This document discusses motor neuron diseases, including amyotrophic lateral sclerosis (ALS). It provides details on the classification, symptoms, signs, diagnosis, prognosis, and management of ALS and related conditions. Key points include that ALS is characterized by the degeneration of both upper and lower motor neurons, leading to muscle weakness, atrophy, and fasciculations. Diagnosis involves finding signs of both upper and lower motor neuron involvement. Prognosis is typically worse if onset is bulbar or simultaneous in multiple limbs. Treatment focuses on managing symptoms while no treatments have been proven to slow disease progression.

1. Dr Chandrashekar K
Assistant Professor
Dept of Medicine
KIMS, Hubballi

2.  Motor Neuron Diseases
 Group of diseases which include progressive degeneration and loss
of motor neurons
 With or without similar lesion of the motor nuclei of the brain
 Replacement of lost cells with gliosis
 “Motor Neuron Disease” = ALS (Charcot’s Disease, Lou
Gehrig’s Disease)
 LMN - limbs (PMA), bulbar (progressive bulbar palsy)
 UMN – limbs (PLS), bulbar (progressive pseudobulbar palsy)

3. Upper motor
neuron
Lower motor
neuron
Diagnostic Triad: ALS
Progression

4. ALS Demographics
 Incidence 2 per 100,000
 Male slightly > Female
 Peak age of onset: 6th
decade (range 20 to 90)
 No racial predilection
 95% sporadic
 5% AD (FALS)

5. ALS Diagnosis: Upper Motor
Neuron Symptoms
 Loss of dexterity (skill in performing tasks, especially with the
hands.
 Slowed movements
 Loss of muscle strength
 Stiffness
 Emotional lability

6. ALS Diagnosis:
Upper Motor Neuron Signs
Bulbar
Jaw jerk
Snout
Palmomental
Pseudobulbar palsy/
affect
Glabellar
Cervical
Pathologic DTRs
Hoffmans Spasticity
Thoracic
Loss of abdominal
reflexes
Lumbosacral
Pathologic DTRs,
Extensor plantar signs,
Spasticity

7. ALS Diagnosis: Lower Motor
Neuron Symptoms
 Loss of muscle strength
 Atrophy
 Fasciculations
 Muscle cramps

11. ALS:
Inconsistent Clinical Features
 Sensory dysfunction
 Bladder and bowel sphincter dysfunction
 Autonomic nervous system dysfunction
 Visual pathway abnormalities
 Movement disorders
 Cognitive abnormalities
 Bedsores

12. Pathology
 Precentral gyrus atrophy
 Sparing of nucleus of Onuf
 Neuronal loss of cranial
nuclei
 Degeneration of
corticospinal tract
 Chromatin dissolution
(chromatolysis), atrophy,
shrinkage, cell loss, gliosis
Nucleus of ONUF

13. Pathology
 Bunina’s bodies –
intracytoplasmic,
easinophilic dense
granular
 Hirano’s bodies – rod
shaped, contain parallel
filaments
 Lewy bodies
 Neuritic plaques
 Neurofibrillary tangles

14. Familial ALS
 AD inheritance, variable penetrance
 Male = Female
 Higher incidence of cognitive changes
 Chorea
 Younger onset
 Reported spongiform changes, plaques, tangles
 15 year survival
 One type maps to chromosome 2

15. ALS: Differential Diagnosis
 Toxins (lead, mercury, ?aluminum)
 Metabolic (hyperthyroidism, hyperparathyroidism,
hypoglycemia)
 Enzyme deficiency (Hexosaminidase A)
 Paraneoplastic (lymphoma, small cell lung)
 Cervical spondylosis

16. ALS: Differential Diagnosis
 Immunologic (paraproteinemia)
 Multi-system degeneration (Creutzfeldt-Jacob, ALS-PD-
Dementia, Spinocerebellar Degeneration)
 Viral (Post-polio)
 Bacterial (Lyme disease)
 Vitamin B12 deficiency

17. ALS: Laboratory Studies
 CK levels are typically normal but may be increased 2-3x
normal in almost half of patients.*
 CSF may show mild protein elevation (less than
100mg/dl).*
 All other laboratory studies should be normal.

18. ALS: Electrodiagnostic Testing
 Normal SNAPs (Sensory nerve action potential)
 CMAPs may be normal or show decreased amplitude*
 Fibrillations/fasciculations in 2 muscles in 3 extremities
(head and paraspinals count as an extremity)*

19. ALS: Prognosis
 Prognosis
 50% dead in 3 years
 20% live 5 years
 10% live 10 years
 Worse prognosis if:
 Bulbar onset
 Simultaneous arm/leg onset
 Older age at diagnosis (onset < 40: 8.2 yr duration,
onset 61-70: 2.6 yr duration)

20. VARIANTS
OF
ALS

21. Primary Lateral Sclerosis
 Upper motor neuron syndrome
 Rare disorder (2% of MND cases) with survival ranging
between years – decades
 Weakness is typically distal, asymmetrical
 Patients present with slowly progressive spastic
paralysis/bulbar palsy
 EMG should not reveal evidence of active or chronic
denervation

22. Primary Lateral Sclerosis
 Patients may develop clinical LMN abnormalities over
the course of their disease.
 Frequently, patients may have subtle evidence of active
or chronic denervation on EMG (rare fibs/decreased
recruitment), and/or muscle biopsy at diagnosis

23. Progressive Muscular Atrophy
 Lower motor neuron syndrome
 Literature suggests 8-10% of patients with MND
 Much better prognosis than ALS (mean duration 3-14
years)
 Bulbar involvement is rare
 Weakness is typically distal, asymmetrical

24. Lower Motor Neuron Syndromes
 Multi-focal motor
neuropathy
 Mononeuropathy
multiplex
 CIDP
 Polyneuropathy/
radiculopathy
 Plexopathy
 Kennedy’s
 Hexosaminidase A
deficiency
 Spinal muscular atrophy
 Post-polio syndrome
 Polymyositis
 Inclusion body myositis
 LMN onset ALS
 PMA

25. Progressive Muscular Atrophy
 The majority of patients presenting with PMA eventually
develop clinical UMN signs.
 Post-mortem examinations of PMA patients frequently
show pathologic evidence of UMN degeneration.
 In some FALS families, the same gene mutation causes the
phenotypes of PMA and ALS in different individuals.

26. Spinobulbar Muscular Atrophy
 Originally reported by Kennedy in 1966 – 11 males in 2
families
 Age of onset
 Usually begins in 3rd or 4th decade
 Genetics
 Most common form of adult onset SMA
 X-linked recessive
 >40 CAG repeats in the androgen receptor gene
 Number of repeats correlates with age of onset

27. Spinobulbar Muscular Atrophy
 Lower motor neuron syndrome with limb-girdle
distribution of weakness/bulbar palsy*
 Facial or perioral fasciculations (90%)
 Tongue atrophy with longitudinal midline furrowing
 Prominent muscle cramps
 Generalized fasciculations and atrophy
 Rarely causes respiratory muscle weakness

29. Spinobulbar Muscular Atrophy
 Reflexes are decreased or absent
 Cognitive impairment may occur
 Hand tremor
 Sensory exam may be normal or minimally abnormal

30. Spinobulbar Muscular Atrophy:
Systemic Manifestations
 Gynecomastia (60-90%)*
 Testicular atrophy (40%)
 Feminization
 Impotence*
 Infertility
 Diabetes (10-20%)

31. Spinobulbar Muscular Atrophy:
Laboratory Studies
 Markedly abnormal sensory NCS
 Sural nerve bx: significant loss of myelinated fibers*
 Elevated CK (may be 10x normal)
 Abnormal sex hormone levels (androgen nl or decreased;
estrogen may be elevated, FSH/LH may be mildly
elevated)*
 Increased expansion of CAG repeats in the androgen
receptor gene*

32. Conclusions
 Although some patients with MND variants evolve into
“classic” ALS over time, others continue to show restricted
clinical features even late in the course of their disease.
 In daily clinical practice, precise definitions may not be
crucial but recognition of the “variants” is important since
each has a different course and prognosis.
 The “treatment cocktail” should be the same until we learn
more about pathogenesis.

33. Pathogenesis
 Nucleic acid metabolism – decreased nucleolus staining,
reduced mRNA/rRNA content
 Glutamate – activation NMDA type receptor, Ca influx,
free radical production (NO/ROS/protein misfolding by
endoplasmic reticulum)
 Increased in CSF and plasma
 Decreased in brain and spinal cord
 Decreased active transport of glutamate into synaptosomes
 Loss of glial glutamate transporters

34. Pathogenesis
 Loss of muscarinic cholinergic repectors of anterior horns
 Decreased choline acetyltransferase in spinal cord
 Decreased glycine and BZD receptors
 Immunology
 CSF IgG ? Elevated in spinal cord
 C3, C4 deposits in spinal cord
 Reported abnormal glycolipid antibodies in serum
 Elevated antibodies to voltage gated calcium channels – disturbance
of calcium homeostasis (binding proteins
parvalbumin/calbindinD28)

35. Pathogenesis
 Viral? – amantadine not effective
 SOD1 – loss of function mutation?
 20% of FALS
 Free radical toxicity
 Chromosome 21
 Cytosolic enzyme
 Transgenic mouse model

36. Pathogenesis
 Heat shock proteins – chaperones, influence shape, shuttle
proteins
 Apoptosis – programmed cell death
 CNS glial cells – retain some reproductive capacity
 Microglial – specialized macrophages
 Macroglia – astrocytes, oligodendrocytes, ependymal cells, radial
glial (neurogenesis/migration)

37. Treatment Issues to Consider
 Symptom management
 Nutritional management
 Respiratory management
 Palliative care
 Therapies to slow disease progression

38. Symptoms Associated with Motor
Neuron Disease
 Dysarthria
 Dysphagia
 Sialorrhea
 Emotional lability
 Depression
 Weight Loss
 Bladder urgency
 Sleep dysfunction
 Constipation
 Edema
 Pain
 Spasticity
 Cramps
 Weight loss
 Fatigue
 Weakness

39. Sialorrhea
 Symptoms result from inability to clear oropharyngeal
secretions
 Common pharmacologic treatments:
 Glycopyrrolate (Robinul) 1-2 mg q 4h
 Amitriptyline (Elavil) 25-100 mg qhs
 Hyoscyamine sulfate (Levsin) 1-2 tsp q 4h
 Transdermal scopolamine
 Suction machines

40. Management of Emotional Lability
 Common pharmacologic treatments:
 Amitriptyline (Elavil) 25-150 mg qhs*
 SSRIs
 Common nonpharmacologic treatments:
 Counseling/support groups

41. Spasticity
 Common pharmacologic treatments*:
 Baclofen 10-40 mg TID-QID
 Dantrolene sodium 25 mg qd - QID
 Tizanidine HCL 12-36 mg TID
 Diazepam 2-5mg TID
 Botox
 Common non pharmacologic treatments:
 Physical therapy
 Occupational therapy

42. Management of Weakness:
Assistive Devices
 Cane
 Roll-aided walker
 AFOs
 Wheelchair
 Hoyer lift
 Cervical collar
 Hospital bed
 Ramps
 Built-up utensils
 Velcro fasteners
 Raised toilet seat
 Shower chair
 Resting hand splints
 Grab bars

43. Management of Dysphagia: Consideration for
PEG (percutaneous endoscopic gastrostomy)
 Consider
 Significant weight loss
 Inadequate fluid or caloric intake
 Difficulty swallowing medications
 Frequent choking during meals
 Prolonged meal times
 FVC < 50%
 Aspiration pneumonia*
 Does not prolong survival
 Malnutrition independent risk factor for worse prognosis

44. Respiratory Insufficiency: Early
Symptoms
 Dyspnea on exertion
 Supine dyspnea
 Marked fatigue
 Excessive daytime somnolence
 Frequent nocturnal arousals
 Vivid dreams
 Morning headaches

45. Management of Respiratory
Muscle Weakness
 Consider initiation of support when:
 Symptoms of nocturnal hypoventilation
 FVC <50% of predicted
 MIP < -60 cm H2O
 Evidence of significant O2 desaturations
 May prolong time to death/trach in longitudinal studies

46. Supportive treatment

47. Treatment
 Riluzole
 IGF-1 - growth factor
 Ceftriaxone – glutamate transporter
 Co-Q10
 Statins
 Memantine with riluzole

48. Treatment
 Tamoxifen with riluzole
 Celebrex
 Thalidomide - TNF alpha
 Buspirone – neurotrophic effect
 Stem cell*

49. RARER
FORMS OF
MND

50. Western Pacific ALS
 ALS-PD-Dementia Guam, West New Guinea, Honshu
Island
 Earlier onset
 UMN precedes LMN features
 Bulbar weakness more common

51. Hexosaminidase A Deficiency
 AR
 Onset childhood
 SMA-like picture
 Mild dementia, neuropathy, ataxia, psychosis
 Atrophy on imaging (cerebellum)