Degenerative and hereditary myelopathies

Degenerative Myelopathies: Amyotrophic Lateral Sclerosis (ALS, Motor Neuron Disease)

Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a progressive neurodegenerative disease that affects nerve cells (motor neurons) in the brain and spinal cord responsible for controlling voluntary muscle movement. While primarily a motor neuron disease, it involves degeneration of upper motor neurons (originating in the cerebral cortex and forming the corticospinal and corticobulbar tracts) and lower motor neurons (located in the brainstem and the anterior horns of the spinal cord).

If a patient presents with symmetric spastic paraparesis (weakness and increased muscle tone in both legs) that is not accompanied by sensory disorders, ALS should be suspected, particularly if other signs are present. Key features include:

• Combination of Upper and Lower Motor Neuron Signs:
  • UMN signs: Spasticity, hyperreflexia, positive Babinski sign, muscle weakness.
  • LMN signs: Muscle weakness, atrophy (muscle wasting), fasciculations (visible muscle twitching), cramps.
• Progressive Muscle Weakness: Can start in the limbs (limb-onset) or with difficulty speaking or swallowing (bulbar-onset).
• Preservation of Sensation: Sensory pathways are typically spared in ALS, which helps differentiate it from many other myelopathies.
• Electromyography (EMG) Findings: EMG studies are crucial for diagnosis, revealing signs of active and chronic denervation (lack of nerve supply to muscles) and fasciculations, indicating damage to motor neurons.

ALS is a relentlessly progressive disease with no cure, though treatments are available to manage symptoms and slow progression to some extent.

Metabolic Myelopathy: Subacute Combined Degeneration of the Spinal Cord (Vitamin B12 Deficiency)

Subacute combined degeneration (SCD) of the spinal cord is a neurological complication of severe and prolonged vitamin B12 (cobalamin) deficiency. This type of myelopathy primarily affects the posterior and lateral columns of the spinal cord, leading to a characteristic pattern of motor and sensory disorders.

Clinical Features and Diagnosis

Patients with SCD typically present with:

• Sensory Disturbances:
  • Paresthesias: Symmetrical numbness, tingling, or "pins and needles" sensations, usually starting distally in the feet and hands and ascending.
  • Impaired Vibration and Proprioception: Due to posterior column involvement, leading to difficulty with balance (sensory ataxia), a positive Romberg sign, and unsteadiness, especially in the dark.
• Motor Symptoms:
  • Progressive Spasticity and Weakness: Primarily affecting the legs (spastic paraparesis) due to lateral column (corticospinal tract) involvement.
  • Ataxia: Gait disturbance due to both sensory loss and corticospinal/spinocerebellar tract involvement.
  • Hyperreflexia and positive Babinski signs.
• Associated Peripheral Neuropathy: Vitamin B12 deficiency can also cause a peripheral neuropathy, which may contribute to distal sensory loss and areflexia (if severe), sometimes creating a mixed picture with UMN signs from the myelopathy.
• Other Neurological and Systemic Manifestations: Cognitive changes (memory loss, confusion, "megaloblastic madness"), optic neuropathy, glossitis (sore tongue), and megaloblastic anemia (pernicious anemia if due to intrinsic factor deficiency). Peripheral nerves and the brain can also be affected.

The diagnosis is confirmed by laboratory tests showing a low serum level of vitamin B12. Elevated levels of methylmalonic acid (MMA) and homocysteine are more sensitive indicators of B12 deficiency. A positive Schilling test (historically used to determine the cause of B12 malabsorption) has largely been replaced by testing for anti-intrinsic factor antibodies or anti-parietal cell antibodies if pernicious anemia is suspected.

Differential Diagnosis and Treatment

Subacute combined degeneration of the spinal cord due to vitamin B12 deficiency should be differentiated from other conditions causing progressive myelopathy, including:

• Cervical Spondylotic Myelopathy
• Other degenerative myelopathies with late onset.
• Symmetric multifocal (multiple) spinal cord sclerosis (Multiple Sclerosis) with late onset.
• Copper deficiency myelopathy (clinically very similar to B12 deficiency myelopathy).
• Other toxic or metabolic myelopathies.

The opinions of experts regarding whether folate deficiency or vitamin E deficiency can lead to a similar clinical syndrome are controversial, though severe deficiencies of these vitamins can also cause neurological problems. It's also noted that sometimes Multiple Sclerosis and B12-deficiency myelopathy can be diagnosed concurrently in the same patient.

SCD is a **well-treatable disease** if diagnosed and managed promptly with vitamin B12 replacement therapy (usually lifelong intramuscular or high-dose oral supplementation). Early treatment can lead to significant neurological improvement, but delayed treatment may result in irreversible neurological damage.

Diagnosis of Degenerative and Hereditary Myelopathies

Diagnosing these complex conditions involves a multifaceted approach:

• Detailed Clinical History: Including age of onset, rate of progression, specific symptoms (motor, sensory, autonomic), family history of neurological disorders.
• Comprehensive Neurological Examination: To characterize the pattern of neurological deficits (UMN vs. LMN signs, sensory levels, cerebellar signs, etc.). Observation for skeletal deformities like kyphoscoliosis or pes cavus.
• Neuroimaging:
  • MRI of the Brain and Spinal Cord: Essential to rule out compressive lesions (tumors, disc herniations, spondylosis), identify structural abnormalities (e.g., syrinx, Chiari malformation), or detect inflammatory/demyelinating lesions. In many primary degenerative/hereditary myelopathies, MRI may show non-specific atrophy or be normal, especially early on. Specific patterns (e.g., "inverted V" sign in SCD) can sometimes be seen.
• Electrophysiological Studies:
  • EMG/NCS: Crucial for diagnosing ALS (showing denervation), differentiating myelopathy from neuropathy or myopathy, and assessing peripheral nerve involvement in conditions like Friedreich's ataxia or B12 deficiency.
  • Evoked Potentials (SSEPs, MEPs, VEPs): Can demonstrate dysfunction in sensory, motor, or visual pathways within the CNS.
• Laboratory Tests:
  • Serum Vitamin B12, MMA, homocysteine levels (for SCD).
  • Tests for other metabolic or nutritional deficiencies (e.g., copper, vitamin E).
  • Blood tests for inflammatory markers, autoantibodies (if an autoimmune condition is suspected).
  • CSF analysis (if inflammatory or infectious myelopathy is in the differential).
• Genetic Testing: Increasingly important for confirming specific hereditary myelopathies (e.g., Friedreich's ataxia, HSP, SCAs, some forms of ALS).
• Biopsy (Rarely): Muscle or nerve biopsy may be considered in specific situations to diagnose certain neuropathies or myopathies that can mimic or accompany myelopathies. Brain or spinal cord biopsy is very rarely performed for these conditions.

General Management Principles

Management of degenerative and hereditary myelopathies is often challenging and primarily supportive, as many of these conditions currently have no cure. The goals are to:

• Slow Disease Progression (where possible): Specific disease-modifying therapies are available for some conditions (e.g., riluzole for ALS, B12 replacement for SCD).
• Symptomatic Treatment: Managing spasticity (e.g., baclofen, tizanidine), pain, fatigue, bladder/bowel dysfunction, dysarthria, dysphagia.
• Rehabilitation: Physical therapy, occupational therapy, and speech therapy are crucial for maintaining function, preventing contractures, improving mobility and activities of daily living, and providing adaptive equipment.
• Genetic Counseling: For patients with hereditary conditions and their families.
• Supportive and Palliative Care: Especially for progressive and life-limiting disorders like ALS, focusing on quality of life, respiratory support, nutritional support, and psychosocial support for patients and caregivers.
• Clinical Trials: Participation in clinical trials for new investigational therapies may be an option for some patients.

Differential Diagnosis of Progressive Myelopathy

Progressive myelopathy presents a broad differential. Distinguishing between degenerative, hereditary, metabolic, inflammatory, and compressive causes is key.

Category	Examples	Key Differentiating Features
Hereditary Myelopathies	Friedreich's Ataxia, Hereditary Spastic Paraplegia (HSP), Spinocerebellar Ataxias (SCAs)	Family history, specific genetic mutations, characteristic age of onset and clinical phenotype (e.g., ataxia + areflexia + sensory loss in FA; pure spastic paraparesis in HSP).
Degenerative Myelopathies (Motor Neuron Diseases)	Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS)	Combination of UMN and LMN signs (ALS) or pure UMN signs (PLS). Progressive weakness, fasciculations, bulbar symptoms. Sensation usually intact. EMG shows denervation.
Metabolic/Nutritional Myelopathies	Subacute Combined Degeneration (B12 deficiency), Copper Deficiency Myelopathy, Vitamin E Deficiency	Posterior and lateral column signs (sensory ataxia, spasticity), peripheral neuropathy. Confirmed by low vitamin/mineral levels and response to supplementation.
Spondylotic Myelopathy (Compressive)	Cervical spondylosis with spinal canal stenosis	Older age group, neck pain, progressive UMN signs in limbs, sensory disturbances, gait difficulty. MRI shows cord compression from degenerative changes.
Inflammatory/Demyelinating Myelopathies	Multiple Sclerosis, Transverse Myelitis, NMOSD	Often relapsing-remitting or acute/subacute onset. MRI shows demyelinating lesions. CSF may show oligoclonal bands or pleocytosis.
Spinal Cord Tumors (Compressive or Intrinsic)	Ependymoma, Astrocytoma, Metastases	Progressive myelopathy, pain common. MRI diagnostic.
Syringomyelia	Often associated with Chiari malformation or post-traumatic.	Dissociated sensory loss ("cape-like"), LMN signs in arms, scoliosis. MRI shows syrinx cavity.

Prognosis and Long-Term Care

The prognosis for degenerative and hereditary myelopathies is highly variable. Some, like SCD due to B12 deficiency, are treatable with excellent outcomes if diagnosed early. Many hereditary ataxias and spastic paraplegias are slowly progressive, with management focused on symptomatic relief and maintaining function for as long as possible. ALS is a relentlessly progressive disease with a poor prognosis, typically leading to respiratory failure within 3-5 years of onset, although some individuals live much longer. Long-term care often involves a multidisciplinary team, adaptive equipment, and support for patients and their families to manage the progressive disability and maintain quality of life.

When to Consult a Neurologist

Consultation with a neurologist is essential if an individual experiences:

• Progressive weakness, stiffness, or clumsiness in the limbs.
• Unexplained gait disturbance or frequent falls.
• Progressive sensory symptoms (numbness, tingling, loss of vibration/position sense).
• Symptoms suggestive of combined UMN and LMN involvement (e.g., weakness with spasticity and fasciculations).
• Family history of a known hereditary neurological disorder with onset of compatible symptoms.
• Suspicion of vitamin B12 deficiency or other metabolic causes of myelopathy.

Early and accurate diagnosis is crucial for initiating any available treatments, providing genetic counseling where appropriate, and planning long-term management and supportive care.