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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 232-238

A Study of the Clinical Characteristics and Severity of Amyotrophic Lateral Sclerosis from North India


Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission03-Jun-2020
Date of Decision23-Jun-2020
Date of Acceptance29-Jun-2020
Date of Web Publication27-May-2022

Correspondence Address:
Vinita Elizabeth Mani
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjhr.cjhr_67_20

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  Abstract 


Introduction: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and severity of disease at presentation decides prognosis and therapeutic options. We aimed to study the clinical characteristics and severity of ALS, and establish a correlation between King's ALS clinical staging and revised ALS Functional Rating Scale (ALSFRS-R) scores. Materials and Methods: All patients with clinically definite ALS presenting to the outpatients clinic of a tertiary care institute in North India were included. Their demographic and risk factor profiles were noted, and patients were categorized according to King's ALS clinical staging and ALSFRS-R scores. Correlations between the two scores were done using appropriate statistical tests. All data were analyzed using IBM SPSS version 26 for Macintosh. Results: Sixty-three patients with clinically definite ALS were included; of which 42 (66.7%) were male, with a sex ratio of 2:1. The mean duration of symptoms was 11.9 ± 6.6 months (range 3–24 months). Forty-five patients (71%) had limb-onset, and 18 (29%) had bulbar-onset ALS. The mean ALSFRS-R score was 36.5 ± 6.3 (range 16-48), and the scores were significantly lower in females (33.76 ± 5.60 vs. 37.81 ± 6.31; P = 0.01). On correlating the King's ALS clinical staging and ALSFRS-R scores, we found a score of >41 on ALSFRS-R was predictive of Stage 1, 34–41 of Stage 2, and 16–34 of Stage 3 disease. Conclusions: ALS has a male preponderance, but females present with more severe symptoms. There is a definite correlation between King's ALS clinical Stages 1-3 and ALSFRS-R scores.

Keywords: ALSFRS-R scores, amyotrophic lateral sclerosis, King's ALS stage, motor neuron disease, severity


How to cite this article:
Mani VE, Thomas J. A Study of the Clinical Characteristics and Severity of Amyotrophic Lateral Sclerosis from North India. CHRISMED J Health Res 2021;8:232-8

How to cite this URL:
Mani VE, Thomas J. A Study of the Clinical Characteristics and Severity of Amyotrophic Lateral Sclerosis from North India. CHRISMED J Health Res [serial online] 2021 [cited 2022 Sep 25];8:232-8. Available from: https://www.cjhr.org/text.asp?2021/8/4/232/346103




  Introduction Top


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to selective death of motor neurons in the spinal cord, brainstem, and corticospinal tract. It was first described in 1839 by a French neurologist Jean-Martin Charcot, but gained fame when Lou Gehrig, an American baseball player, was diagnosed with the disease.[1] ALS affects both upper motor neurons (UMN) and lower motor neurons (LMN), and is the most common form of motor neuron disease (MND).

ALS is mostly a sporadic disease, but in approximately 5%-10% a family history may be obtained (Familial ALS or FALS).[2] ALS may be rarely associated with frontotemporal dementia (FTD-ALS).[3] Many complex molecular mechanisms have been implicated in the pathology of ALS including glutamate excitotoxicity, autophagy, dysregulation of neurotrophic factors, mitochondrial dysfunction, aberrant RNA processing, and transport defects in axons.[4]

Exercise intolerance and fatigue are common early symptoms of ALS. The classical findings include spasticity and brisk reflexes (features of UMN involvement) along with wasting, weakness and/or fasciculations (features of LMN involvement) in the same body segment. Weight loss, muscle cramps, emotional liability, and cognitive dysfunction are some atypical presentations. Mortality is usually due to the involvement of the respiratory muscles.[5]

The diagnosis of ALS is made clinically, and confirmed by neurophysiological testing. Nerve conduction velocity (NCV) studies show reduced compound muscle action potential in the later stages but sensory nerve conductions are usually normal. Electromyography (EMG) is diagnostic with fibrillation potentials, positive sharp waves (PSWs), and fasciculation potentials suggestive of acute denervation. Long duration, large amplitude, and polyphasic motor unit potentials (MUPs) with reduced recruitment are characteristic of neurogenic MUPs. These, along with complex repetitive discharges are suggestive of chronic denervation and re-innervation.[6] Repetitive nerve stimulation test often shows less than 10% decrement.[7]

The Awaji-shima modification of the El Escorial criteria introduced by the World Federation of Neurology in 1990, categorizes patients of ALS into clinically definite, probable and possible ALS.[8],[9],[10] The revised ALS Functional Rating Scale (ALSFRS-R) is a clinical score of functional severity of ALS. It is assessed on the basis of 12 parameters, and scored between 0 and 48, with lower scores indicating poorer functional capacity of the patient.[11] The King's ALS clinical staging classifies patients into 5 stages of disease, with Stage 1 corresponding to onset of disease in one anatomical region, and Stage 5 with death.[12],[13]

As ALS is a progressive and ultimately fatal neurodegenerative disease, and prognosis is linked to severity of disease, it is important to correctly assess the extent and severity of disease at diagnosis. Factors that predict reduced survival include older age, early respiratory involvement, and bulbar-onset of symptoms.[5] We therefore undertook this study to assess the clinical severity with the King's ALS clinical staging, and functional severity with the ALSFRS-R score, and establish a correlation between the two. There are few studies, which have attempted to establish this correlation, and to the best of our knowledge, there have been none from our country.[14]


  Materials and Methods Top


Type, duration, and place of study

This was a descriptive study conducted prospectively over a period of 8 months in a tertiary care institute situated in North India.

Aims and objectives

  1. To study the clinical characteristics and severity of disease in patients with ALS
  2. To determine the correlation between the King's ALS clinical staging and the revised ALS Functional Rating scale (ALSFRS-R).


Inclusion criteria

Consecutive patients with clinically definite ALS presenting to the outpatients department were included in the study.

Exclusion criteria

  1. Patients with clinically probable and possible ALS were excluded.
  2. Those patients with known malignancies, hyperthyroidism, and PLHA were also excluded from the study.


Ethical approval

This study was approved by our Institution Ethics Committee (IEC code: 2019-83-DM-109); dated July 22, 2019.

Consent

All eligible patients had to sign an informed consent form as per protocol of the IEC.

Clinical assessment and investigations

Patients underwent a detailed history and examination to determine the onset, duration, progression, and extent of the disease, to assess etiological factors implicated in the disease, and exclude mimics of ALS. A routine breast examination was performed in all women. All patients underwent routine blood counts, fasting and postprandial blood sugars, serum creatinine, thyroid function tests, chest X-ray, vasculitis screen (antinuclear antibodies, extractable nuclear antigen, and antineutrophil cytoplasmic antibodies), and HIV ELISA.

NCV and EMG studies were performed on each patient according to established techniques. At least three body regions were assessed in every patient – bulbar, cervical, thoracic paraspinal, and lumbosacral. The presence of tongue wasting with prominent fasciculations was considered as bulbar involvement. Spontaneous activity in the form of fibrillations, PSWs, and/or fasciculations during EMG was considered consistent with denervation. Further the characteristics of the MUPs were recorded, and long-duration, large-amplitude, and polyphasic MUPs were labeled as neurogenic MUPs, which are suggestive of chronic denervation and re-innervation. Reduced recruitment was also considered as evidence of chronic denervation.

Categorization of amyotrophic lateral sclerosis

On the basis of clinical evaluation and EMG, patients were classified into three categories as per the Awaji-shima modification of the El Escorial Criteria. The El Escorial criteria which were developed by the World Federation of Neurology in 1990, divides the motor system into four regions – bulbar, cervical, thoracic, and lumbosacral. Based on UMN and LMN involvement in each region, patients are classified into five categories – clinically definite, clinically probable, clinically probable with laboratory support, clinically possible, and clinically suspected ALS.[8] However, these criteria were criticized for being too restrictive and an Awaji-shima modification was published in 2008 by which patients were categorized into three categories – clinically definite, probable, and possible.[9],[10]

A patient with suspected ALS was considered to have “clinically definite ALS” if UMN and LMN signs were present simultaneously in three of four anatomical regions – bulbar, cervical, thoracic, and lumbosacral.[8],[9],[10] Patients with probable and possible ALS were called for review and repeat EMG at 3 months, and were excluded from this study.

Clinical staging

Patients were categorized into five clinical stages (1–5) at presentation according to the King's ALS clinical staging. Balendra et al. from King's College London, classified patients with suspected ALS into five clinical stages with Stages 1–3 corresponding to the number of anatomical regions involved, Stage 4 – nutritional dependence (gastrostomy/Ryle's tube feeding) or ventilator assistance, and Stage 5 – death.[12],[13]

Functional severity classification

Patients were clinically staged for severity using the revised ALS Functional Rating Scale (ALSFRS-R), according to which they are graded as 0, 1, 2, 3, and 4 for 12 clinical parameters – speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bedclothes, walking, climbing stairs, dyspnea, orthopnea, and breathing. The scores range from 0 to 48, with higher scores associated with better functional status.[11]

Correlation between clinical staging and ALSFRS-R

We tried to assess if the King's ALS clinical staging with involvement of ≥2 regions was associated with poorer ALSFRS-R scores, and whether any values for the ALSFRS-R scores could be predicted according to the King's stages.

Assessment of depression and anxiety

Anxiety and depression were evaluated with the Hospital Anxiety and Depression Scale (HADS). Anxiety and depression was assessed on the basis of 7 questions each, with each question scored from 0 to 3. The total scores ranged between 0 and 21, and were graded as normal (0–7), borderline abnormal (8–10), and abnormal (11–21).

Treatment and follow up

All patients were put on standard treatment with tablet Riluzole 50 mg twice daily. Some patients who could afford therapy were started on Injectable Edaravone therapy along with the Riluzole. They were followed up at 1 and 3 months.

Statistical analysis

All data were analyzed using the IBM SPSS statistics package for MacIntosh, Version 26 (SPSS Inc. Chicago, Illinois, USA). Descriptive statistics for categorical variables included frequency analysis with percentages, and mean ± standard deviation was used for continuous variables. To establish relationships between categorical variables, the Chi-square test and Fisher's exact test was used, and the Student's 't' test and ANOVA was used for continuous variables. A relationship was considered statistically significant if the two-tailed P < 0.05.


  Results Top


A total of 63 patients with clinically definite ALS (according to the Awaji-shima modification of the El Escorial criteria) were included between the months of August 2019 and March 2020. All patients signed a written informed consent as per protocol. There were 42 males (66.7%) and 21 females (33.3%), in a ratio of 2:1. Their ages at disease onset ranged between 17 years and 76 years (mean age of onset 51.3 ± 11.4 years). All patients were from North India, with most patients (52 i.e., 82.5%) residing in Uttar Pradesh. Interestingly, all the females in our study were homemakers. We also had 10 farmers (16%) and eight daily wage laborers (12.7%) among others [Figure 1].
Figure 1: Distribution of patients according to occupation

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Most patients (44 i.e., 70%) came from middle-income families, though 17 (27%) were of poor socioeconomic status, and 2 patients (3%) were rich. Out of the 63 patients, 11 were smokers (17.5%), 11 used to drink alcohol (17.5%), and 27 (43%) patients chewed tobacco. Besides, there were eight patients (12.7%) with diabetes mellitus, and 14 (22%) with hypertension. No patient gave history of electric shock or heavy metal exposure, and all farmers (16%) had repeated exposure to insecticides and pesticides.

The mean duration of symptoms was 11.9 ± 6.6 months (range 3–24 months). Most patients (45 i.e., 71%) had onset of symptoms in their extremities (25 patients upper limb and 20 patients lower limb), while 18 (29%) had bulbar onset. We did not get any patient with pure respiratory or truncal involvement [Figure 2].
Figure 2: Distribution of patients according to onset of symptoms

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According to the revised ALS Functional Rating Scale (ALSFRS-R), the clinical features were scored on the basis of functionality (0 = no functionality to 4 = normal). In our study, most patients had scores of ≥2 in each subsection (i.e., needing mild assistance or independent) [Figure 3]. The mean ALSFRS-R score at presentation was 36.5 ± 6.3 (range 16–48). On comparing the ALSFRS-R scores between males and females, interestingly, we found that the scores were significantly lower in females, suggesting more severe disease at presentation to our tertiary care institute (33.76 ± 5.60 vs. 37.81 ± 6.31; P = 0.01). However, there was no significant difference between the sexes for age at onset, or duration of symptoms prior to diagnosis [Table 1].
Table 1: Comparison of clinical characteristics between males and females

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Figure 3: Functional status of the patients according to the revised Amyotrophic lateral sclerosis Functional Rating Scale

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On categorizing patients according to the King's ALS clinical staging, most patients (39.7%) had Stage 3 disease. We did not have any patient with stage 5 disease (death) [Figure 4]. The ALSFRS-R scores of patients in each category of King's ALS clinical stage were tabulated, and it was seen that with increase in clinical staging, the ALSFRS-R scores decreased, suggestive of more severe disease.
Figure 4: Distribution of patients according to the King's Amyotrophic lateral sclerosis clinical staging

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On correlating the King's ALS clinical staging and the ALSFRS-R, we found a cutoff value of > 41 (41–48) on ALSFRS-R was predictive of King Stage 1 with only one patient having a value of 39. Similarly, most patients with King's Stage 2 had ALSFRS-R scores between 34 and 41 (44 in one patient), and most patients (80%) of King's Stage 3 had scores between 16 and 34 (only 5 had 37–40). However, King's Stage 4 disease did not show a lower ALSFRS-R score as expected (all patients had values 36–40). Correlations between the King's ALS clinical staging and the ALSFRS-R scores were done using the one-way ANOVA test for continuous variables [Table 2] and [Figure 5].
Table 2: Correlation between revised amyotrophic lateral sclerosis functional rating scale functional scores and King's amyotrophic lateral sclerosis clinical staging

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Figure 5: Correlation between King's stages and ALDFRS-R scores

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We further categorized patients on the basis of disease severity, taking ALSFRS-R scores of ≤40 as severe disease, and ≥41 as mild disease, and King's ALS clinical staging 1 as mild disease and ≥Stage 2 as severe disease. On analysis however, female sex, bulbar-onset of symptoms, anxiety, and depression did not have any significant association with severe disease.

According to the HADS scale, 15 (24%) had significant anxiety, while 44 were normal and 4 (6%) had borderline anxiety. Besides, only 7 patients (11%) had clinical depression, with 51 patients (81%) normal and 5 (8%) had borderline depression. On comparing males and females, more females had clinically significant depression than males (23.8% vs. 4.8%; P = 0.04) [Table 1]. However, there was no significant difference between the sexes for anxiety levels (33.3% females vs. 19% males; P = 0.23).

At 3 months' follow-up, two patients had died, but the others did not have significant worsening of symptoms, or increase in King's ALS clinical stage or ALSFRS-R scores. Both the patients who died had King's Stage 3 disease and ALSFRS scores of 32 and 34, respectively.


  Discussion Top


ALS is a progressive neurodegenerative MND, affecting both UMNs and LMNs in the spinal cord, brain stem, and corticospinal tracts. Other diseases included in the spectrum of MND include primary lateral sclerosis, progressive muscular atrophy, spinal bulbar muscular atrophy (Kennedy disease), progressive bulbar palsy, and pseudobulbar palsy.[2],[15] Besides, focal motor neuron involvement is seen in monomelic amyotrophy (Hirayama disease) and infections with poliovirus, West Nile virus, and the Japanese encephalitis virus.[16]

Although ALS is the most common form of MND, it is considerably rare, with an incidence ranging between 1.5 and 2.7/100,000 persons per year and a worldwide prevalence of 3–5/100,000 people.[17],[18] Most cases of ALS are sporadic, but approximately 5%–10% is familial, with a Mendelian inheritance pattern (FALS).[2] In our study, however, we did not get any case with a positive family history. Mutations in the Cu/Zn binding superoxide dismutase 1 gene account for 10%–20% of all cases of FALS, which is inherited in an autosomal dominant manner and 2%–5% is due to mutations in the TARDBP gene.[19],[20] FTD-ALS is due to the C9orf72 mutation.[3]

There is a definite male preponderance (1.5–2.0: 1), and this difference was seen in our study as well, with twice the number of males affected compared to females (42 vs. 21).[18],[21] The fact that health of women-folk is not given priority, especially in rural India, may be a contributing factor to this male preponderance.[22] The mean age at onset of disease in our study was 51.3 ± 11.4 years. The average age of onset in India has been described as 51–60 years, which is nearly a decade earlier than what is described in Western literature.[17],[22],[23]

Exposure to chemicals, pesticides, and heavy metals is a known risk factor for ALS.[24] In our study, we had 10 farmers (16%) who had been repeatedly exposed to pesticides. Sports and rigorous physical activity has also found to be a risk factor for ALS.[25] We had eight laborers and two security personnel in our cohort. In our study, population most of our patients belonged to the low- and middle-income groups and only two patients were rich; however, studies have proven that socioeconomic status has no significant association with ALS.[26] Cigarette smoking has been known to increase the risk of ALS, and 38 (60.5%) of patients in our study had a history of nicotine use, either as cigarette smoking or tobacco chewing.[27]

The mean duration of disease in our study was 11.9 ± 6.6 months, though 17 patients (27%) presented within 6 months of disease onset. This agrees with the review by Zarei et al., that there is often a 13–18 months delay between onset of symptoms and definitive diagnosis.[2] Coming to onset of the disease, 70% of ALS patients have onset in the limbs (limb-onset) with spasticity, weakness, wasting, and fasciculations. Another 25% have bulbar-onset of symptoms with dysarthria, dysphagia, tongue atrophy, and fasciculations, and 5% have respiratory onset.[5] Our study showed similar findings, with 71% patients having limb-onset, and 29% with bulbar-onset of symptoms. We did not have any patients presenting with pure respiratory involvement. Bulbar-onset ALS has been associated with reduced survival, along with older age at disease onset and early respiratory involvement.[5]

In our study, we found that the ALSFRS-R scores were significantly lower in females, suggesting a more severe disease at presentation. This finding has been noted in several other Indian studies as well.[22],[28] This may be the case because women, especially in rural areas are taken to the hospitals as a last resort.

On correlating the King's ALS clinical staging and the ALSFRS-R, we found that King's stage 1 correlated with ALSFRS-R scores of 41–48; King's stage 2 with ALSFRS-R scores of 34–41; and King's stage 3 with ALSFRS-R scores of 16–34. This is indicative of decrease in functional capacity with the progression of disease. However, interestingly, King's Stage 4 disease did not show a lower ALSFRS-R score (≤16) as expected (all patients had values 36–40). All our patients categorized as Stage 4 disease had severe bulbar involvement requiring Ryle's tube feeding. However, 3 of the 5 patients with Stage 4 disease had isolated bulbar involvement, and hence had higher ALSFRS-R scores, showing a falsely high functional status. A study by Zhang et al., in their study of 154 patients of bulbar-onset ALS, showed that the mean ALSFRS scores in their patients was 43.4 ± 2.4, which is suggestive of good functionality.[29]

A Chinese study by Cui et al., documented that female sex and lower ALSFRS scores were predictive of anxiety and depression.[30] In our study, we found that significantly more number of female patients were depressed when compared to male patients (23.8% vs. 4.8%; P = 0.04). However, we could not find any correlation between severe disease (ALDFRS-R scores ≤40, and King's ALS clinical stage ≥2) and female sex, bulbar-onset of symptoms, anxiety or depression.

ALS is known to be relentless and progressive culminating in death, with less than 50% patients surviving for longer than 30 months, and 20% for 5–10 years after diagnosis.[31] Although only two patients died during our study, both had been affected for less than a year (disease duration 5 and 10 months). Both had King's Stage 3 disease, and low ALSFRS-R scores (32 and 34) suggestive of severe disease. The median survival in most patients with ALS is noted to be 3.5 years.[32] Besides these two patients, we noted that the remaining patients did not have any significant progression of symptoms over the next 3 months, which is not surprising, as ALS is usually not rapidly progressive. In a Chinese study by Chen et al., they found that patients took 4–5–12 months to progress from one stage to another.[33]

Limitations of the study

As ALS is a progressive disease, and a 3-month follow-up period is too short to comment on the outcome of patients, and comment on worsening of clinical and functional parameters.


  Conclusion Top


ALS is a progressive MND with definite male preponderance. In India, the mean age of onset is in the 6th decade, which is nearly a decade earlier than in the western population. Females had more severe disease at presentation, demonstrated by lower ALSFRS-R scores, when compared to males. There was significant correlation between the King's ALS clinical Stages 1–3 with ALSFRS-R scores. Despite extensive research many risk factors for ALS still remain undiscovered, and its treatment also remains inadequate. Edaravone has shown promising results, especially in the early stages of the disease, but further studies are needed to prove its efficacy among Indian patients.

Acknowledgments

We would like to acknowledge the support and assistance of Dr. Sunil Pradhan, Professor and Head, Department of Neurology, SGPGIMS, Lucknow.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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[TAG2]
[TAG3]
[TAG4]