1. Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a progressive neurodegenerative disease that affects upper and lower motor neurons. 2. The disease causes muscle weakness, disability, and eventually death, with annual incidence rates of 1-3 cases per 100,000 people. 3. While ALS is typically a sporadic disease, about 10% of cases are familial or genetic. The disease progresses relentlessly over time, typically beginning in the limbs or bulbar region and spreading to other areas.

1. MND/ALS

2. INTRODUCTION
• Amyotrophic lateral sclerosis (ALS), first described by Charcot in the
19th century, is a relentlessly progressive, presently incurable
neurodegenerative disorder that causes muscle weakness,
disability, and eventually death.
• Annual incidence of 1 to 3 cases per 1,00,000.
• No ethnic or racial predisposition to ALS.
• Prior to the age of 65 or 70, the incidence of ALS is higher in men
than in women, but thereafter the gender incidence is equal.
• ALS has an age distribution that peaks in the seventh to eighth
decades.
• However, ALS can occur in people in their twenties.
• ALS is most commonly sporadic.
• Genetic or familial ALS represents only 10 percent of all ALS.

3. CLINICOPATHOLOGIC FEATURES
• The UMN findings of weakness with slowness,
hyperreflexia, and spasticity result from degeneration of
frontal motor neurons located in the motor strip
(Brodman area 4) and their axons traversing the corona
radiata, internal capsule, cerebral peduncles, pontine base,
medullary pyramids, and the lateral corticospinal tracts of
the spinal cord.
• At autopsy, the dorsolateral area of the spinal cord, the
region containing the lateral corticospinal tract, is gliotic
and hardened or sclerotic to palpation.
• The LMN findings of weakness, atrophy or amyotrophy, and
fasciculations are a direct consequence of degeneration of
lower motor neurons in the brainstem and spinal cord
producing muscle denervation.

4. NEUROPATHOLOGY
• The neuropathology of ALS is characterized by
pathologic inclusions within both upper and
lower motor neurons and glia.
• Such inclusions also occur in nonmotor frontal
and temporal cortical neurons and in more
widespread areas of the brain not typically
associated with classic ALS.
• Inclusions stain positively for ubiquitin; a large
subset also stains positively for TAR DNA-binding
protein (TDP-43) and smaller subsets stain for
fused in sarcoma (FUS) protein and optineurin.
While it was once presumed to be a pure motor disorder, it has become increasingly
apparent that degeneration of other brain regions such as frontal and temporal cortical
neurons may also occur as part of the clinicopathologic spectrum of ALS.

5. SPECTRUM OF MOTOR NEURON
DISEASE
Progressive muscular atrophy —
• PMA is a progressive lower motor neuron disorder.
• When the disease remains confined to the lower motor neuron, survival may
be prolonged compared with classic ALS.
• The estimated survival in progressive muscular atrophy was approximately the
same as that of ALS. Median survival of 56 months.
• Some individuals with progressive muscular atrophy never develop clinical
upper motor neuron signs. Many, however, develop upper motor neuron signs
later in their clinical course, at which point the disease is called lower motor
neuron-onset ALS.
• Typically, upper motor neuron involvement occurred within two years of
symptom onset.
• At autopsy, patients with progressive muscular atrophy who never developed
clinically apparent upper motor neuron signs frequently have upper motor
neuron pathology, including corticospinal tract abnormalities and TDP-43
positive inclusions in motor cortex, in a pattern identical to that of ALS.

6. Primary lateral sclerosis —
• Primary lateral sclerosis is a progressive isolated UPPER MOTOR
NEURON neurodegenerative disorder.
• Compared with ALS, primarily lateral sclerosis is characterized by
slower progression, lack of weight loss, and absence of lower motor
neuron findings on examination or electromyography in the first
four years after symptom onset.
• Symptoms usually begin in the lower extremities, with loss of
fluidity in gait and spasticity and hyperreflexia on examination.
• Corticobulbar symptoms (eg, dysarthria, pseudobulbar affect)
typically develop later in the course.
• Many patients also have bladder instability and urinary retention.
• The early phase of disease has significant clinical overlap with
hereditary spastic paraparesis.
• Most, however, do develop lower motor neuron signs later in their
clinical course. This is referred to as upper motor neuron-onset ALS.
• Pure primary lateral sclerosis and upper motor neuron-dominant
ALS appear to have a more benign prognosis than typical ALS.

7. PROGRESSIVE BULBAR PALSY
• Progressive bulbar palsy is a progressive UPPER
AND LOWER MOTOR NEURON DISORDER of
cranial muscles.
• This condition may occasionally stay isolated to
the bulbar segment, but more commonly, upper
and lower motor neuron signs and symptoms
spread to involve other segments.
• This is then referred to as bulbar-onset ALS.
• There have been no reports of specific pathology
in progressive bulbar palsy

8. FLAIL ARM SYNDROME
• The flail arm syndrome (also called brachial
amyotrophic diplegia) is characterized by progressive
LOWER MOTOR NEURON weakness and wasting that
predominantly affects the proximal arm.
• It usually begins proximally and spreads distally to the
point where arm and hand function is severely
impaired.
• It is often asymmetric.
• Patients presenting with the flail arm variant of ALS
have a slower rate of progression both to the spread of
signs and symptoms in other body segments and to
development of respiratory muscle weakness.

9. FLAIL LEG SYNDROME
• The flail leg syndrome (also called the
PSEUDOPOLYNEURITIC VARIANT of ALS/motor
neuron disease) is characterized by progressive
LOWER MOTOR NEURON weakness and wasting
with onset in the distal leg.
• Patients presenting with the flail leg syndrome
have a slower rate of progression to involvement
of other body segments and of the development
of respiratory muscle weakness.

10. ALS-PLUS SYNDROME
• Some patients have all of the clinical features of ALS along
with features of other disorders such as
– Frontotemporal dementia (FTD),
– Autonomic insufficiency,
– Parkinsonism
– Supranuclear gaze paresis, and/or
– Sensory loss.
• Such patients are considered to have ALS-plus syndrome.
• In a case report, a patient with clinically definite ALS
accompanied by a supranuclear gaze disorder and an
extrapyramidal syndrome reminiscent of progressive
supranuclear palsy demonstrated diffuse TDP-43 pathology
at autopsy

11. CLINICAL SYMPTOMS AND SIGNS
• The loss of motor neurons results in the
primary clinical symptoms and signs of ALS.
• These may produce impairment affecting limb
bulbar, axial, and respiratory function.
• Initial clinical manifestation of ALS may occur
in any body segment (bulbar, cervical,
thoracic, or lumbosacral) and may manifest as
upper motor neuron or lower motor neuron
symptoms or signs.

14. • Asymmetric limb weakness is the most common presentation of ALS
(80%).
• Upper-extremity onset is most often heralded by hand weakness but may
begin in the shoulder girdle muscles.
• The "split-hand syndrome" describes a frequent pattern of weakness and
atrophy in ALS that predominantly involves the median- and ulnar-
innervated lateral (thenar) hand intrinsic muscles with relative sparing of
the medial (hypothenar) muscles.
• Lower-extremity onset of ALS most often begins with weakness of foot
dorsiflexion (foot drop), while proximal pelvic girdle onset is less common.
• 20 % of patients will have onset in the bulbar segment, which most often
presents with either dysarthria or dysphagia.
• Less common patterns of ALS onset include respiratory muscle weakness
(1 to 3 %),
• Generalized weakness in the limbs and bulbar muscles (1 to 9 %),
• Axial onset with head drop or truncal extension weakness, and weight loss
with muscle atrophy, fasciculations, and cramps.

15. Upper motor neuron symptoms
• Loss of upper motor neurons results in slowness of movement, incoordination,
and stiffness with relatively little overt weakness.
• Arm or hand upper motor neuron symptoms include poor dexterity with
resulting difficulty performing activities of daily living.
• Leg upper motor neuron symptoms manifest as a spastic gait with poor balance
and may include spontaneous leg flexor spasms and ankle clonus.
• Upper motor neuron or spastic dysarthria produces a characteristically strained
vocal quality with slow speech.
• Laryngospasm also result . This is a short-lived (usually <30 seconds) reflex
closure of the larynx that most often occurs in response to aspiration of food
particles or liquids, including saliva. The patient typically describes a squeezing
feeling in the throat accompanied by impaired inspiration and difficulty
speaking; there may be audible stridor.
• Increased masseter tone and difficulty opening the mouth. When severe, this is
referred to as trismus. At times there may be involuntary jaw clenching with
biting of the sides of the tongue and cheeks.
• Upper motor neuron dysphagia results from slow and discoordinated
contraction of the swallowing muscles, which may lead to coughing and choking.
• Axial upper motor neuron dysfunction may contribute to stiffness and imbalance

16. PSEUDOBULBAR AFFECT
• Pseudobulbar affect (also called emotional lability or emotional
incontinence) is a term that describes sudden uncontrollable outbursts of
laughter or tearfulness that occur in many patients with ALS as the disease
progresses.
• It is a result of bilateral corticobulbar tract degeneration.
• Pseudobulbar palsy may affect close to 50 percent of patients with ALS
(though not all affected need treatment for it), and it is more common in
those with the bulbar form.
• Patients should be counseled that the symptoms of pseudobulbar affect do
not reflect a psychological disorder.
• Treatment options for pseudobulbar affect include:
– The combination drug dextromethorphan-quinidine (Nuedexta) (20 mg/10 mg);
the recommended starting dose is one capsule once daily for seven days, then
increase to one capsule twice daily with periodic reassessment to determine if
continued use is necessary
– Tricyclic antidepressants such as amitriptyline 10 to 150 mg at bedtime; the
starting dose is 10 to 25 mg at bedtime, and dosing is increased slowly as needed
– Selective serotonin reuptake inhibitors such as fluvoxamine 100 to 200 mg daily.

17. LOWER MOTOR NEURON SYMPTOMS
• Loss of lower motor neurons results in weakness,
usually accompanied by atrophy and fasciculations,
Muscle cramps are also common.
• Extraocular motor neurons residing in the nuclei of the
oculomotor (CN III), trochlear (CN IV), and abducens
(CN VI) nerves are spared until very late in the disease
course.
• Patients who choose long-term mechanical ventilation
have a longer clinical course that can include
progressive difficulty with ocular motility.
• This may culminate in the locked-in state, a clinical
condition characterized by inability to move any
voluntary muscle. Such patients may be alert and
awake but completely unable to communicate.

21. COGNITIVE SYMPTOMS
• There is a well-established link between ALS and frontotemporal behavioral
and executive dysfunction that may precede or follow the onset of upper
and/or lower motor neuron dysfunction.
• Cognitive impairment includes problems with executive function, language,
and letter fluency with relative sparing of memory and visuospatial function.
• Common behavioral changes include apathy, loss of sympathy/empathy,
changes in eating behaviors, disinhibition, and perseveration.
• While most patients with ALS do not have overt dementia, some degree of
cognitive and behavioral dysfunction is present in approximately one-third to
one-half of patients and becomes increasingly common with advancing
disease.
• Approximately 15 percent of patients with ALS meet criteria for
frontotemporal dementia (FTD).
• Retrospective data suggest that ALS with FTD may be associated with shorter
survival than ALS with normal executive and behavioral function.
• ALS with FTD may be a familial disorder

22. AUTONOMIC SYMPTOMS
• Autonomic symptoms is not an initial manifestation of the disease.
• Constipation occurs frequently and is likely multifactorial.
• Delayed colonic motility has been demonstrated.
• Dysphagia for thin liquids related to pharyngeal muscle weakness
may lead to dehydration that can exacerbate constipation.
Symptoms of early satiety and bloating consistent with delayed
gastric emptying also occur as the disease progresses .
• Urinary urgency without incontinence is common, while
incontinence is uncommon.
• Some complain of excessive sweating, abnormal sympathetic
activity with hyperhidrosis in early ALS and a reduction in sweat
production as the disease progresses have been demonstrated in
one study.

23. PARKINSONISM AND SUPRANUCLEAR
GAZE PALSY
• Extrapyramidal symptoms and signs of
parkinsonism may precede or follow the
upper and lower motor neuron symptoms.
• These extrapyramidal features may include
facial masking, tremor, bradykinesia, and
postural instability.
• At times, a supranuclear gaze abnormality
occurs that is similar to that seen in
progressive supranuclear palsy.

24. SENSORY SYMPTOMS
• Sensory symptoms may occur in 20 to 30 % of patients with ALS,
but the sensory examination is usually normal.
• It is common for patients with ALS, particularly those with distal
limb onset of symptoms, to complain of tingling paresthesia.
• When queried regarding sensory loss, these patients typically will
deny loss of sensation, and physical examination does not detect
objective sensory loss.
• At times, however, objective sensory loss may occur as part of an
ALS-plus syndrome and may precede or follow motor symptoms.
• Electrophysiologic studies may demonstrate reduction of
amplitudes on sensory nerve conduction and/or slowing of dorsal
column conduction on somatosensory evoked potential testing,
even in patients without sensory findings on examination.
• Autopsy may demonstrate evidence of degeneration within sensory
pathways in individuals with and without sensory loss

25. PAIN
• Nociceptive pain in ALS can arise from a variety of causes
that include reduced mobility, muscle cramps, muscle
spasticity, and comorbid conditions.
• Reduced mobility predisposes to skin breakdown and
musculoskeletal pain.
• Respiratory symptoms and interventions can lead to pain,
with discomfort and skin breakdown from noninvasive
ventilation masks, and irritation from suctioning of
secretions and weighing and pulling of ventilator hoses.
• In addition, pain with neuropathic features (eg,
paresthesia, allodynia, hyperalgesia) may affect some
patients with ALS.
• Although generally of mild to moderate intensity, pain in
the later stages of ALS can be severe enough to necessitate
treatment with analgesic and sedative medications

26. CLINICAL PATTERNS OF PROGRESSION
• ALS is a relentlessly progressive disorder with a clinical course that
is nearly always linear, with a relatively constant slope.
• While the rate of progression between individuals is variable, the
history generally reflects gradual and progressive worsening over
time without intervening remissions or exacerbations.
• Symptoms initially spread within the segment of onset and then to
other regions in a relatively predictable pattern .
• In patients with unilateral arm onset, the most common
(approximately 60 to 70 percent of patients) pattern of spread is to
the contralateral arm, then to the ipsilateral leg, then to the
contralateral remaining leg, and then to the bulbar muscles.
• In patients with unilateral leg onset, the most common
(approximately 60 to 70 percent of patients) pattern of spread is to
the contralateral leg, then to the ipsilateral arm, then to the
contralateral arm, and then to bulbar muscles.
• In patients with bulbar onset, the most common pattern of spread
is to one arm and then to the contralateral arm

27. Diagnostic criteria
• The clinical standard for the diagnosis of ALS is the revised
El Escorial World Federation of Neurology criteria, also
known as the Airlie House criteria.
• These criteria allow assignment of diagnostic certainty and
were designed for research purposes to ensure appropriate
inclusion of patients into clinical trials.
• Updated El Escorial criteria from 2015 suggest the following
as the minimum necessary for the diagnosis of ALS
– Progressive upper and lower motor neuron symptoms and signs
in one limb or body segment.
– Clinical lower motor neuron signs in one segment or
electrodiagnostic evidence (electromyography [EMG]) in two or
more segments.
In this context, electrodiagnostic findings may manifest as either the
chronic changes of neurogenic potentials or the acute changes of
fibrillations or positive sharp waves.

29. RESTRICTED PHENOTYPES OF ALS
1. Progressive muscular atrophy is a progressive disorder that is
clinically limited to lower motor neurons. If two regions of the
body are involved clinically or electrophysiologically, then ALS
can be diagnosed. If upper motor neuron signs appear over time,
the disease is referred to as lower motor neuron-onset ALS.
2. Primary lateral sclerosis may be its own disorder, rather than a
restricted form of ALS, although there remains some controversy
about this. It is a progressive disorder that is clinically limited to
the upper motor neurons. Definite primary lateral sclerosis is
present when only upper motor neuron signs are present for at
least four years since symptom onset. If lower motor neuron signs
appear before this time, then the diagnosis converts to upper
motor neuron-onset ALS.

30. 3. Progressive bulbar palsy is a progressive motor neuron disorder of
cranial muscles. When both upper and lower motor neuron findings are
present, the disorder meets criteria for the diagnosis of ALS. In nearly all
cases, upper and/or lower motor neuron abnormalities will eventually
spread to limb, axial, and/or respiratory motor neurons, and these
patients may meet criteria for ALS. In this circumstance, the designation
is changed to bulbar-onset ALS.
4. Flail arm syndrome presents with progressive lower motor neuron
weakness of the arms. Similarly, flail leg syndrome involves lower motor
neuron weakness of the legs. When both arms or both legs are involved,
this is similar to progressive muscular atrophy, as described above, and
can be called ALS.
5. ALS-plus syndrome is the designation for patients who meet the clinical
criteria for ALS and also have features of other disorders that have
historically excluded the diagnosis of ALS, such as autonomic
insufficiency, parkinsonism, supranuclear gaze paresis, and cerebellar
ataxia.

31. ELECTRODIAGNOSTIC STUDIES
Electromyography —
• The EMG findings in ALS combine features of acute and chronic
denervation and reinnervation .
– Acute denervation findings include fibrillations and positive sharp waves.
The Awaji Island criteria allowed fasciculations in muscles with neurogenic
change to be considered equivalent to fibrillations and positive sharp waves.
– Fasciculation potentials may appear in denervated muscle and represent
spontaneous firing of motor units that are not voluntarily recruited.
– Chronic denervation and reinnervation findings include large-amplitude, long-
duration, complex motor unit action potentials (MUAPs) with neurogenic
recruitment and a reduced interference pattern. Instability of MUAPs
indicative of recent reinnervation is considered an important indication of
ongoing denervation and reinnervation by the Awaji criteria.
– The EMG abnormalities noted in muscles of patients with ALS are not
pathognomonic for the disease, but can be seen in any disease causing
chronic and ongoing denervation. However, the diagnosis of ALS should be
suggested by the observation of similar abnormalities in multiple muscles of
proximal and distal limbs, in the absence of radiologic demonstration of
corresponding nerve root compression considered significant enough to cause
the abnormality.

32. Nerve conduction studies
• Sensory and motor nerve conduction studies are most
often normal in ALS, though compound muscle action
potential (CMAP) amplitudes may be reduced in
severely atrophic and denervated muscles.
• Motor unit number estimation is a nerve conduction-
based method that assesses the number of viable
motor axons innervating small hand or foot muscles.
• Although this technique has applications to many
diseases, it has been applied most successfully to ALS.
• Motor unit numbers drop prior to the onset of clinical
weakness, and changes in this measure can be used as
an outcome measure in clinical trials.

33. Repetitive nerve stimulation
• Repetitive nerve stimulation is a nerve conduction technique that
assesses the integrity of the neuromuscular junction and is useful
for the diagnosis of disorders such as myasthenia gravis and the
Lambert-Eaton myasthenic syndrome. Thus, repetitive nerve
stimulation may be useful if these conditions are a consideration in
the differential diagnosis during the evaluation of suspected motor
neuron disease.
• Repetitive nerve stimulation may be normal or abnormal in patients
with ALS, since the physiology of ongoing denervation with
reinnervation can cause unstable transmission through the
neuromuscular junction, which manifests as an abnormal
decrement in the CMAP amplitude. Occasionally, the presence of a
decrement on repetitive stimulation can cause diagnostic
confusion.

34. Single-fiber EMG
• Single-fiber EMG is used to measure jitter (an evaluation of
neuromuscular junction function) and fiber density (an
electrophysiologic assessment of reinnervation following
denervation).
1. Jitter may be abnormally increased in the presence of ongoing
reinnervation and newly formed, unstable neuromuscular
junctions.
2. Increased fiber density is a nonspecific finding that may be
present in any muscle that has undergone denervation and
reinnervation. Collateral sprouting increases the number of
muscle fibers within the territory of reinnervated motor units.
As a result, adjacent muscle fibers within any region of a
denervated/reinnervated muscle are more likely to be part of
the same motor unit.

35. Transcranial magnetic stimulation
• External stimulation with a magnet over the motor cortex, cervical spine,
and lumbosacral spine produces a CMAP that can be recorded from the
surface. The difference between the latency of the response elicited by
cranial versus cervical or cranial versus lumbosacral stimulation is called
the central motor conduction time and is a reflection of the integrity of
central motor pathways.
• Slowing of central motor conduction time has been reported in patients
with ALS.
• Another measure, cortical hyperexcitability, may be an early and specific
feature of ALS.
• Transcranial magnetic stimulation (TMS) remains a largely experimental
technique and is not used or routinely available for clinical diagnosis.
However, correlation with clinical upper motor neuron signs has been
noted. One preliminary study found that the TMS threshold tracking
technique to detect cortical hyperexcitability in patients with suspected
ALS had a reasonable sensitivity and specificity (73 and 81 percent,
respectively) to distinguish ALS from non-ALS disorders at an early stage of
disease.

36. Neuroimaging
• Neuroimaging has traditionally been used to exclude other possible
diagnoses in the evaluation of suspected ALS.
• Magnetic resonance imaging (MRI) is the preferred modality, unless
there is a contraindication.
• Brain MRI should be performed whenever bulbar disease is present.
Cervical and lumbosacral spine MRI can be used to evaluate lower
motor neuron disease in the arms and legs.
• When evaluating upper motor neuron disease, MRI should be
performed in all segments rostral to the clinical findings; this
includes the brain, cervical spine, and thoracic spine when upper
motor neuron findings are in the legs.
• Conventional MRI is usually normal in ALS, although increased
signal in the corticospinal tracts on T2-weighted and fluid-
attenuated inversion recovery images and hypointensity of the
motor cortex on T2-weighted images have been reported.

37. • Magnetic resonance spectroscopy provides biochemical and metabolic
information in the form of a spectrum obtained in a region of interest or in the
whole brain.
• The three major peaks observed on an in vivo proton magnetic resonance
spectrum are from N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr).
• NAA is thought to correlate with neuronal integrity.
• The balance of evidence has shown reduced NAA levels or lower ratios of NAA:Cr,
NAA:Cho, or NAA:Cr+Cho in the motor cortex and corticospinal tract of patients
with ALS.
• Diffusion tensor imaging is a structural neuroimaging technique that measures the
extent and direction of water diffusion. Diffusion of brain water has been shown
to have strong directionality (anisotropy) in white matter.
• Diffusion anisotropy is the result of restricted diffusion of water molecules across
myelinated white matter fibers compared with diffusion along the fibers.
• Patients with ALS have been shown to have decreased fractional anisotropy and
increased mean diffusivity in the corticospinal tracts at multiple levels and in the
corpus callosum.

38. Laboratory testing
• Creatine phosphokinase may be elevated up to approximately 1000 units/L on the basis of denervation.
• If serum calcium level Elevated , the serum parathyroid hormone level should be checked. ALS is rarely associated with
primary hyperparathyroidism.
• Identification of a serum paraprotein should prompt further work-up with a 24-hour urine protein electrophoresis, a
skeletal survey, and computed tomography (CT) of the chest, abdomen, and pelvis to look for myeloma and lymphoma.
• In some cases, testing for Lyme disease may be appropriate in regions where it is endemic. This is particularly important
in the following situations:
•When the clinical manifestations include radicular or neuropathic pain and/or unilateral peripheral facial palsy
•When sensory signs and symptoms are present
•When MRI of the brain demonstrates multiple white matter signal hyperintensities
•When MRI of the brain and spine demonstrates meningeal signal change and/or enhancement
• Testing for HIV may be appropriate, particularly in younger patients.
• Screening for heavy metals, Only lead intoxication has been reported to cause a condition resembling lower motor
neuron-predominant ALS. This condition has been largely eliminated through monitoring of occupational exposure.
• Anti-glutamic acid decarboxylase (GAD) antibody testing may be indicated in the setting of significant upper motor
neuron disease.
• Testing for the antibodies found in myasthenia gravis (acetylcholine receptor antibodies and muscle-specific tyrosine
kinase [MuSK] antibodies) and Lambert-Eaton myasthenic syndrome (voltage-gated calcium channel antibodies) is
appropriate in the right clinical setting and is particularly appropriate in patients with bulbar dysfunction or any ocular
motility disturbance.
• Lumbar puncture and CSF analysis should be performed if there is clinical suspicion for Lyme disease, HIV infection, or
chronic inflammatory demyelinating polyneuropathy.
• Lumbar puncture for CSF analysis that includes cytology and a search for systemic malignancy should be considered in
lower motor neuron disorders
• Elevated levels of CSF neurofilaments are found in patients with ALS, suggesting a possible future role for neurofilaments
as CSF biomarkers of ALS

39. • Genetic testing — familial ALS (FALS) accounts
for approximately 10 percent of all ALS cases.
Autosomal dominant inheritance is the most
common pattern in hereditary ALS.

40. DIFFERENTIAL DIAGNOSIS

42. Multifocal motor neuropathy
• Multifocal motor neuropathy (MMN), also known as MMN with
conduction block, is characterized by lower motor neuron signs that
often present in a bibrachial pattern.
• The typical clinical presentation of MMN is one of subacute onset
with asymmetric weakness and lower motor neuron signs
producing arm and hand weakness without associated sensory loss.
• The neuronal involvement in MMN is typically patchy, with some
nerves unaffected and others severely involved. Motor nerve
conduction studies usually show evidence of conduction block.
• Sensory conduction through the same segment of nerve is normal.
Elevated titers of anti-GM1 antibodies are present in 30 to 80
percent of patients.
• MMN is a particularly important diagnosis to consider, as the
condition is treatable with intravenous immune globulin and other
forms of immunosuppression.

43. • Cervical radiculomyelopathy — Cervical spondylosis with nerve root compression
can cause the combination of lower motor neuron signs at the level of abnormality
with upper motor neuron signs below it. This condition often includes dermatomal
or distal sensory abnormalities and sphincter dysfunction,
• Benign fasciculations — Spontaneous fasciculations may occur in up to 70 percent
of people. A smaller proportion of this group will experience relatively frequent
fasciculations that may be widespread or relatively focal and may be accompanied
by cramps. Long-term follow-up of patients with excess fasciculations who have a
normal examination and normal electromyography (EMG) suggests that this is a
truly benign condition and does not confer an increased risk for the development
of motor neuron disease.
• Inflammatory myopathy — Weakness of voluntary muscles as well as dysphagia
may occur in all of these conditions. Polymyositis and dermatomyositis usually
present with proximal weakness including neck extensor weakness. Inclusion body
myopathy often presents with weakness in the quadriceps and weakness in the
finger flexors that is out of proportion to intrinsic hand muscle weakness.
• Monomelic amyotrophy — Monomelic amyotrophy, also known as focal
amyotrophy, is a condition that presents clinically with early onset of focal atrophy
and weakness, most commonly of a single hand and arm, and rarely of a leg.

44. • Hereditary spastic paraplegia — Hereditary spastic paraplegia is a large group of inherited
neurologic disorders in which the prominent feature is a progressive upper motor neuron spastic
weakness of the legs that is similar to that seen in ALS and primary lateral sclerosis. , have urinary
urgency and high arched feet. Some forms of hereditary spastic paraplegia may be associated with
cerebellar dysfunction, optic atrophy, and peripheral neuropathy (SPG7), or with cognitive decline,
upper-extremity weakness, dysarthria, nystagmus, and thinning of the corpus callosum on MRI
(SPG11).
• Spinobulbar muscular atrophy — An expansion of an unstable cytosine-adenine-guanine (CAG)
tandem repeat in exon 1 of the androgen receptor gene on chromosome Xq11-12 occurs in men
with spinobulbar muscular atrophy (also known as Kennedy disease). This X-linked disorder is
characterized by onset from ages 20 to 60 years of slowly progressive weakness and atrophy
affecting facial, bulbar, and limb muscles that may be predominantly asymmetric, symmetric,
proximal, or distal. There is degeneration of lower motor neurons in brainstem nuclei and spinal
cord. Associated endocrine disturbances include late-onset gynecomastia, defective
spermatogenesis, and a hormonal profile consistent with androgen resistance. The androgen
receptor gene in these men contains an expansion in the number of glutamine repeats in the N-
terminal region from the usual 20 glutamines to >40 repeats. The pathogenesis is not fully
understood, but accumulating evidence suggests that neuronal degeneration and death are related
to accumulation of the toxic expanded androgen receptor.
• Myasthenia gravis — Myasthenia gravis occasionally can present as a bulbar syndrome with
dysphagia and dysarthria but without the ptosis or ocular motility disturbance that commonly
accompany myasthenia. This presentation can mimic bulbar-onset ALS. The absence of upper or
lower motor neuron bulbar signs, the presence of ocular findings, and a history of diurnal variation
of symptoms weigh in favor of myasthenia gravis. In addition, it is more common for myasthenia to
present with ptosis and ocular dysmotility, in which case it is unlikely to be confused with bulbar
ALS.
• Hyperthyroidism — There is no evidence of an association between hyperthyroidism and motor
neuron disease. However, clinical features in patients with thyrotoxicosis may include upper motor
neuron signs related to pyramidal tract dysfunction and lower motor neuron signs related to a
peripheral neuropathy; these may overlap with those of ALS

45. OTHERS
●Adult-onset spinal muscular atrophy
●Late-onset Tay-Sachs disease (GM2 gangliosidosis)
●Motor neuron syndromes with
lymphoproliferative disorders
●Motor neuron syndromes in lung, breast, and
other cancers
●Radiation brainstem injury/radiation myelopathy
●Intraspinal lesions (eg, syringomyelia,
syringobulbia, or tumor)

46. RILUZOLE
• Riluzole is the only known drug to have any impact on survival in ALS.
• The evidence that riluzole is beneficial comes from two multicenter
randomized trials:
– In a prospective, double-blind, placebo-controlled trial in 155 outpatients with ALS,
survival at 12 months was significantly higher for patients receiving riluzole (100
mg/day) compared with controls (74 versus 58 percent). For the subset of patients
with bulbar-onset ALS, an even greater advantage for survival at 12 months
emerged for the riluzole group (73 versus 35 percent).
– In a larger follow-up trial, 959 patients with clinically probable or definite ALS of
less than five years duration were randomly assigned treatment with riluzole (50
mg, 100 mg, or 200 mg daily) or placebo. After a median follow-up of 18 months,
the primary outcome of survival without tracheostomy was significantly higher for
the riluzole-treated group (100 mg/day) compared with controls (57 versus 50
percent, adjusted relative risk 0.65, 95% CI 0.50-0.85). Functional measures did not
differ significantly among the groups.
• Recommend riluzole 50 mg twice daily for patients with ALS.
• Mechanism of action of riluzole are thought to
1. Reduce glutamate-induced excitotoxicity:
2. Inhibition of glutamic acid release,
3. Noncompetitive block of N-methyl-D-aspartate (NMDA) receptor mediated
responses, and
4. Direct action on the voltage-dependent sodium channel.

47. PATIENTS MOST LIKELY TO BENEFIT
FROM TREATMENT WITH RILUZOLE
• Definite or probable ALS by El Escorial criteria,
in whom other causes of progressive muscle
atrophy have been ruled out.
• Symptoms present for less than five years.
• Vital capacity (VC) greater than 60 percent of
predicted.
• No tracheostomy.

48. PATIENTS FOR WHOM NO
RANDOMIZED DATA SUPPORT THE
USE OF RILUZOLE
• Suspected or possible ALS by El Escorial criteria
• Symptoms present for more than five years
• VC less than 60 percent of predicted
• Tracheostomy for prevention of aspiration only
(ventilator independent)
Expert consensus suggests riluzole is of uncertain benefit
in patients who have the following conditions:
 Tracheostomy required for ventilation
 Other incurable disorders
 Other forms of anterior horn cell disease

49. • Riluzole is well tolerated, with the most significant adverse effects
being gastrointestinal and hepatic.
• The most common adverse effects of riluzole are asthenia,
dizziness, gastrointestinal disorders, and elevations in liver enzyme
activities.
• Neutropenia is extremely rare.
• Elevation of the liver transaminases can be expected with riluzole
treatment. At least one alanine aminotransferase (ALT) level above
the upper limit of normal (ULN) will occur in approximately one-half
of patients treated with riluzole.
• Liver function tests are indicated monthly for the first three months
of riluzole treatment and every three months thereafter.

50. EDARAVONE
• Edaravone is a free radical scavenger that is thought to reduce oxidative
stress, which has been implicated in the pathogenesis of ALS.
• Edaravone was found to slow functional deterioration in some patients
with ALS, as observed in randomized controlled trials:
• Edaravone was approved in 2015 for the treatment of ALS in Japan and
Korea, and received US Food and Drug Administration (FDA) approval for
all people with ALS in May 2017 to treat patients with ALS in the United
States. While the evidence for the benefit of edaravone is clearest in
patients with early ALS.
• Edaravone treatment is an adjunct to riluzole for all patients with ALS.
• Edaravone 60 mg is given by intravenous infusion over 60 minutes, started
with daily infusion for 14 days, followed by 14 days off treatment.
Subsequent treatment cycles involve daily edaravone 60 mg infusions on
10 days within a 14-day period, followed by 14 days off treatment.
• The most frequent adverse reactions among subjects treated
with edaravone in clinical studies were injection-site contusion, gait
disturbance, and headache.
• Edaravone contains sodium bisulfite, which may cause allergic reactions
including asthmatic episodes in susceptible individuals.