Diagnosis and clinical management of amyotrophic lateral sclerosis

1. Diagnosis and Clinical Management of
Amyotrophic Lateral Sclerosis and Other
Motor Neuron Disorders
By Dr Rzgar hamed abdwl

3. Jean-Martin Charcot (1825–1893)
1869

8. Motor neuron diseases comprise a clinical spectrum and are characterized by
progressive weakness resulting from degeneration of motor neurons of the brain,
brainstem, and spinal cord.

11. AMYOTROPHIC LATERAL SCLEROSIS
* Is the most common in adults.
* Painless progressive weakness (Classic ALS)
* The spinal form of ALS is most common: onset in a distal limb with rostrocaudal
and contralateral spread eventually involving other limbs.
* 20% to 30% of patients present with bulbar onset.
* A small percentage of patients present with respiratory onset or frontotemporal
dementia.
* Diagnosis may be delayed for about 1 year
* The clinical features of ALS mirror dysfunction of the UMNs and LMNs.
• LMN S&S: weakness, fasciculations, and atrophy
• UMN S&S: spasticity, hyperreflexia, spreading of reflexes, and pathologic
reflexes.
* A retained reflex in a weak limb is considered abnormal and is an important
clinical clue

12. * Bulbar UMN signs include exaggerated gag reflex, snout reflex, pseudobulbar
affect, and forced yawns.
* Cervical UMN signs: include Hoffmann, Tromner, and finger flexor reflexes.
* Thoracic UMN signs: include the loss of the superficial abdominal reflex.
* Lumbosacral UMN signs: include an extensor plantar response or its equivalent.
* The presence of sensory loss or bowel/bladder dysfunction may suggest an
alternative etiology.
* Evidence of cognitive dysfunction leads to consideration of an ALS spectrum
disorder.

23. Disease Course
* Median survival in ALS is 20 to 48 months from the time of symptom onset although 10% of
patients can live longer than 10 years.
* The mean age of onset is around 55 years, although ALS can affect the extremes of age.
* Incidence: 1.4 per 100,000 people,
* prevalence : 5 per 100,000 people in the United States
* Up to 15% of patients will have frontotemporal dementia,
* 50% showing some evidence of executive dysfunction.

30. ALS Regional Variants
* Classic clinical presentations for
sporadic ALS include
- limb onset (about two thirds)
- bulbar onset (about one-third)
- pure lower motor neuron (5%)
*Some patients have disease isolated to
single spinal regions for years , These
potentially slower progressing regional
variants include:
1- Brachial amyotrophic diplegia (BAD)
2- Leg amyotrophic diplegia (LAD)
3- Isolated bulbar ALS (IBALS)

33. Classic ALS

34. Progressive
muscular atrophy

35. Pathology
* amyotrophy (muscle loss) and lateral sclerosis (involvement of the lateral
corticospinal tracts).
* Anterior nerve roots are atrophied on gross examination.
* Motor neuron cells undergo degeneration in the spinal cord, cranial motor nuclei
in the brainstem, and motor cortex.
* Cytoplasmic eosinophilic intracellular inclusions, called Bunina bodies, are found
in the spinal cord and brainstem
motor
* Cytoplasmic ubiquitin-positive skein like inclusions, of which transactive response
DNA-binding protein 43 (TDP-43) is the major protein component, are found in
anterior horn cells.
* These inclusions are also found in the frontal and temporal cortex, hippocampus,
and striatum, sharing pathologic findings with frontotemporal dementia.

38. Pathophysiology
* both neuronal and non-neuronal mechanisms.
1- In neuronal cells, protein aggregation of misfolded SOD1, TDP-43, FUS, and RNA
foci is thought to impair normal cell functioning.
* Impairment in protein degradation via the ubiquitin proteasome system may
further lead to cell dysfunction.
* Additionally, as the cells undergo stress, stress granules containing TDP-43 or FUS
can form, allowing prionlike domains to form protein aggregates.
* Proteins such as TDP-43 and FUS that are mislocalized to the cytoplasm may
cause RNA toxicity.
* Finally, deficiencies in cytoskeletal function impair cellular transport.
2- Non-cell autonomous mechanisms are supported by studies of glia, microglia,
and astrocytes

40. Diagnostic Approach
* Electrodiagnostic testing assesses for the presence of LMN dysfunction and excludes peripheral
nerve disorders, including multifocal motor neuropathy (MMN) with conduction block.
* NCS typically show a pattern of normal sensory responses with reduced motor amplitudes and
a split-hand pattern of involvement, in which the compound muscle action potential (CMAP)
amplitude recorded from thenar and first dorsal interosseus muscles is reduced to a greater
extent than that of the hypothenar muscles.
* Post-exercise motor conduction studies are recommended with this pattern and should be
unchanged in the setting of a motor neuron disease.
* EMG reveals enlarged polyphasic motor unit action potentials activating in a reduced
recruitment pattern (chronic motor axon loss pattern),a result of reinnervation of muscle fibers
by neighboring motor nerve branches from surviving anterior horn cells.

41. * Moment-to-moment amplitude variation, if seen, indicates ongoing denervation
and reinnervation and suggests a progressive process..
* At rest, muscles show abnormal spontaneous activity, including fibrillation
potentials and fasciculation potentials, the latter being abnormal only in the
presence of fibrillations or chronic motor axon loss.
* Abnormalities on EMG may be seen in muscles before clinical signs.
* Testing should sample muscles in multiple myotomes in three regions (cervical,
thoracic, lumbosacral) and cranial muscles, if clinically affected
* Mid thoracic paraspinals followed by lower thoracic paraspinals showed the
highest diagnostic sensitivity.

49. Treatment
* Riluzole has been shown to confer a 2- to 3-month survival benefit, which may
be greater in those with bulbar onset, younger age at onset, and longer diagnostic
delay.
* Riluzole is typically well tolerated, although liver function monitoring is required
and some patients report gastrointestinal side effects.
* On May 5, 2017, the US Food and Drug Administration (FDA) approved
edaravone, but still its benefit has not approved.
* The only other FDA-approved therapy for ALS is the use of Nuedexta for
pseudobulbar affect (bouts of sustained laughter or crying). Nuedexta is a
combination medication containing dextromethorphan and quinidine.

50. Symptom Management and End-of-Life Care in Amyotrophic Lateral Sclerosis
1- SIALORRHEA:
• more than 70% of patients with ALS treated with atropine, glycopyrrolate, or
amitriptyline reported these modalities were helpful.
• Botulinum toxin have great promise in patients resistant to conventional medical
( bilateral parotid and submandibular glands
• Thick secretions who had failed anticholinergic therapy and were treated with
either propranolol 10 mg twice a day or metoprolol 25 mg twice a day found that
75% of patients reported decreased secretions
• Drinking papaya or pineapple juice and reducing caffeine, milk, or alcohol have
been anecdotally suggested
• Radiation therapy for medically refractory sialorrhea reduced salivary production;
but side effects included erythema, sore throat, and nausea.

52. 2- PSEUDOBULBAR AFFECT
* Pseudobulbar affect (PBA) affects 20% to 50% of patients with ALS, especially in
patients with bulbar onset.17 The characteristics of PBA include uncontrolled
laughter or crying, often with minimal or no provocation.

53. 3- SLEEP DISRUPTION
* Multifactorial
* mirtazapine (15 mg at bedtime) can be especially helpful.
* Zolpidem tartrate (10 mg qhs) is often effective and preferred because of the low
risk of respiratory depression.
* Alternative pharmacologic agents, such as melatonin
4- FATIGUE
* reported in 44% to 83% of patients , multifactorial
* Modafinil in dosages ranging from 100 to 300 mg daily resulted in a statistically
significant improvement
5- PAIN
* reported in 57%to 72% of patients
* NSAIDs , nonopioid analgesics, opioids, muscle relaxants, quinine sulfate,
gabapentin, steroids, botulinum toxin, and physical therapy.

54. 6- SPASTICITY
* Common medications used to treat spasticity in patients with ALS include
baclofen, tizanidine, benzodiazepines, and dantrolene.
7- Laryngospasm
* up to 19% of patients have reported it in later stages.
* Common causes of laryngospasm in ALS are liquid or saliva in contact with the
larynx, acid reflux, smoke, strong smells, emotion, alcohol, cold bursts of air, and
even spicy foods.
* Nonpharmacologic measures : upright position of the upper body, fixation of the
arms to stabilize the body, breathing through the nose, swallowing repetitively, and
breathing with slow exhalation through the lips have been reported to shorten
episodes.
* If no benefit benzodiazepines twice a day or 3 times a day can be used.
* Antacid

55. 8- Jaw Quivering/Cheek Biting
* Precipitated by pain, anxiety, or cold.
• Jaw clenching can be severe enough to interfere with oral hygiene.
9- Edema :
• Elevation and mobility
• Diuretics are avoided unless edema is severe because fluid overload is not the
issue, patients with ALS already have trouble with maintaining good hydration,
and diuretics worsen muscle cramps.

56. 10- Constipation and Urinary Urgency
* Autonomic symptoms have been reported in up to 29% of patients with ALS.
* Changes in the intermediolateral columns and the Onuf nucleus provide an
anatomic explanation.
constipation :are multifactorial and include reduced mobility, reduced fluid and
food intake, and medications, such as anticholinergics, tricyclic antidepressants,
narcotics, muscle relaxants, and sedatives.
* TX : dietary fiber and water , Fiber laxatives (methylcellulose, bran, psyllium) are
bulk forming agents , Stool softeners should be recommended on a daily basis
* Stimulant or irritant laxatives like senna, cascara, and bisacodyl tablets and
suppositories should be used at the lowest effective dose and not in slowly
progressive disease as they can cause an atonic colon if used for years.
* Lactulose and polyethylene glycol are effective osmotic agents.
* More intensive treatments, such as enemas, magnesium citrate, and manual
disimpaction, are last resorts.

58. 11- Depression and Anxiety:
* the prevalence of mild and
severe depression was 29%
and 6%, respectively

59. 12- NUTRITION:

60. 13- RESPIRATORY INSUFFICIENCY

62. AMYOTROPHIC LATERAL SCLEROSIS SPECTRUM DISEASES
Pure Upper Motor Neuron:
Primary Lateral Sclerosis
* a slowly progressive disorder of the UMNs
* 4% of motor neuron disease cases.
* Four-limb spasticity, often beginning in the lower limbs symmetrically; although a
minority of patients have a bulbar-onset presentation with dysarthria, dysphagia,
and pseudobulbar affect.
* Urinary urgency
* ocular movement abnormalities may be seen.
* Weakness may develop, although patients will often maintain antigravity
strength.
* Mild denervation may be seen on EMG.
* The mean onset age is around 59 years and the 10-year survival rate is 71.1%.

63. Pure Lower Motor Neuron:
Progressive Muscular Atrophy
* Represents about 3% of all cases of motor neuron disease.
* Patients present with LMN features (weakness, atrophy, fasciculations,
and hyporeflexia) distally and asymmetrically.
* Spread of the disease is common, and bulbar symptoms can develop
later in the disease course.
* One-third of patients will develop UMN features within 2 years.
* Prognosis : matter of debate

64. AMYOTROPHIC LATERAL SCLEROSIS MIMICS
1- Spinobulbar Muscular Atrophy (Kennedy disease)
* a progressive disorder of the anterior horn cells
* Proximal limb and bulbar weakness with onset in the forties.
* An X-linked recessive disease
* symptoms of cramps and tremor may precede weakness.
* Patients may have endocrine abnormalities, including gynecomastia, diabetes mellitus, and
reduced fertility.
* Perioral fasciculations are common, and the tongue has characteristic scalloping and midline
deep furrowing.
* Creatine kinase is elevated, with a mean of greater than 1000 IU/L.
* Clinical sensory loss with sensory neuronopathy on electrodiagnostic testing are characteristic
features.
* Diagnosis can be confirmed with genetic testing demonstrating 40 to 62 CAG repeats.
* Survival is typically 2 to 3 decades following symptom onset, and although spinobulbar
muscular atrophy

65. 2- 5q Spinal Muscular Atrophy
* autosomal recessive degenerative disorder of the anterior horn cells often
caused by a mutation in the survival of motor neuron (SMN) gene on chromosome
5q13.
* Two forms of SMN exist, the telomeric SMN1 and the centromeric SMN2, which
vary by five nucleotides.
* SMN2 is only found in humans.
* SMN2 has a variation in exon 7 that prevents production of the full-length SMN1
protein; however, SMN2 is able to form a functional SMN protein in about 10% of
transcripts.
* While spinal muscular atrophy results from SMN1 deficiency, SMN2copy number
is felt to be one determinant and modifier of
the clinical phenotype severity.
* Hypotonia and weakness are clinical hallmarks.

67. * The pattern of weakness is symmetric and proximal, affecting the lower more than upper
limbs.
* Bulbar and respiratory involvement occurs.
* Spinal muscular atrophy can present anytime from infancy to adulthood, and five clinical
phenotypes are described
* In December 2016, the FDA approved nusinersen for the treatment of spinal muscular
atrophy.
An antisense oligonucleotide, the drug leads to increased production of SMN by promoting exon
7 inclusion from SMN2.

68. Non-5q Spinal Muscular Atrophies/Hereditary Motor Neuropathies
* Are rare, comprising less than 5% of spinal muscular atrophy,
* classified as follows:
- Distal spinal muscular atrophy/distal hereditary motor neuropathies: AR and AD
inheritance
- Proximal spinal muscular atrophy
- non-5q spinal and bulbar muscular atrophies/spinal muscular atrophy-plus types
AR and X-linked

69. * Distal spinal muscular atrophy and distal hereditary motor neuropathies refer to
the same disorder, although the names imply a different source of pathology, eg,
motor nerves versus anterior horn cells.
* They are characterized by slowly progressive length-dependent weakness.
* Symptoms present before the third decade of life.
* Function in the recurrent laryngeal nerve distribution may be affected, but other
bulbar functions are spared.
* Electrodiagnostic assessment demonstrates distal chronic motor axon loss
changes.
* Sparing of sensory fibers differentiates distal spinal muscular atrophy/distal
hereditary motor neuropathies from forms of Charcot-Marie-Tooth disease.

70. * Additionally, the EMG presence of chronic motor axon loss excludes distal
myopathy as the underlying cause of weakness.
* Patients with distal spinal muscular atrophy/distal hereditary motor
neuropathies should also have absent or reduced reflexes; however, some types
are recognized to have corticospinal tract features and are allelic with some genetic
forms of ALS (eg,DCTN1, SETX).

71. * Proximal spinal muscular atrophies are a phenotypically diverse group of
disorders that are characterized by proximal weakness affecting the lower more
than upper limbs.
* This group of disorders can present from infancy to adulthood.
* Genetic overlap exists with allelic disorders to ALS (SETX, VAPB), muscular
dystrophy (LMNA), and Sandhoff disease (HEXB).
*
The non-5q spinal and bulbar muscular atrophies are a group of disorders sharing
features of weakness in combination with other symptoms, including
arthrogryposis (GLE1), pontocerebellar hypoplasias (VRK1, EXOSC3), pontobulbar
palsy, and sensorineural hearing loss (RFT2).

72. Monomelic Amyotrophy (Hirayama Disease)
* Monomelic amyotrophy, commonly referred to as Hirayama disease, is a
malepredominant juvenile-onset disorder, often presenting between the ages of 15
and 25 and characterized by insidious unilateral weakness and atrophy of the
upper limb, typically involving the hand and forearm initially but sparing the
brachioradialis muscle.
* Reflexes in the upper limbs are often normal to reduced and can be increased in
the lower limbs.
* Sensory testing, while often normal, may reveal abnormalities on the dorsum of
the hand.
* Initial progression of weakness and atrophy over a few years gives way to disease
stability.

73. * This disorder is now recognized to be a structural disorder of the spinal canal.
Neutral position cervical MRI shows abnormal cord curvature, asymmetric cord
atrophy, and increased intramedullary signal intensity.
* The cervical cord can be anteriorly displaced when MRI is obtained in the flexed
position
* In the neutral position, loss of attachment between the posterior dural sac and
adjacent lamina is appreciated.
* Pathologically, the spinal cord reveals loss of motor neuron cells and thinning of
the anterior roots from C5 to T1, most severe at C7-C8.

76. Neoplastic and Paraneoplastic Syndromes
* Neoplastic syndromes, such as lymphoma, and the presence of paraneoplastic
antibodies have been rarely associated with motor neuron disorders, but whether
a neoplasm is causal remains uncertain.
* A neoplastic etiology, including a carcinomatous or lymphomatous meningitis,
should be considered in the context of an LMN disorder, especially when the
presentation is atypical, the patient presents with nonmotor features (eg,
abnormal eye movements), or specific imaging features are present (enhancing
nerve roots for example).
* However, routine screening for paraneoplastic antibodies is not considered to be
valuable in individuals with typical motor neuron diseases