This document provides information on motor neuron disease and amyotrophic lateral sclerosis (ALS) in particular. It discusses the pathology, classification, clinical manifestations, investigations, differential diagnosis and treatment of motor neuron diseases with a focus on ALS. ALS is characterized by the degeneration of both upper and lower motor neurons leading to muscle weakness, atrophy and fasciculations. Riluzole and edaravone are approved treatments that can modestly prolong survival.

1. MOTOR NEURON DISEASE
SEMINAR

2. • This general term is used to designate a progressive degenerative
disorder of motor neurons in the motor cortex, brain stem and spinal
cord, manifest clinically by muscular weakness, atrophy, and
corticospinal tract signs in varying combinations.
• It is a disease of middle life, for the most part, and progresses to
death in a matter of 2 to 5 years or longer in exceptional cases.

3. • Credit for the original delineation of amyotrophic lateral sclerosis is
appropriately given to Charcot.
• With Joffroy in 1869 and Gombault in 1871, he studied the pathologic aspects
of the disease.
• In a series of lectures given from 1872 to 1874,he provided a lucid account of
the clinical and pathologic findings.
• Although called Charcot disease in France, amyotrophic lateral sclerosis(the
term recommended by Charcot) has been preferred in the English speaking
world.
• Duchenne had earlier (1858) described labioglosso laryngeal paralysis, a term
that Wachsmuth in 1864 changed to progressive bulbar palsy.

4. CLASSIFICATION
• MOST COMMON- AMYOTROPIC LATERAL SCLEROSIS (BOTH UMN & LMN)
• SELECTED LOWER MOTOR NEURON DISORDERS
• X-Linked Spinobulbar Muscular Atrophy (Kennedy’s Disease)
• Adult Tay-Sachs Disease
• Spinal Muscular Atrophy
• Multifocal Motor Neuropathy with Conduction Block
• SELECTED DISORDERS OF THE UPPER MOTOR NEURON
• Primary Lateral Sclerosis
• Hereditary Spastic Paraplegia

5. AMYOTROPIC LATERAL SCLEROSIS (ALS)
• ALS is the most common progressive motor neuron disease.
• It is a prime example of a neurodegenerative disease.
• Annual incidence rate of 0.4 to 1.76 per 100,000 population.
• Men are affected nearly twice as often as women.
• The disease occurs in a random pattern throughout the world except for a
dramatic clustering of patients among inhabitants of the Kii peninsula in Japan
and in Guam, where ALS is often combined with dementia and parkinsonism.
• In about 10 percent of cases, the disease is familial, being inherited as an
autosomal dominant trait with age dependent penetrance

6. PATHOLOGY
• The pathologic hallmark of motor neuron degenerative disorders is
death of lower motor neurons (consisting of anterior horn cells in the
spinal cord and their brainstem homologues innervating bulbar
muscles) and upper, or corticospinal, motor neurons (originating in
layer five of the motor cortex and descending via the pyramidal tract
to synapse with lower motor neurons, either directly or indirectly via
interneurons).
• Although at its onset ALS may involve selective loss of function of
only upper or lower motor neurons, it ultimately causes progressive
loss of both categories of motor neurons.

7. • Other motor neuron diseases involve only particular subsets of motor
neurons
• In bulbar palsy and spinal muscular atrophy (SMA; also called
progressive muscular atrophy), the lower motor neurons of brainstem
and spinal cord, respectively, are most severely involved.
• By contrast, pseudobulbar palsy, primary lateral sclerosis (PLS), and
hereditary spastic paraplegia (HSP) affect only upper motor neurons
innervating the brainstem and spinal cord.

8. • The affected motor neurons undergo shrinkage, often with
accumulation of the pigmented lipid (lipofuscin) that normally
develops in these cells with advancing age.
• In ALS, the motor neuron cytoskeleton is typically affected early in the
illness.
• Focal enlargements are frequent in proximal motor axons;
ultrastructurally, these “spheroids” are composed of accumulations of
neurofilaments and other proteins.
• The death of the peripheral motor neurons in the brainstem and
spinal cord leads to denervation and atrophy of the corresponding
muscle fibers

9. • Histochemical and electrophysiologic evidence indicates that in the early phases of the
illness denervated muscle can be reinnervated by sprouting of nearby distal motor nerve
terminals, although reinnervation in this disease is considerably less extensive than in
most other disorders affecting motor neurons.
• As denervation progresses, muscle atrophy is readily recognized in muscle biopsies and
on clinical examination. This is the basis for the term amyotrophy.
• The loss of cortical motor neurons results in thinning of the corticospinal tracts that
travel via the internal capsule and pyramidal tracts in the brainstem to the lateral and
anterior white matter columns of the spinal cord.
• The loss of fibers in the lateral columns and resulting fibrillary gliosis impart a particular
firmness (lateral sclerosis).
• A remarkable feature of the disease is the selectivity of neuronal cell death.

10. PATHOGENESIS
• The cause of sporadic ALS is not well defined.
• Several mechanisms that impair motor neuron viability have been elucidated
in rodents induced to develop motor neuron disease by SOD1 or profilin-1
transgenes with ALS-associated mutations.
• Genetic causes of ALS into three categories.
• In one group, the primary problem is inherent instability of the mutant
proteins, with subsequent perturbations in protein degradation (SOD1,
ubiquilin-1 and 2, p62).
• In the second category, the causative mutant genes perturb RNA processing,
transport, and metabolism (C9orf73, TDP43, FUS).
• In the third group of ALS genes, the primary problem is defective axonal
cytoskeleton and transport (dynactin, profilin-1)

11. • Multiple recent studies have convincingly demonstrated that prolif
erating, activated nonneuronal cells such as microglia and astrocytes
importantly influence the disease course.
• A striking additional finding in ALS and most neurodegenerative
disorders is that miscreant proteins arising from gene defects in
familial forms of these diseases are often implicated in sporadic forms
of the same disorder

12. CLINICAL MANIFESTATIONS
• In the most typical forms of disease, the onset is perceived by the
patient as weakness in a distal part of one limb.
• This may be noted first as an unexplained tripping because of slight
foot drop.
• Or there may be awkwardness in tasks requiring fine finger
movements (in handling buttons and automobile ignition keys),
stiffness of the fingers, and slight weakness or wasting of the hand
muscles.
• In other words, features related to upper and to lower motor neuron
degeneration (or both) may appear insidiously in one limb.

13. • The manifestations of ALS are somewhat variable depending on whether
corticospinal neurons or lower motor neurons in the brainstem and spinal
cord are more prominently involved.
• With lower motor neuron dysfunction and early denervation, typically the first
evidence of the disease is insidiously developing asymmetric weakness,
usually first evident distally in one of the limbs.
• A detailed history often discloses recent development of cramping with
volitional movements, typically in the early hours of the morning.
• Abductors, adductors, and extensors of fingers and thumb tend to become
weak before the long flexors, on which the handgrip depends, and the dorsal
interosseous spaces become hollowed, giving rise to the “cadaveric” or
“skeletal”hand.

14. • The muscles of the upper arm and shoulder girdles are typically
involved later.
• When an arm is the first limb affected,all this occurs while the thigh
and leg muscles seem relatively normal, and there may come a time
in some cases when the patient walks about with useless, dangling
arms.
• Later the atrophic weakness spreads to the neck, tongue, pharyngeal,
and laryngeal muscles, and eventually those in the trunk and lower
extremities yield to the onslaught of the disease.

15. • Sphincteric control is well maintained even after both legs have
become weak and spastic, but many patients acquire urinary and
sometimes fecal urgency in the advanced stages of the disease.
• The abdominal reflexes may be elicitable even when the plantar
reflexes are extensor.
• Coarse fasciculations are usually evident in the weakened muscles but
may not be noticed by the patient until the physician calls attention
to them.
• Fasciculations are almost never the sole presenting feature of ALS

17. • Weakness caused by denervation is associated with progressive
wasting and atrophy of muscles and, particularly early in the illness,
spontaneous twitching of motor units, or fasciculations.
• In the hands, a preponderance of extensor over flexor weakness is
common.
• Initial denervation involves bulbar rather than limb muscles, the
problem at onset is difficulty with chewing, swallowing, and
movements of the face and tongue.
• Early involvement of the muscles of respiration may lead to death

18. • There is hyperactivity of the muscle-stretch reflexes (tendon jerks)
and, often, spastic resistance to passive movements of the affected
limbs.
• Patients with significant reflex hyperactivity complain of muscle
stiffness often out of proportion to weakness.
• Degeneration of the corticobulbar projections innervating the
brainstem results in dysarthria and exaggeration of the motor
expressions of emotion.
• The latter leads to involuntary excess in weeping or laughing
(pseudobulbar affect).

19. • Any muscle group may be the first to show signs of disease, but, as
time passes, more and more muscles become involved until
ultimately the disorder takes on a symmetric distribution in all
regions.
• Even in the late stages of the illness, sensory, bowel and bladder, and
cognitive functions are preserved.
• Even when there is severe brainstem disease, ocular motility is spared
until the very late

20. DIFFERENTIAL DIAGNOSIS
• Because ALS is currently untreatable, it is imperative that potentially
remediable causes of motor neuron dysfunction be excluded
• This is particularly true in cases that are atypical by virtue of (1) restriction to
either upper or lower motor neurons,(2) involvement of neurons other than
motor neurons, and (3) evidence of motor neuronal conduction block on
electrophysiologic testing.
• Compression of the cervical spinal cord or cervicomedullary junction from
tumors in the cervical regions or at the foramen magnum or from cervical
spondylosis with osteophytes projecting into the vertebral canal can produce
weakness, wasting, and fasciculations in the upper limbs and spasticity in the
legs, closely resembling ALS.

21. • The absence of cranial nerve involvement may be helpful in differentiation, although
some foramen magnum lesions may compress the twelfth cranial (hypoglossal) nerve,
with resulting paralysis of the tongue.
• Absence of pain or of sensory changes, normal bowel and bladder function, normal
radiologic studies of the spine, and normal cerebrospinal fluid (CSF) all favor ALS.
• Another in the differential diagnosis of ALS is mul tifocal motor neuropathy with
conduction block (MMCB), A diffuse, lower motor axonal neuropathy mimicking ALS
sometimes evolves in association with hematopoietic disorders such as lymphoma or
multiple myeloma.
• The presence of an M-component in serum should prompt consideration of a bone
marrow biopsy.

22. • Other treatable disorders that occasionally mimic ALS are chronic lead
poisoning and thyrotoxicosis. These disorders may be suggested by
the patient’s social or occupational history or by unusual clinical
features.
• Benign fasciculations are occasionally a source of concern because on
inspection they resemble the fascicular twitchings that accompany
motor neuron degeneration.
• The absence of weakness, atrophy, or denervation phenomena on
electrophysiologic examination usually excludes ALS.

23. INVESTIGATIONS
• The needle EMG is the most important study in determining
diagnostic certainty of ALS.
• Acute (denervation evidence via presence of PSW, fibrillations, and
FPs) and chronic neurogenic changes (as evidenced by decreased
MUP recruitment with rapidly firing and reduced numbers of MUPs,
as well as large amplitude, long duration MUP) is required for
diagnosis of ALS.
• MRI Brain
• MRI Spine

24. TREATMENT
• No treatment arrests the underlying pathologic process in ALS.
• The drug riluzole (100 mg/d) was approved for ALS because it
produces a modest lengthening of survival.
• Riluzole is a neuroprotective drug that blocks glutamatergic
neurotransmission in the CNS
• In one trial, the survival rate at 18 months with riluzole was similar to
placebo at 15 months.
• The mechanism of this effect is not known with certainty; riluzole may
reduce excitotoxicity by diminishing glutamate release.
• Riluzole is generally well tolerated; nausea, dizziness, weight loss, and
elevated liver enzymes occur occasionally.

25. • the mechanism of therapeutic benefit afforded by riluzole remains
undetermined.
• Several pathways have been postulated, ranging from central anti-glutaminergic
modulation of excitotoxic pathways, mitochondrial function, and changes to fat
metabolism, to peripheral axonal effects on persistent sodium channel function
and potentiation of calcium-dependent potassium currents.
• The original dose ranging trial comprising 959 patients randomly assigned to
riluzole (50 mg/day, 100 mg/day, or 200 mg/day) or placebo.
• Fang and colleagues showed that 100 mg/day of riluzole was associated with
longer survival in the last clinical stage of ALS before death (stage 4) compared
with placebo

26. • A second drug, edaravone, has also been approved by the U.S. Food
and Drug Administration
• This drug, which is believed to act as an antioxidant, is administered
via recurring monthly 10-day series of daily intravenous infusions.
• Interventions such as antisense oligonucleotides (ASO) that diminish
expression of mutant SOD1 proteinprolong survival in transgenic ALS
mice and rats are also now in clinical trials for SOD1-mediated ALS.

27. • a variety of rehabilitative aids may substantially assist ALS patients.
• Foot-drop splints facilitate ambulation by obviating the need for
excessive hip flexion and by preventing tripping on a floppy foot.
• Finge extension splints can potentiate grip.
• Respiratory support may be life-sustaining.
• For patients electing against long-term ventilation by tracheostomy,
positive-pressure ventilation by mouth or nose provides transient
(weeks to months) relief from hypercarbia and hypoxia.

28. X-Linked Spinobulbar Muscular Atrophy
(Kennedy’sDisease)
• This is an X-linked lower motor neuron disorder in which progressive
weakness and wasting of limb and bulbar muscles begins in males in
mid-adult life and is conjoined with androgen insensitivity manifested
by gynecomastia and reduced fertility.
• The underlying molecular defect is an expanded trinucleotide repeat
(-CAG-) in the first exon of the androgen receptor gene on the X
chromosome.

29. Adult Tay-Sachs Disease
• Several reports have described adult-onset, predominantly lower
motor neuropathies arising from deficiency of the enzymeβ-
hexosaminidase (hex A).
• These tend to be distinguishable from ALS because they are very
slowly progressive and in some cases may have been symptomatic for
years; dysarthria and radiographically evident cerebellar atrophy may
be prominent.

30. Spinal Muscular Atrophy
• The SMAs are a family of selective lower motor neuron diseases of early
onset.
• Despite some phenotypic variability (largely in age of onset), the defect in the
majority of families with SMA is loss of a protein (SMN, for survival motor
neuron) that is important in the formation and trafficking of RNA complexes
across the nuclear membrane.
• Neuropathologically these disorders are characterized by extensive loss of
large motor neurons; muscle biopsy reveals evidence of denervation atrophy.
• Infantile SMA (SMA I, Werdnig-Hoffmann disease) has the earliest onset and
most rapidly fatal course. In some instances, it is apparent even before birth,
as indicated by decreased fetal movements late in the third trimester.
• Though alert, afflicted infants are weak and floppy (hypotonic) and lack
muscle stretch reflexes.

31. • Chronic childhood SMA (SMA II) begins later in childhood and evolves
with a more slowly progressive course.
• Juvenile SMA (SMA III, Kugelberg-Welander disease) manifests during
late childhood and runs a slow, indolent course.
• Unlike most denervating diseases, in this chronic disorder weakness is
greatest in the proximal muscles; indeed, the pattern of clinical
weakness can suggest a primary myopathy such as limb-girdle
dystrophy.

32. Multifocal Motor Neuropathy with Conduction
Block
• In this disorder, lower motor neuron function is regionally and
chronically disrupted by focal blocks in conduction. Many cases have
elevated serum titers of mono- and polyclonal antibodies to
ganglioside GM1; it is hypothesized that the antibodies produce
selective, focal, paranodal demyelination of motor neurons.

33. Primary Lateral Sclerosis
• This rare disorder arises sporadically in adults in mid to late life.
• Clinically, PLS is characterized by progressive spastic weakness of the
limbs, preceded or followed by spastic dysarthria and dysphagia,
indicating combined involvement of the corticospinal and
corticobulbar tracts.
• Fasciculations, amyotrophy, and sensory changes are absent; neither
electromyography nor muscle biopsy shows denervation.
• On neuropathologic examination, there is selective loss of the large
pyramidal cells in the precentral gyrus and degeneration of the
corticospinal and corticobulbar projections.

34. • In its pure form, HSP is usually transmitted as an autosomal trait; most adult-
onset cases are dominantly inherited.
• There are more than 80 genetic types of HSP for which causative mutations in
more than 60 genes have been identified.
• Symptoms usually begin in the third or fourth decade, presenting as
progressive spastic weakness beginning in the lower extremities; however,
there are variants with onset so early that the differential diagnosis includes
cerebral palsy.
• HSP typically has a long survival, presumably because respiratory function is
spared. Late in the illness, there may be urinary urgency and incontinence and
sometimes fecal incontinence; sexual function tends to be preserved

41. REFERENCES
• HARRISSON'S PRINCIPLES OF INTERNAL MEDICINE, 20TH EDITION
• ADAM'S AND VICTOR'S PRINCIPLES OF NEUROLGY, 8TH EDITION
• LANCET JOURNAL
• NCBI
• WILEY
• COCHRANE LIBRARY

42. THANK YOU