Amyotrophic lateral sclerosis (ALS): an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. ALS Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What ALS is Who gets it, the numbers, and the ways it starts.
Upper and lower motor neurons Two neurons, two sets of signs, animated.
TDP-43 and what goes wrong A protein leaves the nucleus and clumps.
Genes: C9orf72, SOD1 and more Familial ALS, repeat expansions and genetic testing.
Diagnosis and criteria The Gold Coast, revised El Escorial and Awaji criteria, as a calculator.
The differential Conditions that can look like ALS, and how they differ.
ALSFRS-R and the course The 12-item scale, the progression rate and the stages.
Riluzole, edaravone and others What each drug targets and what the trials found.
Tofersen An antisense drug that lowers SOD1, for SOD1-ALS.
Breathing and NIV Weak breathing muscles, the tests, and when ventilation is offered.
Swallowing and feeding tubes Why weight matters and when a gastrostomy is discussed.
Living with ALS Communication, cognition, symptoms, planning and end of life.
Nursing care Assessment, giving the medicines, teaching and documentation.
Toward a cure Every route under study, with the evidence for each.
History and people From Charcot to tofersen.
Flashcards, quiz and glossary Revision for students.
Sources Every reference behind the guide.

Part 1 · The disease

Upper and lower motor neurons

Every voluntary movement needs two nerve cells in a row: an upper motor neuron in the brain and a lower motor neuron in the spinal cord or brainstem. ALS damages both, and each kind of damage gives its own set of signs. Choose which neurons fail, then press Play and watch the signs panel fill in.

Which neurons fail

Reflex arc

Timeline

Schematic, not to scale. Three motor units stand for the hundreds in a real muscle. Fibres carry the letter of the lower motor neuron that supplies them.

UMN and LMN signs side by side

	Upper motor neuron (UMN)	Lower motor neuron (LMN)
Where the cell body is	UMN Betz cells in layer 5 of the primary motor cortex. Axons run in the corticospinal tract (to the cord) or to the brainstem motor nuclei. ^73,180	LMN Anterior horn cells of the spinal cord and the cranial motor nerve nuclei of the brainstem. Each one, with its muscle fibres, is a motor unit. ^180,341
Limb examination	Spasticity (tone that rises with the speed of stretch). Slowed, poorly coordinated voluntary movement that weakness does not explain. ^180,463	Weakness, wasting (atrophy) and fasciculations. ¹⁸⁰
Reflexes	Brisk reflexes, spread to nearby muscles, and a reflex kept in a weak, wasted limb. Pathological reflexes: Hoffmann, Babinski (extensor plantar), crossed adductor, snout. ^180,463	The Gold Coast criteria define LMN involvement by weakness with wasting, or by EMG, not by reflexes. UMN signs can be hard to elicit in a limb that is wasting. ^463,488
Bulbar region	Clonic jaw, gag reflex, exaggerated snout reflex, pseudobulbar features, forced yawning. ⁹⁵ Pseudobulbar affect: uncontrollable laughing or crying. ¹⁸⁰	Weakness, wasting and fasciculations of jaw, face, palate, tongue and larynx. ⁹⁵
Needle EMG	No EMG sign. UMN assessment is still clinical, which adds to diagnostic delay. ²⁴⁰	Ongoing denervation: fibrillations, positive sharp waves, fasciculation potentials. Chronic neurogenic change: large, long-duration, polyphasic motor unit potentials with reduced recruitment. ^252,463
Nerve conduction	Not used to show UMN loss.	Motor and sensory conduction usually normal; motor amplitudes may fall. Sensory studies are generally normal in ALS. ^194,252
Research measure	Brain stimulation (TMS) shows cortical hyperexcitability, with less short-interval intracortical inhibition (SICI). SICI change was the primary endpoint of a phase 2 trial. ^180,521	Motor unit number estimation (MUNE) counts surviving units. ^3,252
When only this neuron fails	Primary lateral sclerosis (PLS). Consensus criteria: age 25 or over, progressive UMN symptoms for at least 2 years, UMN signs in at least 2 of 3 regions, no active LMN degeneration. It does not meet the Gold Coast criteria for ALS. ^136,500	Progressive muscular atrophy (PMA). Under the Gold Coast criteria, a pure LMN syndrome in 2 or more regions counts as ALS. In a New York series of 91 people with PMA, UMN signs appeared in 22% within 61 months of diagnosis. ^136,264,432

Exam hookUMN: spasticity, brisk and spreading reflexes, Hoffmann, Babinski, pseudobulbar affect. LMN: weakness, wasting, fasciculations; on EMG, denervation plus large, long motor units. ALS has both, in the same or neighbouring regions.

In plain wordsOne nerve cell runs from the brain to the spine, and a second runs from the spine to the muscle. When the first one fails, muscles get stiff and reflexes jump. When the second one fails, muscles get weak, thin and twitchy. ALS damages both.

EstablishedLMN

Why eye movements and sphincters are spared

The motor neurons that move the eyes (cranial nerves III, IV and VI) persist throughout the disease. This is why eye-tracking devices can support communication late in ALS. ⁴⁰⁴ Onuf's nucleus in the sacral cord, which controls the bladder and bowel sphincters, was well preserved in 5 autopsy cases, which fits with sphincter function often lasting until the latest stage. ³¹⁹

On examination, an eye-movement palsy or a sphincter disturbance argues against ALS and points to another diagnosis. ¹⁹⁴

Early evidence Spared groups contain far more of the calcium-binding proteins calbindin-D28k and parvalbumin than the groups lost early. ¹¹ Extraocular muscles have their own myosin types and several nerve contacts per fibre. In mice, 18 genes differed more than tenfold between resistant and vulnerable motor neurons; IGF-2 was protective and extended the life of SOD1 mice by 10%. ⁴⁰⁴

Communication with eye-gaze is covered in Living with ALS.

EstablishedMechanism: hypothesis

The split hand

In ALS the thumb side of the hand wastes first: abductor pollicis brevis (APB) and first dorsal interosseous (FDI). Abductor digiti minimi (ADM), on the little-finger side, is relatively spared. All three are supplied from C8-T1, and FDI and ADM share the ulnar nerve, so no single nerve or root explains the pattern. ¹⁵⁴

Proposed reasons are cortical (smaller magnetic motor evoked potentials from thenar muscles) and peripheral (larger persistent sodium currents, so more excitable APB and FDI axons). Heavy precision-grip use may add metabolic stress. ¹⁵⁴ Eisen and colleagues link it to the direct cortico-motoneuronal system, which is markedly enhanced in humans. ¹⁵⁵

The sign is reported to have high specificity in early ALS, and clinicians list it among signs with high positive predictive value, though not formally validated. ^154,502 Step 6 of the animation shows it.

Established

Reinnervation hides the loss

Surviving motor neurons sprout and adopt orphaned fibres, so each surviving unit grows. Motor unit counting studies show this can keep strength and CMAP amplitude near normal even when up to half the motor units are lost (a secondary report in a review). ²⁵²

That is why weakness can be a late sign, and why needle EMG, which sees the enlarged units, can show LMN loss in a muscle that still feels strong. Under the Gold Coast criteria, EMG can stand in for clinical LMN signs. ^463,501

Fast-fatigable units are the most vulnerable and are lost first; slow units compensate for a while, then degenerate too. ^341,404

Controversy: does it start at the top or at the bottom?

Two hypotheses compete. They rest mostly on different evidence, human brain stimulation for one and the SOD1 mouse and the neuromuscular junction for the other, and the sources do not settle which comes first. ^185,341,522

HypothesisStarts in the UMN

Dying forward

Over-active cortico-motoneurons drive the death of anterior horn cells through glutamate (excitotoxicity). ^521,522

In 23 people with MND, short-interval intracortical inhibition was 3.6 ± 0.8%, against 8.5 ± 1.0% in controls (P < 0.001), and the cortex was over-excitable even in advanced disease. ⁵²¹
In 3 SOD1 carriers, SICI was absent or reduced before symptoms began, and all 3 later developed ALS. ⁵²²
Eisen and colleagues argue that TDP-43 pathology is limited to the cortex and to nuclei under direct cortical control, placing its origin in the cortex. ¹⁵⁵

HypothesisStarts at the muscle end

Dying back

The lower motor neuron fails first at its far end: the nerve terminal lets go of the muscle, then the axon is lost, then the cell body. ¹⁸⁵

In SOD1(G93A) mice, 40% of end-plates were denervated at 47 days with no loss of cell bodies, and 60% of ventral-root axons were gone at 80 days while motor neurons were still present. ¹⁸⁵
One person with sporadic ALS who died unexpectedly had denervation and reinnervation in muscle but normal-looking motor neurons. ¹⁸⁵
Many molecular changes occur at the neuromuscular junction before symptoms begin. ³⁴¹