Transcript Motor Neuron Diseases

Motor Neuron Diseases
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Motor Neuron Diseases
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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)
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LMN - limbs (PMA), bulbar (progressive bulbar palsy)
UMN – limbs (PLS), bulbar (progressive pseudobulbar palsy)
Diagnostic Triad: ALS
Upper motor
neuron
Progression
Lower motor
neuron
ALS Demographics
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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
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Loss of dexterity
Slowed movements
Loss of muscle strength
Stiffness
Emotional lability
ALS Diagnosis:
Upper Motor Neuron Signs
Cervical
Pathologic DTRs
Hoffmans Spasticity
Bulbar
Jaw jerk
Snout
Palmomental
Pseudobulbar palsy/
affect
Glabellar
Thoracic
Lumbosacral
Pathologic DTRs,
Extensor plantar signs,
Spasticity
Loss of abdominal
reflexes
ALS Diagnosis: Lower Motor
Neuron Symptoms
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Loss of muscle strength
Atrophy
Fasciculations
Muscle cramps
ALS:
Inconsistent Clinical Features
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Sensory dysfunction
Bladder and bowel sphincter dysfunction
Autonomic nervous system dysfunction
Visual pathway abnormalities
Movement disorders
Cognitive abnormalities
Bedsores
Pathology
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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
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Bunina’s bodies – intracytoplasmic, easinophilic dense
granular
Hirano’s bodies – rod shaped, contain parallel filaments
Lewy bodies
Neuritic plaques
Neurofibrillary tangles
Familial ALS
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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
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Toxins (lead, mercury, ?aluminum)
Metabolic (hyperthyroidism, hyperparathyroidism,
hypoglycemia)
Enzyme deficiency (Hexosaminidase A)
Paraneoplastic (lymphoma, small cell lung)
Cervical spondylosis
ALS: Differential Diagnosis
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Immunologic (paraproteinemia)
Multi-system degeneration (Creutzfeldt-Jacob, ALS-PDDementia, Spinocerebellar Degeneration)
Viral (Post-polio)
Bacterial (Lyme disease)
Vitamin B12 deficiency
ALS: Laboratory Studies
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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
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Normal SNAPs
CMAPs may be normal or show decreased amplitude*
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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
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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
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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
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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
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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
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Multi-focal motor
neuropathy
Mononeuropathy
multiplex
CIDP
Polyneuropathy/
radiculopathy
Plexopathy
Kennedy’s
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Hexosaminidase A
deficiency
Spinal muscular atrophy
Post-polio syndrome
Polymyositis
Inclusion body myositis
LMN onset ALS
PMA
Progressive Muscular Atrophy
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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
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Originally reported by Kennedy in 1966 – 11 males in 2
families
Age of onset
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Usually begins in 3rd or 4th decade
Genetics
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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
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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
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Reflexes are decreased or absent
Cognitive impairment may occur
Hand tremor
Sensory exam may be normal or minimally abnormal
Spinobulbar Muscular Atrophy:
Systemic Manifestations
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Gynecomastia (60-90%)*
Testicular atrophy (40%)
Feminization
Impotence*
Infertility
Diabetes (10-20%)
Spinobulbar Muscular Atrophy:
Laboratory Studies
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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
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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
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Symptom management
Nutritional management
Respiratory management
Palliative care
Therapies to slow disease progression
Symptoms Associated with
Motor Neuron Disease
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Dysarthria
Dysphagia
Sialorrhea
Emotional lability
Depression
Weight Loss
Bladder urgency
Sleep dysfunction
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Constipation
Edema
Pain
Spasticity
Cramps
Weight loss
Fatigue
Weakness
Sialorrhea
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Symptoms result from inability to clear oropharyngeal
secretions
Common pharmacologic treatments:
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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
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Common pharmacologic treatments:
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Amitriptyline (Elavil) 25-150 mg qhs*
SSRIs
Common nonpharmacologic treatments:
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Counseling/support groups
Spasticity
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Common pharmacologic treatments*:
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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:
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Physical therapy
Occupational therapy
Management of Weakness:
Assistive Devices
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Cane
Roll-aided walker
AFOs
Wheelchair
Hoyer lift
Cervical collar
Hospital bed
Ramps
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Built-up utensils
Velcro fasteners
Raised toilet seat
Shower chair
Resting hand splints
Grab bars
Management of Dysphagia:
Consideration for PEG
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Consider
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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
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Dyspnea on exertion
Supine dyspnea
Marked fatigue
Excessive daytime somnolence
Frequent nocturnal arousals
Vivid dreams
Morning headaches
Management of Respiratory
Muscle Weakness
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Consider initiation of support when:
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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
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Nucleic acid metabolism – decreased nucleolus staining,
reduced mRNA/rRNA content
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Glutamate – activation NMDA type receptor, Ca influx,
free radical production (NO/ROS/protein misfolding by
endoplasmic reticulum)
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Increased in CSF and plasma
Decreased in brain and spinal cord
Decreased active transport of glutamate into synaptosomes
Loss of glial glutamate transporters
Pathogenesis
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Loss of muscarinic cholinergic repectors of anterior horns
Decreased choline acetyltransferase in spinal cord
Decreased glycine and BZD receptors
Immunology
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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
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Viral? – amantadine not effective
SOD1 – loss of function mutation?
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20% of FALS
Free radical toxicity
Chromosome 21
Cytosolic enzyme
Transgenic mouse model
Pathogenesis
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Heat shock proteins – chaperones, influence shape, shuttle
proteins
Apoptosis – programmed cell death
CNS glial cells – retain some reproductive capacity
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Microglial – specialized macrophages
Macroglia – astrocytes, oligodendrocytes, ependymal cells, radial
glial (neurogenesis/migration)
Treatment
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Riluzole
IGF-1 - growth factor
Ceftriaxone – glutamate transporter
Co-Q10
Statins
Memantine with riluzole
Treatment
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Tamoxifen with riluzole
Celebrex
Thalidomide - TNF alpha
Buspirone – neurotrophic effect
Stem cell*
Western Pacific ALS
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ALS-PD-Dementia Guam, West New Guinea, Honshu
Island
Earlier onset
UMN precedes LMN features
Bulbar weakness more common
Hexosaminidase A Deficiency
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AR
Onset childhood
SMA-like picture
Mild dementia, neuropathy, ataxia, psychosis
Atrophy on imaging (cerebellum)