The phenotypicants per year. Only 5‑10% of cases are familial,presentation is heterogeneous, with variablewith most of the cases being sporadic .

involvement of muscle groups and diﬀerences inSporadic cases are clinically divided into bulbar‑
and limb‑onset subtypes.In general,the progression

Corresponding author:Akinori Nakamura
Intractable Disease Care Center,Shinshu University Hos-is faster and the prognosis is poorer in patients withpital, 3‑1‑1 Asahi, M atsumoto, Nagano 390‑8621, Japanbulbar‑onset ALS than in those with limb‑onset

E‑mail:anakamu＠shinshu‑u.ac.jp

ALS . The rate of invasive positive pressure venti

No. 5, 2016239

Kobayashi.M iyazaki.Kinoshita et al.

lation (IPPV) introduction has been reported

aging population. Our hospital serves as a referral

to range from 26.8% to 40% in ALS patients incenter for other hospitals in the prefecture.Manyof

Japan .However,even with the use of IPPV,gener-

the patients with motor neuron disease are referred

alized muscle dysfunction continues to progress and,for consultation and further examination.

once extraocular movement is lost,leads to the loss

Registry of ALS patientsof communication ability. This condition is called

We retrospectively analyzed the clinical records

the totally locked‑in state (TLS).In addition to theof 232 consecutive patients with ALS diagnosed at

impact of this profound disability on daily life,

Shinshu University Hospital between 1985 and 2014.

introducing IPPV will increase both the burden of

All the patients were consecutively consulted at ourcare and medical costs, which are socially impor-hospital and were interviewed by neurologists.The

tant issues.

onset of illness was determined to be the time at

The cause of ALS is still unknown. However,which progressive muscle weakness in any bodysome hypotheses concerning its pathogenesis havepart was noticed, ascertained by conducting family

been proposed, including excitotoxicity, oxidativeand patient interviews and consultation with initialstress, impairment of neuroﬁlament function, mito-physicians.

chondrial dysfunction, neuroinﬂammation, altered

Full neurological examination and neuro-energy metabolism, RNA misprocessing, and thephysiological diagnostic investigations (spinal tap,

. Several case‑magnetic resonance imaging,needle electromyogra-control studies have analyzed risk factors of ALS,

phy, and nerve conduction velocities) were perfor-

but their results are inconsistent . So far, riluzole

med for each patient at registration to conﬁrm the(which protects neuronalcells from excessiveglutamic

diagnosis. Each eligible case was then classiﬁedacid) and edaravone (which removes free radicals)

according to the revised El Escorial diagnostic

have been used to delay disease progression

criteria .We excluded 30 patients whose diagnoses

misfolding of certain proteins;

however, no radical therapy has been developed.

were not conﬁrmed by using the revised El Escorial

In recent decades, several reports have described

diagnostic criteria and three patients who were

the increasing incidence of ALS.In Italy,Chio,et al.

assessed as having ALS with laboratory abnormal-and Govoni, et al. showed a chronological increase

ities of uncertain signiﬁcance. Finally, the clinicalin mortality from ALS

records of 199 patients were studied (Fig. 1).

.We,too,suspect that asimilar chronological increase in ALS incidence

To investigate whether the incidence of ALS hasexists recently.Thus,the aims of this study were torecently been increasing or not, the 30‑year period

determine whether the incidence of ALS has been

was divided into the following six terms of 5 years

increasing in Nagano prefecture or not and,if so,toeach : 1984‑1989, 1990‑1994, 1995‑1999, 2000‑2004,

identify factors associated with that increase. We

2005‑2009, and 2010‑2014. The incidence (stratiﬁed

conducted a retrospective epidemiological study

by sex)and subtype of ALS (limb‑or bulbar‑onset)

focusing on the occurrence of ALS between 1984

were calculated for each 5‑year term. The age atand 2014 at our hospital.

onset was also measured for each 5‑year term.

Subjects and Methods
Study area

Statistical analyses
The age at onset was presented as mean ± standard deviation (SD).Statistical analysis was perfor-

All the patients in this study lived in Nagano

med using one‑way analysis of variance to evaluate

prefecture,which is located in the central region ofa statistical diﬀerence between the six terms.Inter-Japan. This area has a stable population count,group comparisons were performed using Bonfer-

without much migration. It is racially homogenous

roni correction. Statistical signiﬁcance was set atand,much like the rest of Japan,has a progressively

P ＜0.05.

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Increasing incidence and age at onset of ALS in Nagano

Fig. 1

A ﬂowchart showing participant recruitment process.Of the 232 patients with motor neuron
disease, 199 had deﬁnite, probable, and possible ALS according to the revised El Escorial
diagnostic criteria and were included in the study.

radic, 7 were familial, 78 (52.3%) were younger‑Others
This study was approved by the ethics committee

onset, and 71 (47.7%) were older‑onset. Of the 50of Shinshu University School of M edicine (permis-cases of bulbar‑onset ALS,49 were sporadic,1 wassion No. 3403).

familial, 17 (34%) were younger‑onset, and 33
Results

Characteristics of the patients(66%)were older‑onset.
Increased incidence of ALS in Nagano prefecture in the most recent 10‑year period

Of the 199 patients included,115 were men and 84

The incidences of ALS in the ﬁve‑year terms

were women.The mean age at symptom onset waswere as follows:1984‑1989, 18 patients (6 men and64.6 ± 12.2 years,and the mean time from symptom

12 women ;12 limb‑onset and 6 bulbar‑onset);1990‑

onset to diagnosis was 31.7 ± 46.1 months. Of the1994, 22 patients (14 men and 8 women ; 17 limb‑

cases, 191 were sporadic and 8 were familial.

onset and 5 bulbar‑onset);1995‑1999,26 patients (15The patients were divided into two groups accord-men and 11 women ; 20 limb‑onset and 6 bulbar‑

ing to age as follows:a younger‑onset group (＜65onset);2000‑2004,19 patients (9 men and 10 women ;years old :59 men and 36 women ;age range,28‑64

13 limb‑onset and 6 bulbar‑onset); 2005‑2009, 50years)and an older‑onset group ( 65 years old :56

patients (31 men and 19 women ;40 limb‑onset andmen and 48 women ;age range, 65‑90 years).

10 bulbar‑onset);and 2010‑2014,64 patients (40 men

Of the 199 patients, 149 had limb‑onset ALS (90and 24 women ;47 limb‑onset and 17 bulbar‑onset),men and 59 women ;mean age at onset,62.2 ± 12.4

as shown in Fig.2A,B.In the last decade,the meanyears;mean time from onset to diagnosis, 36.7 ±incidence of ALS was 11.4 per year at our hospital,

53.4 months)and 50 had bulbar‑onset ALS (25 men

which is about three times greater than that in theand 25 women ;mean age at onset,70.3 ± 9.8 years;

decade 1985‑2004 (4.25 per year). The incidence ofmean time from onset to diagnosis, 19.4 ± 13.0

ALS increased in both men and women in the last 10months).

years. In addition, the incidences of both limb‑ andOf the 149 limb‑onset ALS cases, 142 were spoNo. 5, 2016bulbar‑onset ALS have increased.
241

Kobayashi.M iyazaki.Kinoshita et al.

ＡＢ

Fig. 2 The incidence of ALS in terms of 5‑year intervals, from 1984 through 2014.
(A)Changes in incidence of all (gray columns), male (black columns), and female ALS patients (white columns).
(B)Changes in incidence of limb‑ (striped columns)and bulbar‑onset ALS (dotted columns).

Gradual increase in age at onset of ALS

the center of the M atsumoto medical service area

patients in Nagano prefecture(Fig. 4A). The proportions of ALS patients whoThe ages at onset of all ALS patients in the 5‑

were residents of the Matsumoto medical service

year terms were as follows: 55.3 ± 8.48 years inarea in comparison with those of ALS patients from1984‑1989 ;58.8 ± 12.6 years in 1990‑1994;62.2 ±other areas were as follows: 11 (61%) versus 7

11.1 years in 1995‑1999 ;62.7 ± 12.9 years in 2000‑(39 %) in 1984‑1989 ; 8 (36%) versus 14 (64%) in

2004; 65.3 ± 9.26 years in 2005‑2009 ; and 66.2 ±1990‑1994;12 (46%)versus 14 (54%)in 1995‑1999 ;11.0 years in 2010‑2014. The mean age at symptom

7 (37%) versus 12 (63%) in 2000‑2004; 23 (46%)

onset tended to rise year on year,being signiﬁcantly

versus 27 (54%)in 2005‑2009 ;and 30 (47%)versus

higher in 2005‑2009 and 2010‑2014 than in 1984‑1989

34 (53%) in 2010‑2014. The diﬀerences in these(Fig. 3A).

proportions among the 5‑year terms were not statis-

The proportions of patients with older‑onset ALS
in comparison with those of patients with younger‑
onset ALS were as follows: 3 (17%) versus 15

tically signiﬁcant (P ＝0.6971;Fig. 4B).
Discussion(83%) in 1984‑1989 ; 9 (41%) versus 13 (59 %) inIn this study,we found that the incidence of ALS

1990‑1994;14 (54%)versus 12 (46%)in 1995‑1999 ;has increased and that the age at onset of ALS has

11 (58%) versus 8 (42%) in 2000‑2004; 29 (58%)

also became older over the past decade (2005‑2014)

versus 21 (42%)in 2005‑2009 ;and 38 (60%)versus

at our hospital. In particular, the age at onset

26 (40%) in 2010‑2014. The ratio of the patientsamong female patients and among patients withwith older‑onset ALS to those with younger‑onset

bulbar‑onset ALS were signiﬁcantly higher during

ALS has increased chronologically, with older‑on-this period than 30 years ago.

set ALS accounting for more than half of the new

The mortality from ALS has been reported tocases since 1995 (Fig. 3A). Furthermore, in women

have increased in Italy. According to the Italianand bulbar‑onset ALS,the age at onset was particu-report,the mortality rate was 0.8 per 100,000 people

larly high in the two most recent terms than in theprior to 1980 but increased to 1.4 per 100,000 people

ﬁrst term (1984‑1989 ;Fig. 3B, C).

after 1990 . In general, the prognosis of ALS is

No signiﬁcant diﬀerence in residential area ofpoor and the time from diagnosis to death is rela-

ALS patients among the 5‑year terms

tively short. Therefore, chronological increases inNagano prefecture has 10 medical service areas,

the number of deaths most likely reﬂect the in-including our university hospital,which is located increased incidence of ALS. In our study, we found242

Shinshu Med J Vol.64

Increasing incidence and age at onset of ALS in NaganoＡＢＣFig. 3 Changes in the age at onset of ALS patients in terms of 5‑year intervals, from 1984 through 2014.
(A) Dot plots of the age at onset of all the ALS patients. The horizontal lines indicate the mean value of all
determinations. P ＜0.01.
(B)Changes in mean age at onset of the male (black columns)and female patients (white columns).Bar:mean ± SD.
P ＜0.01.
(C) Changes in the mean age at onset of the patients with limb‑ (striped columns) and bulbar‑onset ALS (dottedcolumns). Bar:mean ± SD. P ＜0.01.

ＡＢFig. 4Changes in the proportion of all the ALS patients who were residents of the Matsumoto medical service area
or other areas in Nagano prefecture.
(A)The ten medical service areas in Nagano prefecture.The Matsumoto medical service area is located in the central
region of Nagano prefecture.
(B)The black columns indicate the patients who were residing in the M atsumoto medical service area,and the whitecolumns indicate the patients who were residing in other areas.
No. 5, 2016

243

Kobayashi.M iyazaki.Kinoshita et al.

that the incidence of ALS increased chronologicallyincrease in recent years. Based on demographic

in Nagano prefecture, with a 2.5‑fold greater inci-statistics from Nagano prefecture ,the aging pop-

dence in the period 2005‑2014 than in 1996‑2003.

ulation is increasing at a constant rate (as seen inThus, the incidence of ALS has increased abruptly

other prefectures).However,the rate of increase inin the last 10 years.

the population aged

65 years displays a linear

Recently, obtaining a deﬁnite diagnosis of ALS

function (Fig.5).Bycontrast,our data revealed thathas become possible in many local hospitals outside

the rate of increase in the incidence of ALS displaysof the M atsumoto medical service area due to thea quadric function. Thus, in addition to an increas-advancement of diagnostic techniques and the sup-ingly aging population, other factors may be as-ply of neurologists trained at Shinshu University

sociated with the increased incidence of ALS.

Hospital. Therefore, a large number of ALS

In addition,our study demonstrated that the ages

patients would not have been introduced to Shinshu

at onset in women and in patients with bulbar‑onset

University Hospital. Nevertheless, the number of

ALS were signiﬁcantly higher in the past decade

ALS patients continues to increase in the M at-than in the period 1984‑1989.A signiﬁcant decrease

sumoto medical service area. In addition, nohas been reported in the male‑to‑female ratio,

signiﬁcant change was observed in the proportion ofwhich reduced from 1.8‑2.6:1 in the decade 1959 ‑ALS patients who were residents of the Matsumoto

1974 to 1.1‑1.3:1 in the 1990s. The decrease in themedical service area as compared with that in othermale‑to‑female ratio is particularly apparent inareas between 1984 and 2014 (Fig. 4B).

older‑onset ALS, between 2.9 : 1.4 and 6.6: 1.5 inFurthermore, ALS is a rare disease that shows

1959 ‑1974 falling to between 10.2:7.4 and 10.4:8.6

characteristic symptoms/signs and clinical coursein the 1990s . This indicates that, especially inalong with disease progression. Thus, almost allolder‑onset ALS, the incidence of ALS has in-ALS patients seek medical care and can becreased disproportionately in women. These data

diagnosed as having ALS by neurologists. Thisare consistent with our results that the age at onset

situation has not changed in 30 years.Therefore,weof female ALS patients, in particular, has been

considered that the increased incidence of ALS inincreasing in recent years.

the last 10 years was caused by the increase in theWhy has the incidence of ALS been increasing

incidence of ALS in both the M atsumoto medical

more especially in patients with older‑ and bulbar‑

service area and other areas,and not byan inﬂow ofonset ALS in recent years? The following possible

patients from other medical service areas or by an

hypotheses are considered :1) In the past, patients

increase in the total number of people visiting

who mayhave developed ALS might have died fromShinshu University Hospital.This suggests that theother causes before the onset of typical symptoms

incidence of ALS has been increasing in Nagano

or diagnosis of ALS was made, but owing to theprefecture.

increased life spans, the symptoms now become

An autopsy investigation conducted in Niigata

clinically evident. 2) Neck and bulbar muscles areprefecture (which adjoins Nagano prefecture)

naturally weakened in older individuals, making

showed an increase in both the incidence of ALS

bulbar symptoms more evident at the onset ofolder‑and age at onset of patients with ALS diagnosed inonset ALS.

the period 1990‑2000 as compared with the period

Considering that Japanʼ
s population is progres-1962‑1970 .This is consistent with our results.We

sively aging, the increased incidence of older‑onset

suppose that this trend of increased incidence ofALS could result in various social problems.As theALS will be seen throughout Japan.

progression of ALS is generally rapid and the as-Having identiﬁed an increase in the incidence ofsociated burden of care and medical costs are notALS, we then need to consider the reasons for thisinsigniﬁcant, ALS has an important impact on244

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Increasing incidence and age at onset of ALS in Nagano

Fig. 5

Changes in the population of Nagano prefecture.The black columns indicate the population
aged 65 years, and the white columns indicate the population ＜64 years (16).

patientsʼfamilies,the medical community,and pub-desirable.In addition,guidelines on the medical carelic welfare systems. Aged ALS patients can easilyof (older) ALS patients should be prepared fordevelop many complications, some of which can begeneral physicians.

managed by means of interventions such as gastros-Study Funding

tomy and home‑based IPPV. However, these interventions cannot prevent disease progression. The

This study was supported by Grants‑in‑Aid forcare needs of the aging population,in the context ofScientiﬁc Research from the Ministry of Education,

a population with a progressively declining birthCulture, Sports, Science, and Technology of Japanrate, lead to diﬃculty in providing home care.

to A.N. and A.H., and a Grant‑in‑Aid from theMoreover, spaces in medical institutions and rest

Promotion Project for Education, Research, andhomes for ALS patients are limited, especially in

M edical Care from Shinshu University Hospital toregional towns and cities. Thus, we should bear inA.H.

mind the need to establish a medical framework forDisclosure

patients with older‑onset ALS. Enhancement ofhome care systems and institution of support sys-All authors report no disclosures.

tems to assist in decision making on interventions
such as gastrostomy and home‑based IPPV areConﬂict of interest :None to report.

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