ALS Without a Cure: How Physicians Can Still Make a Difference

Epidemiology and Global Burden

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a relentlessly progressive neurodegenerative disorder affecting motor neurons in the brain and spinal cord. Its global incidence is approximately 1.5 to 2.5 cases per 100,000 people annually, with a prevalence of around 4–6 per 100,000. The disease is more common in males than females, typically manifesting between the ages of 40 and 70. However, it does not spare younger adults or, more rarely, pediatric cases. Geographic and ethnic disparities exist, with the highest rates seen in European and North American populations. Though ALS is considered rare, its emotional and medical impact is profound due to its rapid progression and lack of a cure.

Pathophysiology: A Motor Neuron Catastrophe

The hallmark of ALS is the selective degeneration of both upper motor neurons (UMNs) in the motor cortex and lower motor neurons (LMNs) in the brainstem and spinal cord. This dual involvement creates the characteristic combination of spasticity, hyperreflexia, and weakness (from UMN damage) with muscle wasting, fasciculations, and hyporeflexia (from LMN damage). The precise mechanism behind motor neuron death is still debated, but several pathways have been implicated:

• Excitotoxicity due to glutamate accumulation.
• Oxidative stress with increased free radical damage.
• Protein misfolding and TDP-43 aggregation.
• Mitochondrial dysfunction, impairing neuronal energy metabolism.
• Neuroinflammation with microglial activation.
• Genetic mutations—particularly in familial cases (C9ORF72, SOD1, TARDBP, FUS).

Despite a common clinical endpoint—motor neuron death—the pathological mechanisms may vary from patient to patient, indicating ALS is a syndrome more than a single disease entity.

Clinical Manifestations: A Multifaceted Spectrum

ALS symptoms vary by site of onset and progression speed. The disease is classically divided into two major subtypes based on initial symptoms:

• Limb-Onset ALS (~70% of cases): Presents with asymmetrical distal weakness, often in the hands or feet, associated with cramping, fasciculations, and wasting.
• Bulbar-Onset ALS (~25% of cases): Initial symptoms involve dysarthria, dysphagia, and tongue fasciculations. It typically has a worse prognosis.

Key symptoms to recognize include:

• Progressive muscle weakness (often starting distally)
• Muscle atrophy and fasciculations
• Spasticity and hyperreflexia
• Dysarthria and dysphagia
• Emotional lability (pseudobulbar affect)
• Respiratory insufficiency (eventually fatal)
• Cognitive and behavioral changes (in up to 50% of cases, particularly with frontotemporal dementia)

What is not affected? Sensory function, bowel/bladder continence, and ocular motility are typically preserved—an important diagnostic clue.

Diagnostic Approach: Clinical Suspicion Meets Neurophysiology

There is no single test for ALS. Diagnosis is fundamentally clinical, supported by electrophysiology and imaging, while excluding ALS mimics.

Essential components:

• History and exam: Look for asymmetric motor weakness with mixed UMN and LMN signs.
• Electromyography (EMG): The gold standard for detecting denervation and reinnervation.
• Nerve conduction studies (NCS): Rule out peripheral neuropathies.
• MRI of brain/spine: Exclude compressive or inflammatory lesions.
• Blood tests: Rule out B12 deficiency, HIV, Lyme disease, autoimmune conditions.
• Genetic testing: Consider in patients with a family history or early onset.

Revised El Escorial Criteria and the Awaji Criteria are used to classify patients into “definite,” “probable,” or “possible” ALS, based on the distribution and combination of UMN and LMN signs.

Differential Diagnosis: Look-Alikes That Must Be Excluded

Several treatable or alternative diagnoses must be considered before confirming ALS:

• Cervical myelopathy
• Multifocal motor neuropathy
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Kennedy’s disease (SBMA)
• Myasthenia gravis
• Inclusion body myositis
• Lyme disease
• Lead poisoning
• Paraneoplastic syndromes

Management Strategies: Slowing the Inevitable

ALS currently has no cure, and management is largely supportive. However, a multidisciplinary approach can significantly prolong survival and improve quality of life.

Pharmacologic Treatments:

• Riluzole: A glutamate release inhibitor that extends survival by a few months. Mechanism: Reduces excitotoxicity.
• Edaravone: Antioxidant that modestly slows progression in selected patients.

Symptom Management:

• Spasticity: Baclofen, tizanidine.
• Cramps and fasciculations: Quinine, mexiletine.
• Sialorrhea: Glycopyrrolate, atropine drops.
• Pseudobulbar affect: Dextromethorphan-quinidine.
• Pain and dyspnea: Opioids, benzodiazepines as needed.
• Depression/anxiety: SSRIs, supportive therapy.

Respiratory Support:

• Non-invasive ventilation (NIV): Significantly prolongs survival and quality of life.
• Tracheostomy with mechanical ventilation: Controversial but available in some settings.

Nutritional Support:

• PEG (percutaneous endoscopic gastrostomy): Indicated when dysphagia leads to weight loss >10% or aspiration risk increases.

Rehabilitation and Assistive Devices:

• Physical therapy to preserve mobility and prevent contractures.
• Speech therapy and augmentative communication devices.
• Wheelchairs, braces, and mobility aids.

Palliative and End-of-Life Care:

• Discussing advanced directives early is essential.
• Palliative teams can manage complex symptoms and support caregivers.

Cognitive and Behavioral Management:

• Neuropsychological assessment to identify frontotemporal involvement.
• Education and counseling for family and caregivers.
• Tailored communication strategies.

Genetics and Future Directions in ALS Research

About 10% of ALS cases are familial, and up to 70% of those have identifiable mutations. The most common is C9ORF72, associated with ALS and frontotemporal dementia. SOD1, TARDBP, and FUS are other major genes implicated.

Emerging therapies under investigation include:

• Antisense oligonucleotides (ASOs): Targeting specific gene mutations (e.g., Tofersen for SOD1).
• Stem cell therapy: Aiming to replace lost neurons.
• Gene editing: CRISPR-Cas9 techniques under early exploration.
• Immunomodulators: Targeting neuroinflammation pathways.
• Neuroprotective agents: Enhancing mitochondrial function or protein folding.

ALS clinical trials are ongoing globally, and biomarkers such as neurofilament light chain (NFL) are being evaluated for early diagnosis and disease monitoring.

ALS in Clinical Practice: The Real-World Challenges

• Diagnostic delay: Often over 12 months from first symptom to diagnosis.
• Emotional burden: For both patient and physician, especially in delivering the diagnosis.
• Caregiver stress: High physical and emotional toll, often overlooked.
• Resource limitations: Especially in developing countries, access to multidisciplinary care and ventilatory support is constrained.
• Ethical dilemmas: Decisions regarding feeding tubes, ventilators, and end-of-life care.

Teaching Points for Medical Students and Junior Doctors

• Don’t dismiss fasciculations as benign unless proven otherwise.
• The combination of UMN and LMN signs is a diagnostic red flag.
• Always rule out mimics—especially compressive myelopathy.
• ALS does not affect the senses—if there's sensory loss, reconsider your diagnosis.
• Respiratory function (FVC or sniff nasal inspiratory pressure) should be monitored early and regularly.

The Human Side of ALS: The Disease Behind the Diagnosis

It’s easy to discuss ALS in terms of EMG findings, genetic mutations, and medication algorithms. But this disease teaches the doctor one of the hardest lessons in medicine: managing when we cannot cure. It humbles, it tests our communication skills, and it demands interdisciplinary cooperation. Patients with ALS often remain cognitively aware of their physical decline, trapped in a body they can no longer control—a scenario that challenges our core clinical humanity. In many ways, managing ALS isn’t just about medical expertise; it’s about bearing witness, providing dignity, and staying present.