Motor Neuron Diseases

 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)
Diagnostic Triad: ALS

Upper motor Lower motor

neuron neuron

Progression
 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)
 ALS Diagnosis: Upper Motor
Neuron Symptoms
 Loss of dexterity
 Slowed movements
 Loss of muscle strength
 Stiffness
 Emotional lability
 ALS Diagnosis:
Upper Motor Neuron Signs

Bulbar
Cervical Jaw jerk
Pathologic DTRs Snout
Hoffmans Spasticity Palmomental
Pseudobulbar palsy/
affect
Glabellar

Thoracic
Lumbosacral Loss of abdominal
Pathologic DTRs, reflexes
Extensor plantar signs,
Spasticity
 ALS Diagnosis: Lower Motor
Neuron Symptoms
 Loss of muscle strength
 Atrophy
 Fasciculations
 Muscle cramps
 ALS:
Inconsistent Clinical Features
 Sensory dysfunction
 Bladder and bowel sphincter dysfunction
 Autonomic nervous system dysfunction
 Visual pathway abnormalities
 Movement disorders
 Cognitive abnormalities
 Bedsores
 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
 Pathology

 Bunina’s bodies – intracytoplasmic, easinophilic dense

granular
 Hirano’s bodies – rod shaped, contain parallel filaments
 Lewy bodies
 Neuritic plaques
 Neurofibrillary tangles
 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
 ALS: Differential Diagnosis

 Toxins (lead, mercury, ?aluminum)

 Metabolic (hyperthyroidism, hyperparathyroidism,
hypoglycemia)
 Enzyme deficiency (Hexosaminidase A)
 Paraneoplastic (lymphoma, small cell lung)
 Cervical spondylosis
 ALS: Differential Diagnosis

 Immunologic (paraproteinemia)
 Multi-system degeneration (Creutzfeldt-Jacob, ALS-PD-
Dementia, Spinocerebellar Degeneration)
 Viral (Post-polio)
 Bacterial (Lyme disease)
 Vitamin B12 deficiency
 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.
 ALS: Electrodiagnostic Testing

 Normal SNAPs
 CMAPs may be normal or show decreased amplitude*
 NCV rarely < 80% LLN
 DL rarely > 1.5x normal
 F response rarely > 1.3x normal
 Fibrillations/fasciculations in 2 muscles in 3 extremities
(head and paraspinals count as an extremity)*
 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)

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

 Reflexes are decreased or absent

 Cognitive impairment may occur
 Hand tremor
 Sensory exam may be normal or minimally abnormal
 Spinobulbar Muscular Atrophy:
Systemic Manifestations
 Gynecomastia (60-90%)*
 Testicular atrophy (40%)
 Feminization
 Impotence*
 Infertility
 Diabetes (10-20%)
 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*
 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.
 Treatment Issues to Consider

 Symptom management
 Nutritional management
 Respiratory management
 Palliative care
 Therapies to slow disease progression
 Symptoms Associated with
Motor Neuron Disease
 Dysarthria  Constipation
 Dysphagia  Edema
 Sialorrhea  Pain
 Emotional lability  Spasticity
 Depression  Cramps
 Weight Loss  Weight loss
 Bladder urgency  Fatigue
 Sleep dysfunction  Weakness
 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
 Management of Emotional
Lability
 Common pharmacologic treatments:
 Amitriptyline (Elavil) 25-150 mg qhs*
 SSRIs
 Common nonpharmacologic treatments:
 Counseling/support groups
 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
 Management of Weakness:
Assistive Devices
 Cane  Built-up utensils
 Roll-aided walker  Velcro fasteners
 AFOs  Raised toilet seat
 Wheelchair  Shower chair
 Hoyer lift  Resting hand splints
 Cervical collar  Grab bars
 Hospital bed
 Ramps
 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 < 50%
 Aspiration pneumonia*
 Does not prolong survival
 Malnutrition independent risk factor for worse prognosis
 Respiratory Insufficiency: Early
Symptoms
 Dyspnea on exertion
 Supine dyspnea
 Marked fatigue
 Excessive daytime somnolence
 Frequent nocturnal arousals
 Vivid dreams
 Morning headaches
 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
 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
 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)
 Pathogenesis

 Viral? – amantadine not effective

 SOD1 – loss of function mutation?
 20% of FALS
 Free radical toxicity
 Chromosome 21
 Cytosolic enzyme
 Transgenic mouse model
 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)
 Treatment

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

 Tamoxifen with riluzole

 Celebrex
 Thalidomide - TNF alpha
 Buspirone – neurotrophic effect
 Stem cell*
 Western Pacific ALS

 ALS-PD-Dementia Guam, West New Guinea, Honshu

Island
 Earlier onset
 UMN precedes LMN features
 Bulbar weakness more common
 Hexosaminidase A Deficiency

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