Motor Neuron Disorders: UMN & LMN

Motor Neuron Disorders Overview

• Neurologic diseases with clinical and pathological diversity
• Characterized by progressive motor neuron degeneration
• Can be sporadic or hereditary

Upper Motor Neurons (UMNs)

• Originate in the primary motor cortex of the cerebrum (precentral gyrus)
• Possess long axons that form corticospinal and corticobulbar tracts

Lower Motor Neurons (LMNs)

• Originate in the brainstem (cranial nerve [CN] motor nuclei) and spinal cord (anterior horn cells)
• Innervate skeletal muscles directly

Upper Motor Neuron Disorders

• Primary Lateral Sclerosis
• Tropical Spastic Paraparesis
• Lathyrism
• Epidemic Spastic Paraparesis
• Familial (Hereditary) Spastic Paraplegia

Combined UMN & LMN Disorders

• Amyotrophic Lateral Sclerosis
• Familial ALS
• Western Pacific ALS
• Groote Eyladt MND
• Postencephalitic ALS
• Juvenile Inclusion Body ALS

Lower Motor Neuron Disorders

• Spinal Muscular Atrophies
• Monoclonal gammopathy and MND
• Cancer and MND
• Poliomyelitis and Post-polio syndrome

Primary Lateral Sclerosis (PLS)

• Slowly progressive, degenerative disease
• Affects upper motor neurons
• Progressive spasticity of unknown cause
• Impacts lower extremities, trunk, upper extremities, and bulbar muscles, typically in that order
• Usually sporadic, affecting adults aged 40-60
• Disease duration of 3 years prior to diagnosis
• Defined by isolated Upper Motor Neuron signs for 4 years after symptom onset
• Clinical features include spasticity, spastic dysphagia and dysarthria, and urinary incontinence in later stages
• Pathological findings include a reduced number or absence of Betz's cells in the primary motor cortex or precentral gyri with degeneration of corticospinal pathways
• Slow progression, maintaining high independence levels for years
• Survival typically lasts two to three decades or longer
• Differential diagnosis includes UMN-dominant ALS, structural spinal cord disorders, pure HSP, metabolic disorders (Vitamin B12 deficiency), viral infections, and primary progressive multiple sclerosis (progressive spastic paraparesis mainly in the legs)

Hereditary Spastic Paraparesis

• Also known as Familial Spastic Paraplegias or Strumpell-Lorrain Disease
• Clinically and genetically heterogeneous group of hereditary disorders
• Characterized by slowly progressive spastic paraparesis
• Pure (uncomplicated) or complicated forms exist, based on isolation or major clinical features
• Pure autosomal dominant HSP is the most common form
• Clinical features of pure HSP include onset from infancy to the 8th decade
• Slow progression, severe spasticity, hyperreflexia, weakness in lower extremities (LE) with extensor plantar response, difficulty walking, mild upper extremity involvement, and sensory impairment (diminished vibration and proprioception)
• Urinary sphincter dysfunction occurs in 50% of cases
• No cranial nerve and corticobulbar tract involvement
• Spasticity accompanies conditions related to central and peripheral nervous system involvement, including muscle amyotrophy, optic atrophy, pigmentary retinopathy, mental retardation, extrapyramidal disease, ataxia, dementia, deafness, ichthyosis, peripheral neuropathy, and epilepsy in complicated HSP
• Pathology involves crossed and uncrossed corticospinal tracts to the LE and fasciculus gracilis fibers; axonal degeneration occurs, maximal in terminal portions of corticospinal tracts, lesser in dorsal column fibers
• Prognosis is compatible with normal life expectancy
• Differential diagnosis is PLS, dopa-responsive dystonia, Arginase Deficiency

Amyotrophic Lateral Sclerosis (ALS)

• Also known as Lou Gehrig Disease
• It's the most common adult-onset neurodegenerative disease involving the motor neuron system
• Fatal disorder characterized by progressive skeletal muscle weakness and wasting or atrophy, spasticity, and fasciculations, culminating in respiratory paralysis
• Three types include: sporadic, familial, and Western Pacific ALS (with or without Parkinsonism-dementia complex)
• Most cases are sporadic; 5-10% are familial
• Smoking may increase risk for sporadic ALS
• Peak onset age is 55 – 75 years
• Males are more affected than females, but not as much in familial cases
• Key theories for pathogenesis include glutamate-induced excitotoxicity, oxidative injury, altered mitochondrial function, cytoskeleton alterations, axonal transport dysregulation, neuroinflammation, immunomodulation, and autoimmunity
• Clinical features include increased incidence with age, peaking around 75 years; familial ALS onset is a decade earlier, 2/3 present with focal muscle weakness in upper and lower limbs, 1/4 with dysarthria, 5% with respiratory weakness, flail arm and leg variants with LMN symptoms, and 5% with frontotemporal dementia
• Pathology involves degeneration or loss of motor neurons in the brainstem and spinal cord; also, degeneration of pyramidal neurons and tracts; Onuf's nucleus is preserved.
• Progression is typically relentless
• About 50% survive less than 3 years post-diagnosis, about 20% survive 5-10 years
• Patients invariably develop respiratory weakness and die from pulmonary complications
• Differential diagnosis includes PLS, HSP, SMA, X-linked spinobulbar muscular atrophy, peripheral neuropathies, myopathies, postpolio syndrome, and Hiramaya disease (structural cervical cord disorder from dynamic compression)

Stages of ALS

• Stage 1: Mild weakness, clumsiness, ambulatory, independent with ADLs
• Stage 2: Moderate, selective weakness, slightly decreased independence in ADLs
• Stage 3: Severe, selective weakness in ankles, wrist and hands, moderately decreased independence, tendency to fatigue with long distances
• Stage 4: Hanging arm syndrome with shoulder pain, wheelchair dependent, severe lower extremity weakness, able to perform some ADLs with fatigue
• Stage 5: Severe lower extremity weakness with moderate-severe upper extremity weakness, wheelchair dependent, increasingly dependent in ADLs, risk for skin breakdown
• Stage 6: Dependent with all positioning, completely dependent in all ADLs, extreme fatigue

Spinal Muscular Atrophies (SMA)

• A group of genetically determined neuromuscular disorders
• Characterized by progressive degeneration of spinal LMN
• Autosomal recessive inheritance is most common
• It’s the 2nd most common autosomal recessive disease in humans
• The International SMA Consortium defined the following clinical groups: Type I SMA (Acute form, Werdnig-Hoffmann Disease), Type II SMA (Intermediate form), Type III SMA (Juvenile form, Kugelberg-Welander Disease), Type IV (Adult form)

Types of SMA

• Type I (Werdnig Hoffman, Acute Infantile): Onset before 6 months, unable to sit independently, poor survival
• Type II (Werdnig Hoffman, Chronic Infantile): Onset before 18 months, can sit but not ambulate independently, 50% survival to mid-20s
• Type III (Kugelberg-Wellander, Chronic Juvenile): Onset after 18 months, can ambulate, normal survival
• Type IV (Adult Onset): Onset in mid-30s, normal survival

Acute Infantile SMA

• Severe, resulting in death before age 2
• Will not attain independent sitting
• At birth, baby is hypotonic with generalized weakness and absent reflexes
• Infant lie motionless with LE abducted in frog leg position
• Face has no expression because of weakness
• Cause of death – respiratory failure

Chronic Infantile SMA

• Less severe with symptoms apparent 6-18 months
• Attains sitting but not ambulation without assistance
• Median onset of death is 12
• Weakness and atrophy predominantly proximal with LE more involved initially than UE
• Muscle stretch reflex are reduced or absent
• Sensation is normal
• Scoliosis, thoracic deformities and equinus deformity of the feet apparent as child grows
• Tongue fasciculations is diagnostic

Juvenile SMA

• Symptoms onset between 5 and 15 years
• Developmental milestone including independent walking are acquired
• Initially, child would have frequent falling and difficulty climbing stairs
• Proximal muscle weakness > distal
• Weakness is relatively static or slowly progressive
• (+) hand tremor, tongue fasciculation and areflexia
• Limb fasciculation is predominant

Adult-Onset SMA

• Mean age onset at mid 30s
• Can be inherited as either autosomal recessive of dominant
• Slowly progressive proximal limb weakness and fasciculations
• DTRs are either absent or depressed
• Normal life span with benign disease course

Rehabilitation in SMA

• Early stage: stretching of wrist flexors, intrinsic hand muscles, hip ER and abductors, strengthening of wrist extensors, TLSO for scoliosis
• Intermediate stage: physical therapy
• Advanced stage (supportive): electrical stimulation, splinting for positioning and contracture prevention, PROMEs, ventilatory support

Poliomyelitis

• Disease of the anterior horn motor neurons of the spinal cord and brainstem
• Caused by poliovirus (RNA virus, Picornavirus family)
• Hallmark: Flaccid asymmetric weakness and muscle atrophy
• Due to loss of motor neurons and denervation of their associated skeletal muscles
• Can be effectively prevented through immunization but cannot be treated
• Associated signs and symptoms like fever, malaise, myalgia, sore throat, GI upset, aseptic meningitis, localized fasciculation, asymmetrical weakness, and dysautonomia.
• Paralysis remains static for several days, then slow recovery over months to years
• Strength improvement through recovery and collateral sprouting

Types of Poliomyelitis

• Abortive: Minor illness, fever, headache, vomiting, diarrhea, sore throat
• Non-paralytic: Abortive symptoms with signs of meningeal irritation and muscle spasms
• Paralytic: Paralysis during febrile state; spinal vs. bulbar involvement

Poliomyelitis Prognosis

• Possible to progress and remit
• 25% severe disability
• 25% mild disability
• 50% complete recovery
• Mortality is 1-4% in children, 10% in adults with bulbar and respiratory involvement

Postpolio Syndrome

• Loss of anterior horn cell
• Death of motor neuron due to burnout
• Halstead-Ross Criteria: history of polio, recovery, stability for 15 years, return of symptoms, no other explaining factor
• Prognosis: Slowly progressive with periods of stability from 3-10 years
• Differential Diagnosis: Anemia, chronic infection, deconditioning, hypothyroidism, Myasthenia Gravis, ALS, Multiple Sclerosis

Neuromuscular Junction (NMJ) Disorders

• Interfere with transmission of electrical impulses from peripheral nerve to muscle
• Can be acquired or inherited
• Presence of autoantibodies against presynaptic calcium channels or postsynaptic acetylcholine receptors
• Common presentation: weakness and fatigue on exertion, improves after rest

Myasthenia Gravis (MG)

• Acquired autoimmune disorder
• Presence of autoantibodies targeting ACh receptors at motor end plate
• Circulating AChR antibodies present in up to 90% of cases
• IgG and complement components deposited on postsynaptic membrane
• Female to male ratio is 6:4
• Women in 3rd decade
• Men in 6th to 7th decade

Types of MG

• Ocular MG: Involves external ocular muscles, usually bilateral, asymmetric, with ptosis and diplopia; 50% progress to generalized MG within 2 years
• Generalized MG: Involves general voluntary muscles; may be Muscle-specific Tyrosine Kinase (MuSK) positive → poor response to acetylcholinesterase and thymectomy; AChR clusters in the postsynaptic NMJ; 40% will be AChR negative on blood testing
• Signs and symptoms: Fluctuating symptoms, provoked by exertion, fatigue, curtain sign, proximal muscles affected more than distal, commonly associated with thymoma
• Diagnostic tests: Endrophonium (Tensilon) test- acts within seconds, assess ptosis/ ocular movements
• Diagnostic tests: Electromyography- supramaximal stimulation shows >10% amplitude decrement; Blood tests- AChR antibody test
• Treatment involves anticholinesterases, thymectomy, alternate-day prednisone, azathioprine, rituximab, IV immunoglobulin, plasmapheresis
• Treatment in pregnancy requires individualization; mild disease can be treated with pyridostigmine; corticosteroids, Azathioprine, IVIg and Plasmapheresis are safe

Lambert-Eaton Myasthenic Syndrome

• Acquired autoimmune disease
• Autoantibodies are directed at the calcium channels in the presynaptic area
• Associated with small cell lung cancer (60% of cases)
• Patients >40 years old (70% men, 30% women)
• Syndrome may precede tumor diagnosis by several years
• Signs and symptoms: Weakness & fatigability of proximal limb, extraocular/bulbar muscles spared, mainly lower limbs, hypoactive reflexes and autonomic manifestations.
• Treatment: 3,4 Diaminopyridine, pyridostigmine

Drug-Induced Myasthenic Syndrome

• Seen in overdose or renal/hepatic impairment
• Associated drugs: Polymyxin and Aminoglygcoside antibiotics, antiarrhythmic drugs, B-adrenergic blockers, phenothiazines, Lithium, Succinylcholine,Trimethaphan, Methoxyflurane, Magnesium, and Organophosphate intoxication

Botulism

• Caused by toxin produced by clostridium botulinum
• Spore forming anaerobic gram-positive bacteria
• Toxin A and B are most potent.
• Pathophysiology: Toxin prevents release of acetylcholine at the presynaptic cleft; binds to acetylcholine
• Symptoms- descending symmetric flaccid paralysis, cranial nerves affected,
• Prognosis: Mortality rate- Foodborne (5-10%), Wound (15-17%), Infant and Prolonged Months for recovery.