MND Early Symptoms: How to Spot Disease Early

Introduction

Motor Neuron Disease (MND) develops as subtle neuromuscular changes that challenge its early detection. The initial symptoms are rooted in progressive degeneration in upper and lower motor neurons. MND is fatal and progresses rapidly. Global statistics reflect 1-5 year survival after diagnosis [1]. 

MND Early Symptoms involve fasciculation (twitching), asymmetric weakness, or early bulbar dysfunction long before the definite diagnosis appears. The recognition of the early neurobiological signals is crucial for early diagnosis, timely intervention, and management.   

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Understanding MND: A Brief Overview 

MND is a rapidly progressive neurological disease. Alternatively, MND is called amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease. MND attacks the lower and upper neural motor system and disrupts muscular control—the disease traps an individual inside a failing body. The patient cannot move, talk, or breathe. 

MND has Four SubTypes, Such As:

• Amyotrophic Lateral Sclerosis (ALS): Characterized by muscle weakness (arms and legs). Individuals experienced a trip or a drop
• Progressive Bulbar Palsy (PBP): Majorly affects facial, tongue, and throat muscles. Characterized by slurred speech or difficulty in swallowing
• Progressive Muscular Atrophy (PMA): Experiences weakness in the hand
• Primary Lateral Sclerosis (PLS): Affects the lower limbs; sometimes, speech dysfunction appears

*NOTE: MND gets worse within a few months, shortening the lifespan of the individuals.

What is the Underlying Pathophysiology?

MND Arises Due to Several Interlinked Intracellular Processes, Such As:

• Glutamate Excitotoxicity: Astrocyte uptake of glutamate is compromised, leading to accumulation in the synaptic cleft. It results in excessive NMDA/AMPA receptor activation and toxic calcium influx in neurons
• Protein Aggregation: Impaired protein homeostasis (c9orf72, SIGMAR 1M, CHMP2B), or aberrant RNA metabolism (ANG, FUS, SETS)
• Mitochondrial Dysfunction: Oxidative stress and damaged mitochondria lead to excessive free radical accumulation. It results in neurotoxicity
• Neuroinflammation: Microglia and astrocyte activation lead to neuronal deaths
• Axonal Transport Dysfunction: Cellular transportation disruption prevents signal and nutritional supply to the axonal terminal. It results in axon retraction, neuromuscular junction dysfunction, and muscle denervation.  

MND Symptoms: Subtle Clinical Red Flags

Motor Neuron Disease (MND) Early Symptoms Involve:

• Upper limb Muscle stiffness and weakness: Weakened muscles in the hands, one finds difficulty in gripping or holding things.
• Lower limb muscle stiffness: Individuals find difficulty in climbing stairs, increased incidences of tripping, or foot drop
• Muscle tightening: Muscle cramps, twitching, or spasms 
• Early Bulbar Signs: Difficulty in speech and swallowing 
• Reduced endurance: low energy, and fatigue

Motor Neurone Disease Symptoms (advanced) Include:

• Severe problem with breathing, speaking, and swallowing
• Drooling, that is, producing lots of saliva
• Significant change in mood and personalities
• Difficulty with movement or walking
• A change in the thought process characterizes cognitive impairment 
• Increased cognitive dependency in performing daily life activities

What are the Differential Diagnoses that MIMIC Early MND?

Identification or Diagnosis of Early MND Symptoms is Difficult, as it MIMICS other Disorders. This includes:

• Peripheral Neuropathies: Damaged nerve outside the brain or spinal cord (characterized by numbness, tingling, pain, weakness) 
• Cervical Myelopathy: Spinal cord compression occurs in the neck region. Characterized by numbness, walking difficulties, and balancing problems
• Myopathies and Metabolic Disorders: Affect muscular energy production. Weakness, exercise tolerance, muscle pain, or fatigue

What is the Diagnostic Approach to Identify MND?

MND Diagnostic Test Includes:

• Patient Medical History & Physical Examination: Detailed medical history of the patients and physical examination, determining strength, coordination, reflexes, and mobility
• Blood Test: Analysis of elevated markers, e.g., Creatine kinase. Other tests include CBC, LKFT, determination of inflammatory markers (ESR or CRP), and metabolic tests.
• Electromyography (EMG): Identification of the motor neuron’s ability to transmit electrical signals to the muscles
• Magnetic Resonance Imaging (MRI): MRI scan for the brain and spinal cord. Identifies the structural abnormalities, enabling the ruling out of other neurodegenerative diseases
• Genetic Test: Identification of genetic mutation with familial MND
• Lumbar Puncture: Examination of cerebrospinal fluid 

When to Seek Medical Attention in MND? 

• Appearance of red flag combinations: asymmetric limb weakness (no definite musculoskeletal cause)
• Appearance of upper or lower motor neuron signs
• Bulbar symptoms or widespread fasciculation
• Unexplained muscle wasting or rapid functional decline
• Early respiratory symptoms

What are the Treatment Approaches in MND?

There is no cure available for MND Treatment in India. The current treatment regime focuses on a multidisciplinary approach. The common options include: 

• Medication: No medication can halt MND. Clinicians prescribe medication for specific symptom management. E.g, Riluzole, Edaravone for slowing progression. Other medications prescribed are for the management of pain, relaxants, drooling control, etc.
• Physiotherapy: Exercise for maintaining muscle strengthening, improving mobility, and preventing muscle contractures. 
• Occupational Therapy: Assist the individual in performing daily life activities 
• Speech or Swallowing Therapy: Improves speech or communication. Support swallowing and reduce the risk of choking.
• Nutritional Interventions: Dietitians plan adequate nutrient supply via modifying dietary intake and supplementation. Recommends the use of feeding tubes
• Psychological Support: Psychological support provides emotional support, aids in coping with stress or anxiety, and manages psychological decline 

What is the Emerging Treatment in MND?

Regenerative medicine in the form of MND stem cell treatment is emerging as a supportive option. In the future, stem cell therapy might potentially transform into curative, but currently, poor evidence exists in terms of replacing faulty motor neurons with healthy ones. Mesenchymal stem cells are widely explored for MND treatment. Researchers reflect on crucial aspects in stem cell therapy MND research:

• Neuronal replacement via the regeneration of new cells and the replacement of damaged ones. The success is limited in this aspect.
• Neuroprotection mediated by neurotrophic factor (NurOwn) released by stem cells. 
• Immunomodulation and trophic support to enhance neuronal survival and slow degeneration
• MSCs release various growth factors that modulate neuroinflammation and reduce excitotoxicity.   
• Current clinical evidence (Phase I/II trials) launched in the USA and Israel suggests safety and modest functional benefits with MND Stem Cell Treatment. For instance, slow ALSFRS-R decline. The results obtained are inconclusive and heterogeneous [2]
• The future research focuses on gene-modified stem cell use, the development of precision stem cell therapy, and the development of large-scale clinical trials. 

Conclusion 

MND early symptoms recognition possesses substantial clinical value in early diagnosis and management. Timely recognition of the disease facilitates prompt initiation of multidisciplinary care that can improve the quality of life of the patient. The advances in biomarker discovery, neuroimaging, and regenerative medicine can potentially aid in developing disease-modifying interventions. 

References

1. State Government of Victoria. Motor neurone disease (MND). Melbourne: Better Health Channel. Available from: Motor neurone disease (MND) 
2. Motor Neurone Disease Association. Stem cell therapy. Northampton (UK): MND Association. Available from: Stem cell therapy 

FAQ’s

Q- What are the Early Signs and Symptoms of MND?

MND early symptoms and signs include upper and lower stiffness, fasciculations, muscle cramps, spasm, and difficulty in swallowing or speech. 

Q- How is MND Diagnosed?

The diagnostic method includes blood test, neural imaging, MRI scan, neurological examination, nerve conduction studies, etc. 

Q- Is Stem Cell Therapy in MND Successful?

Researchers are widely exploring the potential of stem cell therapy in treating MND. At present, the studies are still at an early stage. The clinical trials reflected its safety profile. In the future, large-scale clinical trials are required for establishing definite outcomes.