INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized
by selective death of upper motor neurons (UMNs) and lower motor neurons (LMNs), typically
may die from respiratory failure within 2–5 years of symptom onset.[1] About 10% of
ALS patients are familial whereas the remaining patients are sporadic. ALS is highly
heterogeneous in genetic and clinical phenotype, with lack of definitive diagnostic
tools, making it extremely difficult to make early diagnosis. Considerable resources
have been devoted to unravel the pathogenesis of ALS since the first pathogenic gene
SOD1 was found in 1993. With the advances in sequencing and genome technology, the
pace of pathogenic gene discovery has been greatly accelerated. At present, more than
20 ALS genes including SOD1, TARDBP, FUS, C9ORF72, OPTN, VCP, UBQLN2, PFN1, TBK1,
and CHCHD10 have been discovered.[2
3] Several potential molecular pathways leading to motor neuron degeneration have
been identified.[4] Although riluzole and edaravone (RADICAVA) have been shown to
slow the disease progression and have a modest improvement in survival by several
months,[5] currently, ALS is still lack of effective cures. Here, we discuss the problems
in precise diagnosis and individualized treatment of ALS patients.
PRECISE DIAGNOSIS OF AMYOTROPHIC LATERAL SCLEROSIS
Problems in diagnosis of amyotrophic lateral sclerosis
According to the El Escorial criteria and its revisions, diagnosis of ALS relies on
identification of UMN and LMN signs within different body regions defined as bulbar,
cervical, thoracic, and lumbar, respectively. In the early stage of ALS, misdiagnosis
remains a common clinical problem, particularly for young clinicians who did not receive
specific training on neuromuscular disorders. Diagnosis can be difficult at early
stage partly because ALS showed great clinical variability in presentation and prognosis.
The patients can be demonstrated as limb onset or bulbar onset, and neurological signs
can be UMN or LMN lesion only or both. And, in limb-onset cases, symptoms may appear
distally or proximally in either the upper or lower limbs. Besides, a broad spectrum
of disorders called as ALS mimic syndromes should be taken into account in the differential
diagnosis. So far, no specific biomarkers or tests are available to distinguish them
although a number of studies have reported several potential biomarkers.[6
7
8] For instance, the plasma galectin-3 level has been reported to be significantly
increased in ALS patients with limb-onset in Chinese population.[9]
As ALS is a disabling and life-threatening disease, misdiagnosis will give substantial
implications for patients and caregivers.[10] Many clinicians tend not to make an
ALS diagnosis which leading to diagnostic delay. The mean time from the onset of symptoms
to confirmation of the diagnosis is 10–18 months according to EFNS guidelines.[11]
Recent years, with the progress of our knowledge in pathogenesis of ALS and the insights
from clinical drug test performed in several neurodegenerative diseases, more and
more clinicians recognized the importance of early diagnosis of ALS. An early and
accurate diagnosis is not only essential for ALS patients to receive specific clinical
management but also important for the correct inclusion of patients in clinical trials.
Diagnosing amyotrophic lateral sclerosis early and accurately
First of all, carefully record the patient's chief complaint and the history of symptom
development, followed by the family history, personal history, and any clinical features
regarding the main body systems according to standard practice. A systemic neurological
examination is crucial to achieve an accurate diagnosis.
Second, diagnosis should base on standardized criteria. The El Escorial criteria which
developed by the World Federation of Neurology Research Group on Motor Neuron Diseases
were the most accepted diagnostic criteria for ALS, though these criteria were originally
developed for research purposes. The levels of diagnosis depended on clinical assessment
of the extent and distribution of UMN and LMN lesion. These criteria were specific
for ALS;[12] however, sensitivity is a challenge, especially in the early stages of
the disease, leading to diagnostic delay and limiting the accurate diagnosis of ALS.
The El Escorial criteria underwent several revisions. The Awaji-Shima criteria (revision
in 2008) recommend using electrophysiological data in the diagnosis of ALS. The Chinese
Medical Association criteria (2012) were developed on the Awaji-Shima criteria [Table
1]. Several studies reported that these criteria have higher diagnostic sensitivity,
supporting that electromyography (EMG) should be performed in early stage.[13] Some
developing LMN degeneration is detectable only on EMG which is in line with a series
of studies focused on the usage of EMG in ALS early diagnosis and the disease progression
assessment.[6
7] Subclinical UMN dysfunction may be identified by transcranial magnetic stimulation
techniques. Besides, tests to rule out other ALS mimic syndromes may include routine
laboratory tests, EMG, nerve conduction study, magnetic resonance imaging (MRI), lumbar
puncture, and sometimes muscle biopsy.
Table 1
Criteria of amyotrophic lateral sclerosis
Criteria
Clinically definite ALS
Clinically probable ALS
Clinically possible ALS
Suspected ALS
El Escorial criteria (1994)
UMN and LMN signs in three regions of the body
UMN and LMN signs in at least two regions, with some UMN sign rostral to LMN signs
UMN and LMN signs in only one region, or UMN signs alone in two or more regions, or
LMN signs rostral to UMN signs
LMN signs only
Awaji-Shima criteria (2008)
Clinical or electrophysiological evidence of UMN and LMN signs in the bulbar region
and at least two spinal regions, or UMN and LMN signs in three spinal regions
Clinical or electrophysiological evidence of UMN and LMN signs in at least two regions,
with some UMN signs rostral to LMN signs
Clinical or electrophysiological evidence of UMN and LMN signs alone in two or more
regions, or LMN signs rostral to UMN signs
Chinese Medical Association criteria (2012)
Clinical or electrophysiological evidence of UMN and LMN signs in at least at three
regions
Clinical or electrophysiological evidence of UMN and LMN signs in at least two regions,
with some UMN signs rostral to LMN signs
Clinical or electrophysiological evidence of UMN and LMN signs in one region, or UMN
signs alone in two or more regions
ALS: Amyotrophic lateral sclerosis; UMN: Upper motor neuron; LMN: Lower motor neuron.
For familial ALS (FALS) cases, the targeted sequencing approach which was designed
covering all of the already known mutations should be performed to identify the pathogenic
mutations.[3
14] However, nearly more than 30% of the FALS cases still have unidentified genetic
etiology. For these cases, additional genetic tests such as whole exon sequencing
or whole genome sequencing were needed to unravel the disease-causing mutations.[15]
Another important and useful strategy to help early diagnosis is to establish a patients’
database and follow-up system. A patents’ database should carefully record all aspects
of patients’ features including age, family history, site of onset, symmetry, severity
of symptoms, balance of UMN and LMN involvement, extramotor features, disease progression,
prognosis, and all tests data. As ALS is a progressively developed disease, patients
in early stage may have symptoms limited to one or two regions that are difficult
to identify and make a diagnosis. A follow-up system will help to early recognize
the disease during its progression. Patients with an ALS suspicion should be evaluated
at least in 3–6 months in specialized ALS center. Besides, it is necessary to well
communicate with patients, so that patients will understand and cooperate with the
doctor's diagnosis and treatment plan.
Finally, the most important point which deserves additional attention is when the
diagnosis is unclear, it is recommended to refer patients to the ALS specialists,
which can greatly minimize the diagnostic delay.
INDIVIDUALIZED TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS
Clinical management of amyotrophic lateral sclerosis patients
Although mean survival in ALS patients is only 2–5 years, some of the patients tend
to have a more slowly progressive disease form and can survive for over a decade,
demonstrating the importance of clinical management throughout the course of the disease.
So far, there is no breakthrough for the treatment of ALS. The main treatments are
neuroprotective treatment, symptomatic and supportive treatment as well as some unproven
disease-modifying therapies such as stem cell transplantation and gene therapy. Multidisciplinary
specialist team can provide optimized individualized clinical management for patients
with ALS. The Revised ALS Functional Rating Scale is the most accepted and widely
used assessment tool during the course of the disease.
Unapproved disease-modifying therapies
Stem cell transplantation therapy is still practiced in animal model level or under
clinical trial. A new stem cell treatment that injected intramuscularly and intrathecal
administration of autologous mesenchymal stem cells in patients with ALS was successful
in slowing disease progression in a small group of ALS patients in a Phase 2 clinical
trial,[13] showing this therapy may have possible clinical benefit.
Gene therapy is a molecular level intervention for the treatment of the disease. It
has greatly broadened the prospects of disease's treatment. However, this therapy
is only developed for familial patients who carry specific gene mutations and is not
suitable for most sporadic patients who have no specific target. It still needs a
long way to enter the clinical stage of treatment.
Neuroprotective treatment
Medication with riluzole should be initiated as early as possible. Another neuroprotective
drug edaravone (RADICAVA) has also been approved by the Food and Drug Administration
recently. However, both of them have a modest improvement in survival by several months.
Clinicians should pay more attention on individualized treatment for ALS patients,
improving the overall life quality of patients. A recent study pointed out that formal
classification systems such as the El Escorial criteria and the International Classification
of Diseases are lack of features that are important for clinical management, for example,
site of onset, extramotor features, rate of progression, genetic basis, and functional
effect.[16] All of these individualized clinical features should carefully record
in the patient's database which may give guidance information during the course of
the disease.
Symptomatic treatment and supportive care
Evidence-based symptomatic treatment of complications is important to improve patients’
life quality.[11] Depression and anxiety frequently occur in patients and their caregivers,
particularly prevalent during the diagnostic and terminal phases. Empirically tricyclic
antidepressants and selective serotonin reuptake inhibitors are effective. For most
patients, sialorrhea is common and sometimes socially disabling. Symptomatic treatment
drugs such as amitriptyline oral doses of 5–10 mg three times a day are often sufficient.
Cramp is also a troublesome symptom. Levetiracetam is shown to be beneficial. Physical
therapy is the mainstay of effective treatment of spasticity in ALS patients. Medullary
paralysis is another suffering symptom for patients, particular for the bulbar onset
patients who have this symptom in an early stage. Percutaneous endoscopic gastrostomy
feeding will greatly improve nutrition and quality of life. Ventilator involvement
may occur in terminal phases. Noninvasive positive-pressure ventilation improves survival
and quality of life.
Dietary counseling is a common concern for patients. Education of patients and their
caregivers in feeding high-protein and high-caloric foods is important as weight loss
is an independent prognostic factor of survival in ALS. Another concern that patients
want to know is the course of the disease. In this case, the biomarkers that could
reflect the disease progression are useful for management. Slower elimination rate
of serum lactate has been reported to be associated with faster disease progression
in Chinese patients.[17] The introduction of alternative communication devices is
needed for maintaining the patients’ ability to communicate which is usually affected
by dysarthria. As the evidence base for symptomatic treatment increases, individual
decisions become more complex. With the rich amount of information on unproven therapies
available on the internet, patients’ choices are further complicated that they often
make decisions about their medical care using these sources. Thus, patients and caregivers
must be fully and reliably informed about their options.
CONCLUSIONS AND FUTURE PROSPECTS
We have come a long way since the first ALS pathogenic gene SOD1 was discovered 20
years ago. However, great challenges still exist in all aspects of the disease including
diagnosis, pathogenesis, and treatment that far from be fully addressed. Further work
is needed to strengthen the cooperation between ALS experts’ teams. We need to build
a standard ALS diagnostic and treatment criteria that can provide enriched, broaden
spectrum of phenotypic information about ALS based on Chinese patients. Establish
patients’ database that linking signs, symptoms, laboratory findings, results from
imaging studies, and follow-up information together will help develop diagnostic and
prognostic biomarkers. A nationwide shared resource platform will be helpful for integrating
multicenter clinical data and human sample resource which can accelerate the research
on ALS pathogenesis as well as the step to find new therapeutic drugs. Discovery of
effective disease-modifying therapies remains a critical need for patients with this
devastating disease.