Motor Neuron Diseases

1
Motor Neuron Diseases
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 (Charcots Disease,
  Lou Gehrigs Disease)
• LMN - limbs (PMA), bulbar (progressive bulbar
  palsy)
• UMN limbs (PLS), bulbar (progressive
  pseudobulbar palsy)

3
Diagnostic Triad ALS
Progression
4
ALS Demographics

• Incidence 2 per 100,000
• Male slightly gt Female
• Peak age of onset 6th decade (range 20 to 90)
• No racial predilection
• 95 sporadic
• 5 AD (FALS)

5
ALS Diagnosis Upper MotorNeuron Symptoms

• Loss of dexterity
• 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

8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
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

13
Pathology

• Buninas bodies intracytoplasmic, easinophilic
  dense granular
• Hiranos 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
• 20 are SOD

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
• CMAPs may be normal or show decreased amplitude
• NCV rarely lt 80 LLN
• DL rarely gt 1.5x normal
• F response rarely gt 1.3x normal
• 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 lt 40 8.2 yr
  duration, onset 61-70 2.6 yr duration)

20
Anatomical Variants
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

• Hexosaminidase A deficiency
• Spinal muscular atrophy
• Post-polio syndrome
• Polymyositis
• Inclusion body myositis
• LMN onset ALS
• PMA

• Multi-focal motor neuropathy
• Mononeuropathy multiplex
• CIDP
• Polyneuropathy/
• radiculopathy
• Plexopathy
• Kennedys

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
• gt40 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

28
(No Transcript)
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 AtrophySystemic
Manifestations

• Gynecomastia (60-90)
• Testicular atrophy (40)
• Feminization
• Impotence
• Infertility
• Diabetes (10-20)

31
Spinobulbar Muscular AtrophyLaboratory 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
Treatment Issues to Consider

• Symptom management
• Nutritional management
• Respiratory management
• Palliative care
• Therapies to slow disease progression

34
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

35
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

36
Management of Emotional Lability

• Common pharmacologic treatments
• Amitriptyline (Elavil) 25-150 mg qhs
• SSRIs
• Common nonpharmacologic treatments
• Counseling/support groups

37
Spasticity

• Common pharmacologic treatments
• Baclofen (Lioresal) 10-40 mg TID-QID
• Dantrolene sodium (Dantrium) 25 mg qd - QID
• Tizanidine HCL (Zanaflex) 12-36 mg TID
• Diazepam (Valium) 2-5mg TID
• Botox ?
• Common nonpharmacologic treatments
• Physical therapy
• Occupational therapy

38
Management of WeaknessAssistive 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

39
Management of Dysphagia Consideration for PEG

• Consider
• Significant weight loss
• Inadequate fluid or caloric intake
• Difficulty swallowing medications
• Frequent choking during meals
• Prolonged meal times
• FVC lt 50
• Aspiration pneumonia
• Does not prolong survival
• Malnutrition independent risk factor for worse
  prognosis

40
Respiratory Insufficiency Early Symptoms

• Dyspnea on exertion
• Supine dyspnea
• Marked fatigue
• Excessive daytime somnolence
• Frequent nocturnal arousals
• Vivid dreams
• Morning headaches

41
Management of Respiratory Muscle Weakness

• Consider initiation of support when
• Symptoms of nocturnal hypoventilation
• FVC lt50 of predicted
• MIP lt -60 cm H2O
• Evidence of significant O2 desaturations
• May prolong time to death/trach in longitudinal
  studies

42
(No Transcript)
43
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

44
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)

45
Pathogenesis

• Viral? amantadine not effective
• SOD1 loss of function mutation?
• 20 of FALS
• Free radical toxicity
• Chromosome 21
• Cytosolic enzyme
• Transgenic mouse model

46
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/migrat
  ion)

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
Western Pacific ALS

• ALS-PD-Dementia Guam, West New Guinea, Honshu
  Island
• Earlier onset
• UMN precedes LMN features
• Bulbar weakness more common

50
Hexosaminidase A Deficiency

• AR
• Onset childhood
• SMA-like picture
• Mild dementia, neuropathy, ataxia, psychosis
• Atrophy on imaging (cerebellum)