Post Polio Syndrome, Guillan-Barre, Amyotrophic Lateral Sclerosis Pathology

What is acute poliomyelitis?
Acute disorder caused by polio enterovirus type 1, 2, or 3 (GI Tract Virus)

Who developed the polio vaccine? When?
Jonas Salk, 1955 #H2P

Why is acute polio in the developed world a rarity?
D/t widespread use of vaccine

Where is polio still present?
In some region (e.g., endemic in Pakistan, Nigeria, and Afghanistan

How many new cases reported world wide in 2014?
Just over 400

What are the classic phases of polio?
Acute illness
Period of recovery
Stable disability

Poliovirus is an:
Enterovirus: picornaviridae

Which type of polio is the most paralyzing, most common cause of epidemics?
Type 1 (of 3 types)

Infection occurs via:
Mouth, direct contact

Is polio contagious?
Yes, highly

What percentage of all infections are asymptomatic or cause flu-like illness?
95%

Polio acute illness is characterized by:
Asymmetric paralysis of mm. served by motor units originating in the SC anterior horn cells

What cells does the polio virus damage or destroy?
SC anterior horn cells

What is often very sudden and sometimes very severe?
Paralysis

What happens as a result of paralysis?
Affected mm. become flaccid
DTRs decreased or absent
Atrophy begins within 1st week

Describe the bulbar form of acute polio.
Causes paralysis of respiratory mm. and swallowing and speech mm.

Does bulbar polio have a low or high rate of mortality
High mortality rate

What is required as an intervention for bulbar polio?
Positive ventilation and tracheostomy or negative pressure ventilation (“iron lung”)

Describe the recovery phase of acute polio.
“Orphaned” mm. fibers become re-innervated by axon sprouts (collateral sprouting)

What re-innervates some mm. fibers?
Terminal sprouts from an unaffected motor neuron in the vicinity

Large numbers of hypertrophied mm. fibers may be innervated by:
Small numbers of overworked surviving neurons

Some mm. fibers and groups of mm. are never re-innervated. What happens to the remaining mm. groups?
Compensate by hypertrophying and working much harder

How PT treat patients with acute polio?
Mobilization, stretching, splinting, orthoses
– To retrain affected mm. and help regain function
Survivors of bulbar polio were weaned off ventilation
– Some survivors still use intermittent positive pressure ventilation

Although polio is a chronic disease, it is also:
Stable; period of stable disability following rehab in recovery phase

Severity of disability varies greatly from:
Imperceptible mm. weakness to significant weakness causing numerous activity limitations and participation restrictions AND from no bulbar problems to intermittent dependence on assisted ventilation

The epidemics of the 1940s-50s affected how many people?
640,000

What percentage recovered with no residual weakness?
50%

What percentage of people were left with persistent paralysis?
50% – most people with paralytic form of polio were able to regain strength in affected mm., e.g., orthotics not needed anymore

What is PPS?
A condition resulting in new symptoms in people who had polio years earlier, but who have had functional and neurological stability for at least 15 years

Researchers estimate that the condition affect what percentage of polio survivors?
25-40 percent (depends on criteria used and population)

What is the cardinal symptoms of PPS?
New mm. weakness

Other symptoms of PPS:
New mm. weakness
Fatigue
Mm. and joint pain
Atrophy
New difficulties with ADLs, mobility
Cold intolerance
Sleep impairments
Speech difficulties
Dysphagia
Respiratory dysfunction

How do you diagnose PPS?
No lab tests, diagnosis of exclusion, based on clinical evaluation – history, observation, exam to rule out other diseases or causes of symptoms (lab tests, diagnostic imaging used to r/o other causes)

What is the criteria for PPS?
Confirmed history of polio
partial or fairly complete recovery after acute episode
Period of at least 15 years of neurological and functional stability
2 or more symptoms occurring after a stable period
No other medical explanations
Gradual or abrupt onset of new weakness

What is the cause of PPS?
No definitive explanations
Most widely accepted theory = “neuron fatigue”
– Many motor neurons destroyed by original infection, leaving small numbers of overworked motor neurons to innervated many (orphaned) mm. fibers
– With time and overuse, these few neurons simply wear out

Possible etiologies of PPS:
Motor unit dysfunction, degenerative change with motor units
Mm. overuse
Mm. underuse
Loss of motor units with aging
Hormonal effects
Combination of disuse, overuse, weight gain or other illnesses

How do you manage PPS?
1) No effect pharmaceutical treatments to stop deterioration or reverse deficits caused by syndrome itself (researchers at NIH tried high doses of steroid prednisone and found mild improvement in condition, but nothing statistically significant –> determined side effects outweighed the benefits)
2) Symptomatic care – e.g., sleep disturbances/sleep apnea – CPAP or IPAP
3) Some meds may aggravate symptoms of PPS e.g., benzodiazepines, beta blockers
4) Multi-disciplinary care is key!

Describe collateral sprouting that results from acute polio virus?
The unaffected neighbors receive a chemical message to go help out
– Neural cell adhesion molecules or N-AM
– Causes axonal sprouting to denervated mm. fibers –> attaches to denervated mm. fiber –> new NMJ –> re-innervation –> Strength increase

Describe mm. fiber hypertrophy that results from acute polio virus?
When mm. is overloaded –> increase in CSA to adapt to workload
PPS reports identity that fibers are 2-3x normal size – allows person with PPS to have almost normal strength even with 75% decrease # of motor units
Also remaining unaffected fibers have to work harder d/t stress
Occurs in most affected mm.

Describe fiber type transformation that results from acute polio virus?
Some mm. may transform mm. type (type 2/fast twitch –> type 1/slow twitch)
Estimated tha tin partially denervated mm. excessive use can force unused fibers to fuse together for common tasks: walking

What mm. do some people with PPS exhibit weakness in, yet have normal amounts of fast and slow twitch fibers?
Tibialis anterior (<2/5)

Other people with PPS have what grade on MMT and exhibit what with TA during ambulation?
3-4/5, overuse
– Have primarily type 1 fibers
– Hypertrophy also present
– In general ambulation: type 1 fibers are recruited maximally

What is Guillain-Barre Syndrome?
Acute, inflammatory polyneuropathy causing demyelination and axonal damage; largely motor dysfunction with or without sensory and autonomic dysfunction

Where does inflammation predominately occur in the PNS?
Proximal parts of the PNS
– Spinal n. roots – cervical, thoracic, and lumbar; sacral roots typically spared
– Peripheral nerves
– Cranial nerves (~50% of cases) – most commonly affected: CVII; others – CN III, V, VI, IX, X, XII
– Inflammation is typically low grade and continues for about one month
– Inflammation causes demyelination which slows conduction of electrical impulses, causes dispersion/disruption of impulses or blocks impulses
– In inflammation is severe – necrosis of axons

Explain the several variants of GBS:
Acute motor axon neuropathy – good prognosis
Acute motor and sensory axon neuropathy – decreased prognosis
Miller-Fisher Syndrome: CNIII, ataxia, arefelxia: diplopia and ataxia are first reported symptoms

What is the world wide incidence of GBS per year:
1.1-1.8/100,000

Incidence increases age >50 y/o from 1.7/100,000 to…
3.3/100,000 per year

In the US, how many people develop GBS each year?
3000-6000

What is the male to female ration of GBS:
1.5:1

When are the two peaks of onset of GBS:
Between ages 16 and 25, 50 and 74

What percentage of patients with GBS have no preceding illness?
What percentage have respiratory illness preceding GBS?
27%

49%

To be classified as GBS it has to be less than how long to reach peak disability?
Less than 4 weeks

What percent usually reach peak disability in <2 weeks?
50%

What are causes of GBS?
1) Evidence of an immune mediate response – analysis of CSF typically demonstrates elevated protein levels
2) Infections: campylobacter jejuni (axonal form) – food borne; about 40%; typically associated with more severe disease and disability; cytomegalovirus, Epstein Barr, herpes
3) Toxins (alcohol)
4) Metabolic (diabetes)
5) Exposures (metals)
6) Post surgical
7) After immunization; GBS cases associated with vaccination has decreased since 1990
8) Geographical pattern may exist

What is the pathogenesis of GBS?
Complex
– Demyelinating inflammatory polyradiculoneuropathy
– Associations with auto-immune disorders (autoantibodies for myelin)
– Patchy demyelination occurs along peripheral nerve roots/nerves, axons usually spared
– Inflammation is also present in DRG
– Within 2-3 weeks inflammation decreases and remyelination occurs
– AP is decreased, slow velocity

How many phases make up GBS’s clinical course? What are they?
Three
1) Progressive deterioration over the course of about 1-4 weeks
2) Plateau: no further deterioration, can take up to 1-2 months to reach plateau
3) Recovery: takes up to 6 months to a year, mechanisms responsible for recovery are remyelination and axonal regeneration 9e.g., sprouting)

The degree of recovery depends on:
The severity of the nerve damage that occurred in the infection phase

What percentage of people with GBS recover with no permanent disability?
85%

Half of those who recover from GBS with no permanent disability are left with:
Mild impairments, e.g., weakness of small mm. of hands and face

What percentage of patients with GBS are left with activity limitations of varying severity?
15%

Recurrence rates vary from:
4% to 6-7%

What factors are predictive of recurrence?
None have een identified

When can recurrence occur?
3 months to 25 years after initial episode

What is a poor prognosis for GBS?
Rapidity of onset
Progression to quadriparesis
Respiratory dependence
Failure to improve in 3 weeks of plateau phase

What percentage of indivdiuals die from secondary complications?
5%

What are common long term deficits?
Weakness of anterior tibialis, hand intrinsics, quads, gluts

What is the first priority in medical management of GBS?
Management of impaired respiratory and autonomic functions – hospitalization and ventilation/respiratory assist

What else is involved in medical management of GBS?
1) Prevent secondary infections/complications
2) Meds – steroids, immunosuppressives
3) Plasmaphoresis (plasma exchange)
4) IVIG – intravenous immunoglobulin (less invasive)

What are s/s of GBS?
1) Motor weakness
2) Hypotonia, atrophy, hyporeflexia
3) CN involvement
4) Mild sensory symptoms, paresthesias, hypesthesias, stocking and glove distribution
5) Pain
6) Autonomic dysfunction
7) Respiratory dysfunction
8) Mm. fatigue

What are typical first s/s of GBS?
Acute mm. tenderness and aching, distal LE weakness, distal paresthesia or hypoesthesia (stocking or glove distribution)

Does motor weakness begin distal and progress proximal or begin proximal and progress distal?
Distal –> proximal

What are characteristics of motor weakness?
Rapidly progressing
Symmetrical, typically B
Leg weakness first noted
Distal –> proximal –> full quadriplegia/respiratory/CN

Onset and progression of what symptoms coincide with paresis/paralysis?
Hypotonia, atrophy, hyporeflexia

What percentage of individuals with GBS have CN involvement?
50%; VII, III, pharynx, larynx, tonue

GBS also has mild sensory symptoms, such as:
Paresthesias, hypesthesias, stocking and glove distribution

Where does pain occur in individuals with GBS?
Back and LE pain

Describe autonomic dysfunction in GBS:
1) 50% of people
2) More common in those with severe quadriparesis and respiratory failure
3) Fluctuating BP, paroxysmal hypertension
4) Orthostatic intolerance
5) Tachycardia, bradycardia
6) Arrhythmia
7) Trophic skin changes
8) Reflex sympathetic dystrophy

Describe respiratory dysfunction in GBS:
15-30% will require assisted ventilation d/t decreased lung volumes or respiratory failure
Increased risk of infection, especially those requiring mechanical ventilation

What are motor neuron diseases?
A group of disorders that results in impairments of upper or lower motor neurons or both UMNs & LMNS

What are the three main forms of motor neuron disease?
1) Classic ALS: amyotrophic lateral sclerosis; UMN and LMN involvement
2) Progressive Bulbar Palsy: includes primarily the bulbar neurons and mm.
3) Progressive Muscular Atrophy: involves only spinal motor neurons (LMN)

What is ALS often called in the USA?
Lou Gerhig’s disease

What are the bulbar mm.?
Mm. of the throat and mouth responsible for speech and swallowing

Do motor neuron diseases affect white or gray matter?
Can affect one or the other, or both

What is a common factor in all degenerative diseases of the CNS?
Slow deterioration of body functions controlled by brain and SC

What is the most common and devastatingly fatal of all motor neuron diseases?
ALS

ALS is characterized by:
A progressive degeneration and loss of motor neurons in the SC BS, and motor cortex

What is the most frequently presenting symptom of ALS:
Focal weakness in the UE, LE, or bulbar mm.

What typically remains unaffected in ALS?
Sensory function, voluntary eye movements, and bladder typically remain unaffected

Degeneration of what cells in the motor cortex create UMN symptoms?
Betz

How do you diagnose ALS?
Through exclusion
– Lab studies, EMG, nerve conduction studies, mm. and nerve biopsies, and neuro-imaging studies are used to support diagnosis of ALS and to exclude possibility of other diagnoses

What do you need to diagnose as “definite” ALS?
Concomitant UMN, LMN, signs in 3 regions (region – cervical, thoracic, lumbar, and bulbar)

Incidence of ALS in North America: US: Europe:
NA: 1.8/100,000
US: 1.75/100,000
Europe: 2.08/100,000

What is the prevalence of ALS in the US general population?
3.9/100,000

Who is ALS more common amongst?
White males, non-Hispanic, age 60-69 years

What are the lowest number of cases at one time?
People aged 18-39 y/o and >80 y/o

Is ALS more prevalent in males or females?
Slightly more prevalent in males

What is the average age at diagnosis?
Mid to late fifties

When can onset occur?
Anywhere from teens to very old age

What environmental agents can cause ALS?
Metals, pesticides

What potential pathological mechanisms can cause ALS?
Glutamate excitotoxicity
Oxidative stress
Impaired axonal transport
Protein aggregation
Apoptosis

What genetic susceptibility can cause ALS?
Gene mutations in familial ALS, candidate genes in sporadic ALS

What lifestyle factors can cause ALS?
Cigarette smoking, diet (fat, fiber, antioxidants)

What are known risk factors for ALS?
– Disease causing mutations (SOD1, alsin) in Mendelian ALS
– Gender (male > female)
– Clusters: Persian Gulf War, Western Pacific ALS/PDC
– Family history of ALS
– Age

Possible risk factors for ALS:
1) Neurotoxicant exposures: lead, mercury, pesticide exposure, solvent exposure
2) Vigorous physical activity: heavy manual labor, athleticism
3) Lifestyle factors: cigarette smoking, alcohol intake, anthropometric measures
4) Certain occupation characteristics: electrical workers, farmers, industrial occupation
5) Diet: high fat intake (saturated > monounsaturated), high glutamate intake, lower fiber intake, low antioxidant intake
6) Trauma: skeletal trauma, fractures, severe electrical shock (with unconsciousness)

What else may cause ALS?
1) Superoxide dismutase, decreased SOD enzyme activity, free radical accumulation leading to damage
2) Glutamate toxicity – excess glutamate triggers a cascade of events leading to cell death
3) Neurotrophic factor deficiency – neurotrophic factors are important in motor neuron survival
4) Apoptosis
5) Viral infection
6) Heavy metals/trace metals
7) Environmental toxins
8) Autoimmune disorder

Describe the progressive motor neuron degeneration that occurs in ALS:
– Degeneration and loss of anterior horn cells in SC
– Degeneration and loss of pyramidal cells in the primary motor cortex
– Loss of myelinated fibers of corticospinal tracts – those with heavy myelination are most often involved
– Degeneration and loss of motor cells in BS motor nuclei
— BS nuclei for cranial nerves V (trigeminal), VII (facial), IX (glossopharyngeal), X (vagus), and XII (hypoglossal) are affected
— BS nuclei for cranial nerves controlling external ocular mm., III (oculomotor), IV (trochlear), and VI (abducens), are usually spared, and if degeneration occurs, it does so late in the course of the disease

What else occurs in the pathology of ALS?
1) Prominent shrinking of anterior horn cells
2) Atrophy of anterior roots
3) Pallor of corticospinal tracts in lateral and anterior columns
4) Posterior and spinocerebellar tracts are generally spared, but can be affected – degeneration of the spinocerebellar tracts and posterior column are in people with FALS
5) Pyramidal tracts are more involved below the medulla
6) Cell bodies and axons are involved, the primary symptoms are d/t damage closest to the cell body
7) Damage of LMN causes mm. to degenerate, similar to peripheral neuropathy
8) Atrophy occurs in mm. fibers, in motor unit, IDs loss of specific motor neuron – compared to PN injury: the whole mm. will atrophy because more motor units are involved

ALS LMN Pathology Impairments:
Mm. weakness, atrophy, hyporeflexia, hypotonicity, mm. cramps, fasciculations

ALS UMN Pathology Impairments:
Spasticity, pathological reflexes, hyperreflexia, mm. weakness

Other Impairments of ALS:
Cognitive impairments, pseudobulbar affect, dysphagia, dysarthria, sialorhea, psychosocial issues

Secondary/Composite Impairments of ALS:
Fatigue, deconditioning, restrictive pulmonary dysfunction, subluxation, contractures, impaired postural control and balance, gait disturbances

Rare Impairments of ALS:
Sensory impairments, bowel and bladder dysfunction, ocular palsy

What are initial s/s of ALS?
Focal mm. weakness e.g., fine motor movements (buttoning, pinching); tripping (foot drop); changes in voice (bulbar onset)

What is considered the cardinal sign of ALS?
Mm. weakness

What are UMN signs of ALS?
Spasticity, hyperreflexia, positive Babinski

What are LMN signs of ALS
Hypotonicity, weakness and mm. wasting, atrophy, decreased DTRs, mm. cramping

Is ALS disease course progressive or stable?
Progressive and deteriorating disease trajectory

How long is the time of onset to death?
Ranges from several months to 20 years

What is the duration of illness?
Average = 27-43 months
Median = 23-52 months

What is the 5 year survival rate? 10 year?
5 year: 9-40%
10: 8-16%

What is the survival probability after initial symptom slightly greater than 3 years, unless mechancially ventilated?
50%

For most individuals with ALS, when does death occur? Why?
3-5 years, d/t respiratory failure

What is an improved prognosis for ALS?
Younger patients (<35-40 years) Less severe involvement at diagnosis Longer time of onset to diagnosis Limb onset - Limb onset 5 year survival rates = 37-44% - Bulbar onset 5 year survival rates = 9-16% No dyspnea symptoms at onset Improved psychological well-being Improved psychological well-being

How can you diagnose ALS?
By clinical exam and EMG
By exclusion of all other possible disorders

Testing for ALS:
1) Lab tests – create phosphokinase levels elevated in 0%
2) Genetic testing to ID mutation (SOD1)
3) NCV and EMG: to ID the LMN involvement
— Fibrillations, + waveforms, fasciculations, motor unit potential changes in 3 limbs and paraspinal mm.
4) MRI – helps to r/o other disorders

Medications for ALS:
Rilutek: inhibits glutamate release also antagonises the glutamate receptors
– 50 mg twice/day
– Shown to have modest effects on survival
Myotrophin: promotes survival of motor neurons and regeneration of nerves
Antioxidants

Aggressive symptomatic care for ALS includes:
E.g.,
– Anticholinergic meds: decrease drooling
– Baclofen, diazepam: spasticity control
– Phenytoin, carbamazepine, diazepam: mm. cramping
– Dextrometorphan + quinidine: fluvoxamine, amitriptyline, citalopram for pseudobulbar affect

How you can manage depression in patients with ALS?
Counseling, support groups, prozac, zoloft, tricyclics (e.g., Amytriptiline)

How can you manage anxiety in patients with ALS?
Counseling, support groups, benzodiazepines, buspirone (Buspar)

Describe the multidisciplinary team approach for ALS:
E.g., PT, Speech, OT, nutritionist referrals
– Prevent contractures, skeletal deformity
– Prevent respiratory complications
– Assist with swallowing problems
– Nutrition maintenance d/t swallowing and chewing problems

What are differential diagnosis for ALS?
Lymphedema
Lyme disease
SC compression (cervical)
Heavy metal poisoning
Other neuro diseases: MS, GBS

Describe Progressive Bulbar Palsy:
Bulbar motor neurons and mm. are involved
CN involvement: swallowing, chewing, and facial gestures involved
Oculomotor system not involved, eye movement is normal
Dysarthria is common
Dysphagia and difficulty chewing
Tongue weakness
Atrophy and fasciculations are common
Most UMN and LMN signs are confined to bulbar mm., but will later involve limbs

Describe Progressive Muscular Atrophy:
– Primarily LMN involvement of limb mm. d/t anterior horn cell damage
– Often begins in c/spine
– Progressive weakness, wasting, fasciculations in small mm. of hand
– Other symptoms are: impaired motor function, may be floppy infant, to deteriorating athletic ability later in life; symmetric proximal weakness, no eye weakness, or sphincter problems, diaphragm is normal
– Less CN involvement
– No signs of UMN, decreased/absent DTRs
– No sensory or intellect affected
– Deformity is common, worst ones when it develops as a child
– Widespread denervation

Treatment for Progressive Muscular Atrophy:
Maintain joint mobility, prevent contractures and deformity, promote active exercise, PROM and AROM

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