Disorders of Anterior Horn Cells, Part I 2024 PDF

DISORDERS OF ANTERIOR HORN CELLS, Part I PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of Amyotrophic Lateral Sclerosis (ALS) and Post-Polio Syndrome (PPS).  Identify diag...

DISORDERS OF ANTERIOR HORN CELLS, Part I PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of Amyotrophic Lateral Sclerosis (ALS) and Post-Polio Syndrome (PPS).  Identify diagnostic parameters and tests used to determine a medical diagnosis of these 2 neuromuscular conditions  Describe the general course of, and prognosis, for ALS and PPS.  Discuss the medical and/or surgical management of common signs & symptoms for each of these conditions  Identify key rehabilitation considerations for individuals with ALS and PPS. AMYOTROPHIC LATERAL SCLEROSIS (ALS) ALS – Introduction/Incidence  Progressive, degenerative neurogenic disorder  “Lou Gehrig’s Disease”  Most common form of motor neuron disease Motor Neuron Diseases A group of inherited and sporadic clinical disorders of UMN’s, LMN’s or a combination of both – ALS – Primary Lateral Sclerosis  Degeneration of upper motor neurons – Progressive bulbar palsy  Degeneration of motor neurons of CN IX - XII – Progressive muscular atrophy  Loss of lower motor neurons ALS – Introduction/Incidence  U.S. Prevalence: 9.9 per 100,000 adults  U.S. Incidence: 1.6 persons per 100,000  Approx. 32,000 current cases in U.S.  6045 new cases/year in United States  Average age at onset = mid to late 50’s – Most commonly develops between ages of 55 and 75 – Can occur at any age between 20 & 90  Incidence in males > females  Military veterans 1.5 to 2 times more likely to develop ALS ALS - Etiology  Cause unknown: – 90% -95% sporadic – 5% - 10% familial: various genes may be involved:  Mutation in C9ORF72 gene: most common genetic cause of ALS: about 1/3 of cases – also linked to Frontotemporal dementia (FTD)  Mutation in superoxide dismutase-1 (SOD 1) gene on chromosome 21: about 20% of cases  TDP43 gene; FUS gene; ubiquilin 2 gene  June 2021: newest discovery: childhood form of genetic ALS (as young as 4 y.o.a)- linked to SPTLC1 gene ALS - Etiology  Theories: – Glutamate Excitotoxicity  Excess extracellular glutamate in CNS – Oxidative Injury  Accumulation of free radicals leads to cell death by oxidizing cell membranes, proteins or genetic material – Protein Aggregates  Abnormal clumps of protein in motor neurons found in persons with ALS ALS - Etiology  Theories: – Axonal Strangulation:  Neurofilamentsof axons become tangled, so nutrients cannot reach cell bodies & cell death occurs – Autoimmune-Induced Calcium Influx:  Calcium channel antibodies have been isolated which may lead to prolonged influx of calcium into neurons, resulting in cell death ALS - Etiology  Theories: – Viral infections – Deficiency of Nerve Growth Factor – Apoptosis (programmed cell death) – Physical trauma – Strenuous physical activity – Environmental toxins:  Lead  Aluminum  Agricultural chemicals  Selenium in drinking water  Exposure to electrical shocks ALS - Pathology  Affects Upper motor neurons (UMN) & Lower motor neurons (LMN) – Progressive degeneration of motor neurons in spinal cord, brainstem & motor cortex  Massive loss of Anterior Horn Cells of spinal cord (LMN): – Results in muscle atrophy & weakness (amyotrophy)  Loss of Betz cells in motor cortex (UMN) leads to demyelination & gliosis of corticospinal & corticobulbar tracts (lateral sclerosis): – Results in UMN symptoms ALS - Diagnosis  Primarily based on clinical findings – Pattern of signs & symptoms along with inclusionary & exclusionary diagnostic tests  Consistent diagnostic criteria: – Absence of sensory involvement BUT:  Recent research shows some sensory impairments may exist in ALS  Essential for confirmed Dx of ALS: – Progression of S & S ALS - Diagnosis  No single lab test can confirm Dx of ALS – 70% of patients have increased CPK (creatine phosphokinase) – Genetic testing for patients with family Hx of ALS  EMG/NCV: – Confirm LMN disorder without peripheral neuropathy or polyradiculopathy – NCV – usually normal – EMG: signs of active denervation  Spontaneous fibrillations  Fasciculations with giant or large unit spikes with voluntary movement ALS - Diagnosis  MRI – Primary role of imaging in ALS is to exclude other causes  MS  Cervical degenerative disc disease – Some typical MRI findings in ALS have been described in literature  Highsignal intensity of corticospinal tract, extending from corona radiata through posterior limb of internal capsule, ventral brain stem and into spinal cord Subcortical white matter fibers of motor cortex Posterior limb of internal capsule Coronal view: cerebral cortex, through corona radiata, internal capsule & ventral brain stem ALS - Diagnosis  World Federation of Neurology: – Suggested diagnostic criteria for patients with ALS in clinical practice, clinical trials and research: looks at UMN/LMN findings in 4 regions of body:  Clinically Possible  Clinically Probable with Laboratory Support  Clinically Probable  Clinically Definite: – Concomitant (simultaneous) UMN & LMN signs in 3 spinal regions (cervical, thoracic, lumbar) OR – UMN & LMN signs in bulbar region and at least 2 spinal regions Revisions of Diagnostic Criteria ALS – Clinical Manifestations  Earliest clinical markers: – Muscle weakness:  Hallmark initial sign  Focal, asymmetrical  Occurs in hands, feet, arms, legs and/or muscles of speech, swallowing or breathing  Occurs in 60% of patients with ALS  Most patients have lost 80% of motor neurons by the time weakness is noticeable ALS – Clinical Manifestations  Later in disease process: – Weakness spreads to include most musculature throughout body:  Earlydistal limb involvement, then proximal limb then bulbar symptoms  Flexors weaker than extensors  Asymmetrical weakness characteristic – Dysphagia – Dysarthria – Respiratory dysfunction ALS – Clinical Manifestations  80% with UMN signs  Cognitive function often normal – 35%- 50% may have cognitive impairments  Pseudobulbar affect – Pathologic (uncontrollable) crying or laughing  Bowel& bladder function usually normal  Oculomotor nuclei usually spared ALS – Clinical Manifestations  LMN Signs & Symptoms – Muscle weakness – Hyporeflexia – Hypotonicity – Muscle cramps (denervated & not contracting properly due to painful signal) – Fasciculations (especially of tongue) – Atrophy ALS – Clinical Manifestations  UMN Signs & Symptoms – Spasticity – Pathological reflexes – Hyperreflexia – Muscle weakness ALS – Clinical Manifestations  Bulbar Signs & Symptoms – Dysphagia – Dysarthria – Sialorrhea – Pseudobulbar affect ALS – Clinical Manifestations  Respiratory Signs & symptoms – Exertional dyspnea – Nocturnal respiratory difficulty – Orthopnea – Hypoventilation – Secretion retention (cannot cough out stuff) – Ineffective cough ALS – Clinical Manifestations  Cognitive Signs & Symptoms – Range from mild to severe  Frontotemporal dementia (FTD) or ALS-Frontotemporal spectrum disorder – Difficulty with:  Verbal fluency (cannot find correct word and may sound like stuttering)  Visual attention  Language comprehension  Memory  Planning & Abstract reasoning  Intellectual/executive function (problem solving, planning) ALS – Clinical Manifestations  Cognitive Signs & Symptoms – ALS-Frontotemporal spectrum disorder  About 10% of individuals with ALS  Most common variant is Behavioral variant FTD (bvFTD) – Personality changes – Apathy – Progressive decline in socially appropriate behavior, judgment, self-control and empathy  Disinhibition, compulsive behaviors, overeating/other changes in eating habits or diet, lack of insight ALS – Clinical Manifestations  Rare impairments – Sensory – Bowel & bladder dysfunction – Ocular palsy ALS – Clinical Manifestations  Secondary & Composite impairments – Fatigue/ deconditioning – Weight loss – Cachexia (muscle wasting, atrophy, weakness, etc – ROM – Tendon shortening – Joint contracture or subluxation – Pain – Balance/postural control – Gait disturbances ALS – Disease Course  Onset with UE or LE weakness: more common  Onset with bulbar symptoms: least common  Unremitting spread of weakness throughout body: – Total paralysis of spinally innervated musculature & muscles innervated by cranial nerves  More rapid loss of strength in UE’s than LE’s  Death usually due to respiratory failure – Death most often occurs 3 – 5 years after diagnosis ALS – Disease Course  Assessment Tools to chart progression of ALS: – Amyotrophic Lateral Sclerosis Severity Scale: 4 categories of function: LE, UE, Speech & Swallowing  10 point ordinal rating scale  Provides rapid functional assessment of disease stage – 5 stage scale being used in clinical drug trials ALS - Prognosis  Death from respiratory failure in almost all cases  More rapid progression to death if onset with bulbar S & S vs limb onset  Median survival 4.08 years after onset: – 50% die within 18 months of DX – 9% to 40% survive 5 years – 8% to 16% survive10 years (usually on ventilator) – 5% survive > 20 years ALS - Prognosis  Factors related to better prognosis – Age at time of onset strongest relationship to prognosis < 35 to 40 yrs of age at onset with better 5 year survival rates – Less severe involvement at time of diagnosis – Longer time between onset & diagnosis – No symptoms of dyspnea at onset – Psychological well-being ALS - Prognosis  Small number of patients with ALS exhibit halting of progression of disease or remittance of symptoms – No known reason why or how this occurs ALS – Medical Management  Drugs approved by FDA to treat ALS:  Riluzole (3 variations) – Prolongs survival of patients with ALS by slowing progression of disease  slowsdamage to motor neurons but does not reverse damage that has already occurred  Decreases levels of glutamate – Rilutek: oral tablet – Tiglutik: thickened liquid form (uses syringe) – Exservan – oral film (dissolves on tongue) ALS – Medical Management  Drugs approved by FDA to treat ALS (cont’d)  Edaravone (Radicava):Approved by FDA in May 2017 – Neuroprotective effect: Slows decline of physical functioning/progression of ALS  Free radial scavenger: counteracts oxidative stress caused by free radicals  AMX0035 (Relyvrio): Approved by FDA in Sept 2022 but voluntarily withdrawn from market after phase 3 trial failed to show efficacy ‒ Combination of sodium phenylbutyrate and taurursodiol ‒ Slows disease progression by slowing or preventing motor neuron cell death by targeting the endoplasmic reticulum and mitochondria of the MNs and blocking stress signals in the cells ALS – Medical Management  Drug approved by FDA to treat ALS associated with SOD1 mutation:  Tofersen (Qalsody): approved by FDA in April 2023 ‒ An antisense oligonucleotide (ASO) which binds to specific molecules of RNA produced from the mutated SOD1 genes ‒ Mutations in the SOD1 gene are thought to cause abnormal clumps of proteins within motor neurons which interfere with normal cell function ‒ The ASO stops these toxic SOD1 proteins from being made ALS – Medical Management Tofersen mechanism of action: ALS - Research  Pharmacological treatments  Gene therapy approaches  Stem cell treatments – Brainstorm study: use patient’s own stem cells from bone marrow – Fetal-derived neural cells introduced into patient’s spinal cord ALS – Medical Management  Symptomatic treatment – Muscle cramps  Various meds (dilantin, atretol, valium) – Spasticity  Baclofen, tizamidine, diazepam – Fasciculations  Avoid or minimize caffeine & nicotine  Ativan – Pain  Non-prescription or prescription meds ALS – Medical Management  Symptomatic treatment: – Dysphagia:  Speech/OT/PT consult  Dietaryconsult  Meds to help with excessive drooling& increased mucus  Feeding tubes – Pseudobulbar affect:  Nuedexta  Uncontrollable emotional state ALS – Medical Management  Symptomatic treatment: – Dysarthria:  Speech therapy  Adaptive communication devices – Respiratory management  Respiratory therapy  Pulmonary PT – Chest PT – Breathing exercises – Energy conservation ALS – Medical Management  Respiratory management (cont’d): – Long term mechanical ventilation:  Home mechanical ventilation (HMV)  Sometimes > 1 year on HMV  Non-invasive ventilation: – BiPAP = bilevel positive airway pressure unit – Provides greater inspiratory pressure than expiratory pressure to decrease work of breathing ALS – Medical Management  Respiratory Management (cont’d): – Non-invasive ventilation:  Extends survival by several months  Improves quality of life – Progress to ventilation via tracheostomy OR – Palliative care ALS – Medical Management  Maintenance of nutrition  Family education  Psychological support  Palliative care Rehabilitation Considerations  To develop plan of care, need to consider: – Rate of disease progression – Stage of disease – Extent & areas of involvement – Need to re-examine at regular intervals  Atend stage, goal : optimize health & improve quality of life Rehabilitation Considerations  Goals: – May be difficult to set due to progressive nature of ALS – Related to maintaining maximal independence in daily life & positive quality of life as long as possible Rehabilitation Considerations  Patient/family/caregiver education  Psychological support  Referral to other healthcare professionals Rehabilitation Considerations  Special Therapeutic Considerations: – Prevention of disuse atrophy:  Prevent further disuse beyond level caused by disease process itself – Prevention of overuse injury:  “Do no harm”  Research: vigorous exercise damaged muscles with less than 1/3 of motor units functional  Amount of strengthening proportional to # of intact motor units  Avoid heavy eccentric exercise Rehabilitation Considerations  Prevention of overuse injury (cont’d): – Studies:  Weakened, denervated muscle may not be able to tolerate amount of exercise needed for training effect to occur in normal muscle  Strength training of muscles with less than 10% of normal strength is ineffective https://www.youtube.com/watch?v=KHgu H9sRN7M https://www.youtube.com/watch?v=b5lGe usOCxw POSTPOLIO SYNDROME (PPS) Poliomyelitis - Introduction  Caused by poliovirus  Most commonly affects children  95 - 99% of people infected with poliovirus develop no illness or only mild case  1- 5% of infected people develop polio: – Poliovirus spreads to CNS & attacks motor neurons in spinal cord & brain – Results in assymmetric flaccid muscle paresis or paralysis  LE’s more affected than UE’s Poliomyelitis - Introduction  Neurological recovery from acute poliomyelitis affected by: 1. Motor neurons that recover & resume normal function 2. Recovered neurons develop terminal axon sprouts (collateral sprouting) to reinnervate orphaned muscle fibers: giant motor units 3. Innervated muscle fibers can be hypertrophied by intensive exercise: denervation hypertrophy Poliomyelitis - Introduction  Functional recovery from acute poliomyelitis: 1. Increased functional ability by neuromuscular learning: practice of a task leads to increased skill & performance without increased muscle strength 2. Increased recruitment of giant motor units for the task with use of the muscles at high levels of their already reduced capacity Poliomyelitis - Introduction  Functional compensation: – In early epidemics, patients with polio told to exercise for years – Used “heroic” compensatory methods for function:  Used muscles at high level of capacity  Substitute stronger muscles with increased energy expenditure  Used ligaments for stability with resultant hypermobility Poliomyelitis - Introduction  Long term effects of substitution & overcompensation: – Microtrauma of ligaments & joint structures – Exhaustion of neuromuscular units Postpolio Syndrome  In1970’s & ‘80’s, polio survivors developed new weakness in muscles previously affected by polio & in unaffected muscles  Late effects of poliomyelitis = postpolio syndrome: – Complex combination of primary & secondary impairments resulting in neuromuscular, musculoskeletal & psychosocial problems Postpolio Syndrome: Prevalence  Affectsbetween 20% to 85% of polio survivors  In 1987, 1.6 million cases estimated in U.S. – No recent surveys; exact incidence is unknown  Onset is approximately 15 to 30 yrs after acute polio infection Postpolio Syndrome – Etiology/Pathology  Unknown but several theories:  Decompensation of a chronic denervation & reinnervation process – Remaining healthy motor neurons can no longer maintain new sprouts – Denervation exceeds reinnervation  Central mechanism dysfunction – Motor cortex with decreased capacity to control locomotor activity Postpolio Syndrome – Etiology/Pathology  PPS due to loss of strength 20 to the usual stresses of aging – Normal loss of motor neurons due to aging but patients with polio already have depleted motor neuron pool Postpolio Syndrome – Etiology/Pathology  Neurons previously affected by polio that had showed recovery may not have returned to normal – would be at risk for premature aging & failure  Metabolic exhaustion of giant motor units – pruning of axon sprouts to decrease the # of muscle fibers innervated by a single motor unit Postpolio Syndrome – Etiology/Pathology  Neuromuscular junction transmission deficits: – May result in muscle fatigue/decreased muscle endurance  Scarring within the motor units  Increased weakness due to weight gain Neurons affected by acute polio and post polio Schematic representation of motor units to a muscle Postpolio Syndrome – Clinical Manifestations  Fatigue: – Most common symptom – Sudden, overwhelming exhaustion – More prominent in late afternoon & early evening – May not improve after rest periods – Somnolence & difficulty concentrating & remembering – Decreased muscular endurance – Increased muscular fatigability Postpolio Syndrome – Clinical Manifestations  New muscle weakness: – Asymmetric & scattered weakness may be present; proximal &/or distal – Most prominent in previously affected muscles BUT  Previously unaffected muscles may become weak – May be due to disuse, overuse, chronic weakness & weight gain  Muscle atrophy Patient with Postpolio Syndrome: Atrophy of involved LE muscles Postpolio Syndrome – Clinical Manifestations  Muscle pain: – Usually described as deep pain/high intensity – May be component of myofascial pain syndrome or fibromyalgia – Extremely prevalent in PPS – Can include muscle cramps & fasciculations  Cramping pain in proximal LE  Aching pain in neck & shoulders, low back – Associated with mechanical stress on muscles, ligaments, tendons, joints Postpolio Syndrome – Clinical Manifestations  Swallowing dysfunction – Occur in patients with bulbar & nonbulbar postpolio – Subclinical asymmetric weakness in pharyngeal constrictor muscles almost always present in PPS Postpolio Syndrome – Clinical Manifestations  Gait Disturbance: – Progressive weakness – Pain due to osteoarthritis – Joint instability – Common in patients who have ceased to use assistive devices  New difficulty with ADL’s – Associated more with LE function than UE Functional Compensation in Gait Postpolio Syndrome – Clinical Manifestations  Respiratory Dysfunction – Most prevalent in patients with residual respiratory muscle weakness – May be due to:  New respiratory muscle weakness  Scoliosis  Poor posture  Pulmonary emphysema  Cardiovascular insufficiency Postpolio Syndrome – Clinical Manifestations  Cold intolerance  Sleep disorders: – Sleep apnea:  Residual dysfunction of surviving bulbar reticular neurons  Obstructive apnea due to pharyngeal weakness & musculoskeletal deformities  Diminished strength of respiratory, intercostal & abdominal muscles Postpolio Syndrome – Diagnosis Diagnostic Criteria – Confirmed medical hx of – Recent muscular polio weakness with sudden – Partial or almost onset & quick complete neurological progressing deterioration recovery after acute – At least two new period symptoms from the – Period of neurological following: stability for at least 15  Excessive fatigue yrs  Muscle or joint pain  Muscle atrophy  Cold intolerance – No other medical explanation Postpolio Syndrome - Diagnosis  Differential Diagnosis: need to rule out: – ALS – MS – Hypothyroid myopathy – Other conditions:  Anemia  Chronic infection  Infectious myopathy  Myasthenia gravis  Weakness due to aging  Weight gain Postpolio Syndrome - Diagnosis  Lab studies: CBC, CSF & imaging studies: – Blood test for creatine kinase  Elevated in PPS – Used to exclude other conditions  EMG/NCV: – Sensory NCV – usually normal – Motor NCV – normal but may be slowed – EMG:  Abnormalities of chronic denervation – Muscle biopsy Postpolio Syndrome - Diagnosis  National Rehabilitation Hospital Postpolio Limb Classification: – I No clinical polio – II Subclinical polio – III Clinically stable polio – IV Clinically unstable polio – V Severely atrophic polio NRH Postpolio Limb Classification Clinical Course of Postpolio Syndrome Postpolio Syndrome - Prognosis  Symptoms of PPS slowly progressive  Periods of stability from 3 – 10 years Postpolio Syndrome – Medical Management  Symptomatic treatment: – Fatigue – drugs such as anticholinesterases  Only partial success reported – Pain  Pain meds – Orthopedic support/interventions  Surgery, orthotics  IVIg (infusion treatment)  Reduced pain, improved quality of life, improved strength  Autoimmune problem? Rehabilitation Considerations: Examination  Habitual postures: History  Muscle strength – Sleeping – –Sitting Test specific muscles, not just gross motions –  ROMStanding – Walking – Hypermobile joints  Aerobic capacity/fatigue – Hypomobile joints   Orthotic/adaptive History of physicalequipment needs activity & intensity Rehabilitation Considerations  Decrease workload of muscles: – Energy conservation – Weight reduction – Locomotion – Correction of posture & gait deviations – Orthotics – Exercise  Strengthening and aerobic exercise programs  Rotate exercise types: stretching, aerobic conditioning, strengthening, ROM to avoid fatigue Rehabilitation Considerations  Muscle & Joint Pain: – Heat – Electrical stimulation – Stretching exercises/ROM – Muscle relaxation exercise – Biofeedback – Lifestyle changes Postpolio Syndrome – Psychosocial Considerations  Coping styles  Response to new diagnosis  Compliance https://www.youtube.com/watch?v=5XfDG 7BqRO8 https://www.youtube.com/watch?v=MYze5 ZGGi-c