Background: Motor neuron disease (MND) is largely understudied in many underdeveloped and developing countries, including the Philippines. The practice and management of MND is generally insufficient, and thus, the quality of life of these patients are consequently compromised.
Objectives: The aim of this study is to determine the clinical profile and describe the management of MND patients seen in the largest tertiary hospital in the Philippines for one year.
Methods: This is a cross-sectional study of MND patients diagnosed clinically and via electromyogram-nerve conduction study (EMG NCS) in the Philippine General Hospital (PGH) from January to December 2022. Clinical characteristics, diagnostics and management information were obtained and summarized.
Results: The incidence of MND in our neurophysiology unit was 4.3% (28/648), with amyotrophic lateral sclerosis (ALS) being the most common variant (67.9%, n = 19). Male to Female ratio was 1:1, with the median age of onset of 55 (36–72) years old and median onset duration to diagnosis of 1.5 (0.25–8) years. Limb onset was more prevalent (82.14%, n = 23) with upper limbs initially involved (79.1%, n = 18). Split hand syndrome was found in almost half (53.6%) of the patients. The median ALS functional rating score-revised (ALSFRS-R) and medical research council (MRC) scores were 34 (8–47) and 42(16–60) respectively while the median King’s clinical stage was 3 (1–4). Only half of the patients were able to undergo magnetic resonance imaging (MRI) and only one had neuromuscular ultrasound. Only one of the 28 patients was able to take riluzole, and only one was on oxygen support. None had gastrostomy and none used non-invasive ventilation.
Conclusion: This study showed that the management of MND in the Philippines is largely inadequate and further improvement in the health care system in handling
rare neurologic cases must be implemented to enhance their quality of life.
1. Introduction
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition of the motor neurons in the brain, brainstem and spinal cord.[1] Upper motor neuron (UMN) signs resulting from the affection of the cortical motor neurons are characterized by spasticity and hyperreflexia while lower motor neuron (LMN) signs secondary to degeneration of brainstem and spinal cord alpha motor neurons manifest as asymmetric atrophy and weakness in the bulbar region and limbs respectively.[1,2] The etiology is multimodal with patients having genetic mutations in SOD1, TARDBP, FUS and C9orf72 noted to have sooner incidence of ALS. Several environmental risk factors such as being male, athleticism, geographic location, being exposed to pesticide among others were also investigated, although until now, only cigarette smoking and military service were the only factors noted to have possible association.[2–4] In developed countries, it usually affects patients older than 55 years old with a male to female ratio of 1.7:1 with first onset of symptoms to definitive diagnosis duration of about one year.[2,3,5] Almost all patients die within 2–3 years from onset, although 10% survive past 10 years.[2,6,7]. No disease modifying drug has been proven to cure ALS, however, non-medication interventions such as non-invasive ventilation can prolong survival and improve quality of life for up to 1 year while invasive mechanical ventilation can extend this up to 2 years.[2,8–10]
Gastrostomy may decrease the risk of death by 30% when it is done in ALS patients with 5% weight loss, <20 mg/kg2 BMI or those with dysphagia. Although riluzole may prolong survival by 3 months when it is taken for at least 18 months, it is not available in the Philippines, hence non-drug treatments, including respiratory care, nutrition management and physical rehabilitation among others through multidisciplinary therapy (MDT) are supposed to be maximized but not. [2,8,10–12].
The global prevalence of ALS is 2 cases per 100,000 individuals, with notable spikes in countries like Italy, Japan, and the United States. Around 15% have familial causes, while 70% are sporadic. Fifty percent have some form of cognitive deficit, and 15% develop frontotemporal dementia (FTD). In 2004, awareness about ALS markedly increased thanks to the ice bucket challenge, which was perpetuated by the ALS society to increase funding for research. In the Philippines, a senate bill was created urging the Department of Health to create a local support group and pursue research about the condition. However, to this date, this has not been realized as no support group was established, and no research was conducted. Since ALS is not covered by insurance, patients are forced to buy medications and undergo expensive medical tests using their own money (out-of-pocket scheme). An average Filipino family only earns 11,800 Philippine Pesos (215 USD) per month; hence, the impact of having MND is palpable. As there are only around 435 adult neurologists and 30 neurophysiologists, mostly concentrated in Metro Manila, in the whole country of 110 million people, patients tend to deal with anxiety and their symptoms a little longer than usual. The burden of ALS has not been studied in the Philippines despite its devastating nature. The heterogeneous phenotypic presentation, the lack of specialists and specialized centers for neuromuscular disorders, the perceived rarity of the condition, and the lack of funding and support from the government are possible explanations.
Despite its approval by the US FDA in 1995, riluzole has never been available in the Philippines, although a patient may avail the drug from other countries through compassionate use. Ideally, after diagnosis communication, the patient is managed symptomatically and advised about future complications. Specifically, respiratory distress is managed mostly by non-invasive ventilation, and 15% even opt to undergo tracheostomy to prolong survival. To prevent weight loss, dehydration, and malnutrition, patients are advised to consider enteral tube feeding or parenteral nutrition prior to the occurrence of respiratory distress. A multidisciplinary approach to management is essential.
The practice and management of ALS/MND in the Philippines is inadequate, and there is a high chance that patients were not even able to see doctors prior to demise. The primary aim of this study is to determine the clinical profile and describe the management of MND patients seen in the largest tertiary hospital in the Philippines over one year. Specifically, this study aims:
- To determine the incidence of ALS/MND among patients seen in our Neurophysiology laboratory;
- To describe their demographic profile in terms of age, sex, symptomatology, ALSFRS-R, neurophysiologic findings, imaging, and types;
- To describe their management in the local setting;
- To compare ALS and non-ALS variants of motor neuron disease.
2. Methods
2.1 Sample size and study type
This study utilized a cross-sectional study design with data collection done prospectively. All patients diagnosed by neurophysiologists over the span of one year (January 1, 2022, to December 31, 2022) in the Neurophysiology laboratory of the Philippine General Hospital (PGH) were included in the study.
2.2 Study site
Only patients seen in the PGH Neurophysiology laboratory by the authors (MBP, KBA, and OHJ) were included. Patients suspected to have MND/ALS but not seen by the authors were excluded unless repeat NCSEMG was done in our laboratory. This is to ensure consistency in the diagnosis and to decrease information bias.
2.3 Inclusion criteria
Filipino patients older than 18 years who satisfied the suspected, probable, and definite diagnosis of ALS based on the revised El-Escorial or Awaji Criteria, including other patients with MND variants such as progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), flail arm syndrome (FAS), flail leg syndrome (FLS), and progressive bulbar palsy (PBP), were included. We also decided to include atypical MND, such as spinobulbar muscular atrophy (SBMA).
2.4 Exclusion criteria
Patients who were not examined in PGH and those with similar presentation like multifocal motor neuropathy (MMN) and spinal muscular atrophy (SMA) were excluded.
2.5 Data collection
All suspected cases of MND were referred to one of the authors. An NCS-EMG was done to increase the probability of MND diagnosis. Once MND was confirmed by one of the three neurophysiologists (MBP, KBA and OHJ), consent was obtained. If the patient consents, a pre-made abstraction form was filled out. Demographic and clinical data such as age, sex, age of onset of symptoms, duration from onset until confirmed diagnosis, the initial limb affected, family history, and ALSFRS-R score were recorded. Further, neurophysiologic, imaging and ultrasonographic data were analyzed if available. The patients were classified based on the Revised El Escorial Criteria, or Awaji criteria and the severity was based on ALSFRS-R score and King’s Stage.[19] The patients were also asked if they are willing to be enrolled to international studies, form a support group, and enrolled into a registry.
2.6 Data analysis
Continuous and dichotomous variables were presented using medians and proportions with their corresponding standard deviation and range as spread measures. Incidence rate of MND was computed using the new number of cases as numerator and the number of adult patients seen in the Neurophysiology laboratory for a year, mostly consisting of radiculopathies, Guillain Barre Syndrome, compression neuropathies and myasthenia gravis among others, served as the denominator. MND was divided into 2 groups using ALS and non-ALS as stratification variable. Continuous variables were compared using Wilcoxon Rank Sum test while proportions were compared using Fisher Exact test. Obtained data were inputted and analyzed using Stata BE 17.0 and Microsoft Excel with alpha set at 0.05 to determine statistical significance.
2.7 Ethics
This study was submitted to the Philippine General Hospital Ethics Boards for ethics review and approval. It followed the Declaration of Helsinski and followed local ethical guidelines.
3. Result
3.1 Clinical characteristics of MND patients
There were 28 MND patients included in the study, 50% (n = 14) of which were male. The median age was 55 years while the median duration from onset to diagnosis was 1.5 years. Overall, the one year incidence of MND in our hospital/neurophysiology laboratory was 4.3% (28/648), of which 67.9%(n = 19) were ALS. This was followed by PMA (10.71%) and FAS (10.71%). This implies that out of 100 patients referred to our EMG laboratory, 5 patients will be diagnosed as MND. The median follow-up was 3 months (range: 0.5 months to 12 months). Upper motor neuron (UMN) signs were most prevalent in the bulbar segment (60.7%) while lower motor neuron signs (LMN) were more common in the cervical region (89.3%). Around 93% (n = 26) of MND patients had abnormal needle EMG in the lumbosacral segment. The median number of segments affected was 2 (segments with both UMN + LMN Signs) (See Supplementary Table 1).
3.2 Diagnostics
Among ALS patients (n = 19), 57.9% and 63.2% were diagnosed as definite ALS using Revised El Escorial and Awaji Criteria, respectively (See Supplementary Table 1 for complete breakdown). Among MND patients, 82.14% (n = 23) had their limbs initially affected and among these, 79.1%(n = 18), the upper limbs were initially involved. Around 53.6%(n = 15) had split hand syndrome. The median ALSFRS-R, MRC scores and King’s Clinical Stage were 34, 42,and 3 respectively. Only 1 patient had an unconfirmed family history of MND (4.5%).
Around 82 % (n = 23) had abnormal compound muscle action patient amplitude (CMAP) in nerve conduction study (NCS). The median number of segments with active and chronic denervation changes were 3 and 4. respectively.
Fourteen patients (50%) already had MRI prior to consult, 35.7%(n = 5) of which showed isolated mild lumbar or cervical disc herniations not compressing the roots and spinal cord. In addition, these patients did not present with signs and symptoms of multilevel radiculopathies. Only one of the patients underwent neuromuscular ultrasound where fasciculations were detected.
3.3 Management
Only 1 (3.6%) patient was able to take riluzole on follow up. Likewise, only 1 patient was on oxygen support. None were on enteral tube feeding or parenteral nutrition and symptomatic medications on follow up despite their myriad of complaints such as severe weight loss and painful cramping of extremities. Around 75% (n = 21) were on some form of unguided physical therapy while 25% had no forms of rehabilitation at all. None of the patients experienced speech or occupational therapy despite the repeated advise from the attending physicians. The median MRS was 3.
Seventy-nine percent (n = 22) expressed interest in joining local or international clinical trials for the treatment of MND. Almost all (96.4%) were willing to form an MND/ALS support group (see Table 1).
3.4. ALS vs Non-ALS variants of MND
ALS patients had a shorter median duration of onset to diagnosis (1.7 years vs. 2.6 years, p = 0.10), although the difference was not statistically significant. There were more ALS patients with upper motor neuron (UMN) signs in the bulbar (84.2% vs. 11.1%, p < 0.0001), cervical (78.9% vs. 11.1%, p = 0.001), and lumbosacral regions (73.4% vs. 0%, p < 0.0001). The median number of segments affected in the ALS group was also statistically higher compared to the non-ALS group (2.7 vs. 0.11, p < 0.0001), and there was a higher proportion of ALS patients with split hand syndrome (72.2% vs. 22.0%, p = 0.019).
No difference in terms of ALSFRS-R, MRC score, and MRS was detected. Likewise, no other statistical difference between the two groups was noted in terms of other parameters (see Supplementary Table 2).
| Parameter | MND (n = 28) |
|---|---|
| Age (Median, range) | 55 (36–72) |
| Sex (Male) | 50% |
| Duration (Onset to NCS) (Median, range) | 1.5 (0.25–8) |
| Type of MND | |
| Amyotrophic Lateral Sclerosis | 67.86% |
| Progressive Bulbar Palsy | 3.57% |
| Primary Lateral Sclerosis | 0 |
| Progressive Muscular Atrophy | 10.71% |
| Flail Arm Syndrome | 10.71% |
| Flail Leg Syndrome | 3.57% |
| Spinal Bulbar Muscular Atrophy | 3.57% |
| Segments Affected (Median, range) | 2 (0–4) |
| El Escorial Criteria (n = 19) | |
| Definite | 57.89% |
| Awaji Criteria (n = 19) | |
| Definite | 63.16% |
| Initial Part Affected | |
| Limb | 82.14% |
| Bulbar | 17.86% |
| Initial Limb Affected (n = 23) | |
| Upper | 79.13% |
| Lower | 25% |
| Split Hand Syndrome | 53.57% |
| ALSFRS-R (Median, range) | 34 (8–47) |
| Family History | 7.14% |
| MRC Score (Median, range) | 42 (16–60) |
| King’s Clinical Stage (n = 19) | 3 (1–4) |
| Presence of Diffuse Motor Axonopathy in NCS | 82.14% |
| Proportion with MRI | 50% |
| Proportion with Abnormal MRI (n = 14) | 35.72% |
| Proportion with NMUS | 3.57% |
| Proportion Taking Riluzole | 3.57% |
| Proportion Taking Edaravone | 0% |
| Proportion on Respiratory Assistive Device | 3.57% |
| Proportion on Enteral/Parenteral Nutrition | 0% |
| Proportion on Symptomatic Medications | 0% |
| Proportion with Rehab Intervention | 75.0% |
| None | 25% |
| Speech Therapy | 0 |
| Occupational Therapy | 0 |
| Physical Therapy | 100% |
| Proportion Willing to be Enrolled in Clinical Trial | 78.57% |
| Proportion Willing to be Enrolled in an ALS Support Group | 96.43% |
| Current MRS (Median, range) | 3 (1–5) |
4. Discussion
The incidence of MND in our study cannot be compared to the global and the neighboring countries’ incidence rates as our data only represents that of our Neurophysiology laboratory. However, the median age of onset and median duration from onset to confirmed diagnosis of 55 years old and 18 months we obtained are comparable to the global median for sporadic MND, which are 58–63 years and 10–18 months respectively. In most studies, MND is more prevalent among males, unlike in our data where the proportion of males and females was equal. Nevertheless, consistent with previous research, ALS is still the most common MND even with our data.
Although a 4.3% incidence rate is relatively high for MND, this can result from referral or selection bias. As there are limited NCS machines and neurophysiologists/neurologists in the Philippines adept at confirming MND/ALS, physicians who first see the patient usually send these cases to centers with these resources. However, we believe that even though high, this 4.3% is still underestimated, as some patients may not even afford the logistics of going to these centers in urban areas. As expected, a higher proportion of patients had UMN signs in the ALS variant compared to non-ALS variants since ALS affects both the central and peripheral motor neurons. The thoracic segment, however, is not sensitive and specific in differentiating between the two variants probably because detection of UMN signs in this segment is not routinely done and abdominal reflex is a subjective test. Interestingly, the proportion of patients with abnormal bulbar EMG in the ALS group is significantly higher than in the non-ALS variant, even though progressive bulbar palsy (PBP) belongs to the latter. Nevertheless, only 3.57% of MND patients had PBP in our cohort. Consistent with previous studies, split hand syndrome is more specific among ALS patients. As the observation time is too short (less than a year), there is still a possibility that some MND variants will eventually become ALS in future studies; hence these findings may vary depending on when the cases were seen.
Similar to previous research, Awaji criteria improved the proportion of patients diagnosed with definite ALS in our study, from 57.9% to 63.2%. Most initially presented with upper limb involvement, and most have split hand syndrome. While neuromuscular ultrasound is already a common adjunct to electrodiagnosis for ALS in other countries, especially for visualizing fasciculations, it was done in only 1 of our patients. Only 50% of patients had MRI done to rule out other mimicking conditions.
The median ALSFRS-R, MRC, and King’s stage were 34, 42, and 3, respectively, while the median MRS was 3. These are relatively low compared to published studies from developed countries. Although particularly for ALS, the median onset to diagnosis was a little delayed by 4 months (1.7 years = 20.4 months, see Supplementary Table 2) compared to a published paper by Richards et al. (10–16 months), the difference may not be enough to explain the relatively worse state of our patients upon diagnosis. As patients can come directly to a specialist hospital without being seen by a primary caregiver in our country, a referral bias may explain the relatively not-so-late median onset to diagnosis. In addition, most patients in this cohort live in urban and suburban areas; hence the median onset to diagnosis may be overestimated and not really reflective of the MND situation of the whole country. As for the severity of cases, aside from the slightly delayed diagnosis, the presence of genetic mutations, which has not been tested, may be a factor, although another study should be done to establish this.
Unlike in Japan, where management of MND is free due to their specific disease treatment program, most patients in the Philippines use their own money to buy medications, pay specialists, and undergo tests for their diagnosis. For those who cannot afford it, they are directed to charitable institutions such as the sweepstakes office or Malasakit centers in regional hospitals to get partial payment for some of the diagnostic tests available in public hospitals. Often, since all patients (not only MND) go to these institutions, the waiting time is too long. In addition, as medications are only available outside the country and procedures such as EMG NCS are mostly done in private hospitals, these are not covered by the government’s subsidy. In Canada and Korea, the mean monthly out-of-pocket resources being paid for a patient with ALS by his/her family are 1,631.17 USD and 3,540 USD, respectively. These are 7.6 to 16.5 times higher compared to the monthly wage of an average Filipino. Aside from the financial burden, caregiver fatigue secondary to behavioral, physical, and emotional deterioration also affects the family.
There are only 465 adult neurologists in the Philippines, which has a population of 110 million, spread across more than 7 thousand islands. Of these, only around 30 neurophysiologists are capable of electrodiagnostics. These specialists are concentrated in urban and suburban areas. A patient suspected of having ALS is often referred by neurologists or other physicians to neurophysiologists, who often decide the diagnosis of MND or ALS. There is no current data about the management of ALS in the country; however, once a patient is diagnosed with such, he/she is automatically referred to a rehabilitation medicine physician since riluzole is not available and edaravone is expensive. Gastrostomy, non-invasive ventilation, and other non-drug treatments are only discussed superficially, but most of the time, no formal referral to gastroenterologists, pulmonologists, nutritionists, or family physicians is done, as there are no MND multi-specialty clinics available, and patients are only seen once or twice before they are lost to follow-up. Although the internet is available for teleconsultations, this is not accessible in far-flung areas, where neurologists and other specialists are also unavailable. Often, due to their cultural and spiritual beliefs, these patients go to local healers to tend to their symptoms.
There are also no MND support groups in the Philippines. As mentioned, riluzole is not available locally even though it has been in the international market for more than a decade. Edaravone has been approved recently for stroke but not for MND. Even when riluzole and edaravone are present, these are not cheap. Locally, these are not subsidized by the government. A Senate resolution was made to increase awareness and promote research about MND in the country; however, up to this date, only a few unfunded research projects have been conducted, and no support groups have been established.
The mediocre management of MND/ALS is further reflected by the dismal proportion of patients on medical and rehabilitation management. Only one was on a respiratory assistive device while none were on enteral/parenteral nutrition despite most patients having a median MRS of 3. Although euthanasia has been accepted for a long time in developed countries as part of palliative care, this is still not acceptable in a largely Catholic country like the Philippines. Unfortunately, most patients with MND die at home either due to inanition or respiratory failure. This suggests the need for the immediate establishment of MND multispecialty clinics and support groups similar to those in other countries. Collaborative or independent local research for the improvement of quality of life or a cure should also be sought since most MND patients are willing to be enrolled in these trials.
5. Conclusion
The incidence of MND in our neurophysiology laboratory in the largest hospital in the Philippines was 4.3%, with limb onset ALS being the most common variant. Less than half of the patients were able to complete the necessary diagnostics, and only one out of the 28 patients was able to start riluzole. This study showed that the management of MND in the Philippines is largely inadequate and that further improvement in the healthcare system in handling rare neurologic cases must be implemented to enhance their quality of life.
Originality of submitted research: The content of this original article has not been published previously, is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright holder. All authors have read and agreed to the contents of the paper (on initial submission and on any revisions or subsequent resubmissions).
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