Introduction to Clinical Neurology

Approach to Weakness and Neuromuscular Diseases

Daniel Lowenstein, MD Andy Josephson, MD Wade Smith, MD, PhD

John Engstrom, MD
Betty Anker Fife Endowed Professor of Neurology Neurology Residency Program Director Clinical Chief of Service Department of Neurology, UCSF School of Medicine Potential Conflicts of Interest
! None

Learning Objectives

Learning Objectives
o! Be able to provide a neurologic description for the following: 1) weakness 2) the motor unit 3) myopathy, and 4) neuropathy o! Be able to distinguish between weakness as described by patients and weakness as found on neurologic examination

Learning Objectives
o! Be able to describe how injury to different portion of a motor unit produces weakness o! Be able to elicit motor and reflex examination findings that are used to assess weakness o! Be able to describe the pattern of motor, reflex, and sensory exam findings typical for myopathy, polyneuropathy, and radiculopathy

Learning Objectives
o! Be able to describe when weakness is a neurologic emergency o! Be able to describe the three mechanisms of nerve tissue recovery following nerve injury resulting in weakness

Introduction

Overview of Weakness
o! Very common symptom with highly variable clinical significance o! Distinguish what patients mean by weakness from true neurologic weakness using objective information from the neurologic examination

Weakness Defined by Patients

o! Impaired power with movement
! ! ! ! Decreased force when moving a painful limb Fatigue Excessive mental effort to initiate movement Inability to grip or use objects
!! Consider decreased sensation !! Consider impaired coordination or dexterity

Neurologic True Weakness

o! Failure to generate expected muscle force due to injury to the nervous system
! Upper motor neuron-injury to brain, brainstem, spinal cord-covered in other lectures ! Lower motor neuron-injury to motor nerve cell, nerve root, peripheral nerve, neuromuscular junction, or muscle

Anatomy and Normal Function

Weakness: The Motor Unit

o! Motor unit-a single motor nerve cell plus the muscle cells it innervates o! Many motor units in a nerve provide the electrical input to a muscle to generate muscle contraction and associated power

Weakness: The Motor Unit

How the Motor Unit Functions

o! Electrical impulses from the cortex activate the upper motor nerve cell which provides stimulation of the lower motor neuron cell in the spinal cord o! The spinal cord motor nerve cells generate current down the axons (action potentials) to the neuromuscular junction and ultimately to muscle o! Myelin insulates the axon so that the energy of electrical conduction can be transmitted over long distances without decay

Anatomy of a Motor Unit

Mixed Sensory and Motor Nerve

o! Motor and sensory neurons travel together from the nerve root into limbs
! Sensory nerve twigs to skin ! Motor nerve twigs to muscles

o! Nerve injuries affect sensory, motor, or both neurons, often in distinctive patterns

Pathophysiology

Type of Nerve Cell Injury

o! Myelin disorders-axonal conduction failure with extensive myelin loss o! Axonal disorders-structural or metabolic injury resulting in conduction failure o! Describe as sensory, motor, or sensorimotor o! Describe as demyelinative, axonal, or axonal and demyelinative

Motor Unit-Potential Injury Sites

o! Only 5 locations for Weakness in the PNS:
! ! ! ! ! Motor nerve cell Nerve root Nerve Neuromuscular junction Muscle

Motor Nerve Cell Body Injury

o! Site of injury-anterior horn of spinal cord o! May be accompanied by other signs of spinal cord injury o! If only motor nerve cell bodies, then no sensory examination findings o! Etiologies-Infectious (e.g.-poliomyelitis), degenerative, neoplastic, genetic, other

Nerve Root Injury (Radiculopathy)

o! Commonly due to narrowing of foramina for nerve root exit from spine or from inflammation induced by a herniated disk o! Often severe shooting pain from the spine o! Can be accompanied by focal motor and sensory findings in a nerve root distribution

Distal Axonal Polyneuropathy

o! Distal polyneuropathy-multiple nerves
! ! ! ! ! Begins in toes, spreads to feet, then ankles Eventually to knees, then thighs and hands Stocking-glove circumferential distribution Sensory > motor most common pattern Disrupted bioenergetics or axonal transport may be most evident at sites most distant from the motor or sensory nerve cell bodies

4 Buckets of Distal Polyneuropathy

o! Diabetes-likely a metabolic injury o! Alcoholism-likely a toxic injury o! Idiopathic-No specific cause is ever found o! Other-B12 deficiency, chronic renal insufficiency, hypothyroidism, vasculitis, autoimmune
! Subject of very long 1000 page+ textbooks! ! Beyond the scope of this lecture

Acquired Demyelinating Polyneuropathy

o! Random foci of demyelination of nerves o! Equally likely to affect proximal and distal muscle strength or sensation o! Diffusely absent reflexes with rapidly progressive weakness over hours to days o! Treat acutely to reduce need for artificial ventilation and prevent loss of ability to walk

Mononeuropathy: CTS
o! Mononeuropathy-Injury to a single nerve, often by compression or direct trauma o! Carpal Tunnel Syndrome-Median nerve compression at the midline palmar wrist
! Most common treatable mononeuropathy ! 90-95% with full recovery of sensory and motor function, resolution of symptoms

N e u r o m u s c u l a r J u n c t i o n ( N M J ) We a k n e s s
o! Neuromuscular transmission failure-nerve to muscle o! Symmetric proximal arm or leg weakness with normal reflexes and sensation o! Example: myasthenia gravis
! Fluctuating diplopia and proximal limb weakness ! Loss of acetylcholine receptors needed for chemical signaling of motor nerve cell to muscle

o! Uncommon disorders that usually mimic muscle diseases

Myopathy
o! Muscle disease producing weakness o! Symmetric proximal arm or leg weakness with normal reflexes and sensation o! Diverse etiologies-inflammatory, genetic, metabolic, drug-induced, many others

Signs of Neuromuscular Resp Failure

o! Low O2 saturation or pO2 arterial blood gas o! Accessory muscles of respiration o! Vital capacity < 15-20 cc/kg o! 2/3 of air movement due to diaphragm contraction; 1/3 from chest wall muscles
! Injury to phrenic nerves, diaphragm muscle ! Injury to motor nerve cells at C3-5 in cord

Clinical Presentation

Approach to the Patient

o! Patients present with symptoms and signs, not diagnostic answers! o! How do we determine if the symptom of weakness makes neurologic sense o! Is the weakness true weakness or nonneurologic weakness?

Weakness Defined by Patients

o! Impaired power of movement
! ! ! ! Decreased force when moving a painful limb Fatigue-inability to sustain constant effort Excessive mental effort to initiate movement Inability to hold or use objects
!! Consider decreased sensation !! Consider impaired coordination or dexterity

Weakness Mimics: Breakaway

o! Breakaway weakness-variable resistance provided by the patient during the exam of a muscle
! Associated with pain-due to no true weakness or may mask mild weakness ! Unassociated with pain-due to lack of effort or inattentiveness

Describing Weakness
o! Neurologic weakness in following muscles! o! Breakaway weakness with pain in! o! Breakaway weakness without pain in! o! The same patient can have all three types! o! Do not over interpret breakaway weakness without pain-Lack of effort or inattentiveness; may just be part of the clinical context

Weak Patient: Pertinent History

o! Temporal sequence to establish tempo o! Shortness of breath o! Use functional activities as benchmarks
! Time from independent ambulation to cane to walker to wheelchair ! Ability to stand independently from a chair or reach overhead-proximal arms and legs

Weak Patient: Muscle Bulk

o! Bulk-compare the same muscles on the right and left placing your line of vision on a perpendicular to contour of the muscle
! Check for symmetry ! When reduced often indicates nerve or nerve root injury, but can also indicate disuse

Weakness: MRC Scale-Grade

o! 5-normal power o! 4-mild to moderate weakness o! 3-severe weakness, moves against gravity o! 2-moves across joint, not against gravity o! 1-flicker of muscle contraction o! 0-no muscle contraction

Weak Patient-Limb Power

o! Distal muscles
! Hand-Abductor pollicis brevis, first dorsal interosseous, finger extensors ! Foot-Toe flexors, great toe dorsiflexion, tibialis ant

o! Proximal muscles
! Upper arm-deltoids, biceps, triceps ! Leg-ilopsoas, quadriceps, hamstrings ! Trunk-neck flexors, neck extensors, sit up

Weakness: Deep Tendon Reflexes

o! Reflexes reduced or absent in association with loss of motor or sensory axons in a nerve or nerve root distribution o! Preserved in vast majority of muscle, nmj, or anterior horn cell disorders o! May be absent if no muscle left to contract or no anterior horn cells left to activate

Weakness: Sensory Findings

o! If no sensory findings, consider NMJ, muscle, or anterior horn cell disease o! If sensory loss distal and circumferential in legs, consider polyneuropathy or CNS o! If limb sensory loss in patch, is distribution in a nerve or nerve root distribution? o! Pain or tingling indicate abnormal sensory nerve function, not loss of function

Diagnosis

Weakness: Pattern Recognition

o! Use combination of power, reflex, sensory findings to localize motor unit injury o! Localization along the motor unit determines the differential diagnosis
! Can look to references for detailed Ddx and further evaluation of anterior horn cell, nerve root, nerve, nmj, and myopathic weakness

Weak Patient: Key Evaluation Features

o! o! AHC o! Nerve Root o! Polyneuropathy-Axonal o! Polyneuropathy-Demyelination o! NMJ o! o! Muscle o! * - in distribution of affected root Power Patchy ! or normal ! distal ! diffuse ! proximal (+/- bulbar) ! proximal Reflexes ! or normal !* ! distal ! diffuse normal normal Sensation normal ! or normal ! distal ! patchy/ normal normal normal

Weakness-Beyond Hx and Exam

o! The history/exam may not lead to a specific cause for weakness. Whats next?
! Consider imaging of spinal cord, nerve roots, nerves, or muscles ! Consider EMG-additional localization ! Consider blood tests for treatable causes ! Consider muscle biopsy for muscle disease ! Review medications for neuromuscular toxicity

T h e We a k P a t i e n t : H i s t o r y a n d E x a m i n a t i o n
NEUROLOGIC
UPPER MOTOR LOWER MOTOR NEURON NEURON

NON-NEUROLOGIC
FATIGUE BREAKAWAY

ANTERIOR HORN NERVE CELL ROOT

PAIN NMJ NERVEAxonal OR Demyelination MUSCLE

POOR EFFORT, INATTENTIVENESS

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Management

Emergent Neurologic Weakness

o! Establish ABCs-Airway, Breathing, Circulation o! Neuromuscular respiratory failure-due to acute demyelinating polyneuropathy (GBS or AIDP), advanced myopathy or advanced ALS, myasthenia gravis, or botulism o! Access to supplemental oxygen and mechanical ventilation o! Rx underlying cause-promote nerve recovery

Weakness-Management Approach
o! Treatment directed at underlying cause
! Halt ongoing nerve tissue injury (e.g.-IVIg for AIDP) ! We allow the natural history of nerve recovery to occur in the absence of ongoing injury ! Consider Physical or Occupational Therapy, bracing ! Aerobic conditioning ! Good nutrition

o! Maximize return of function (activities of daily living)

o! Share available prognostic information with patientmust be able to explain mechanisms of nerve recovery

Nerve Injury: Focal Demyelination

Nerve Recovery: Remyelination

o! Remyelination is robust-occurs over days to weeks, sometimes months o! Assumes underling cause for nerve damage is arrested
! Decompression of median nerve for CTS ! Autoimmune injury halted with IVIg in GBS

Collateral Sprouting Before Injury

Motor Axons Muscle Fibers

I II III IV

Collateral Sprouting After 3+ Months

Motor Axon

Muscle Fibers

I II III IV

Nerve Recovery: Local Reinnervation

o! Collateral sprouting from surviving axons close to the target muscle lead to reinnervation of the target muscle
! Onset 3-4 months after initial injury ! Need to have some residual power in the muscle after injury indicating that some axons are present ! Process may continue 18-24 months after initial injury

Axonal Degeneration Distal to Injury

Axonal Regeneration Distal to Injury

Axonal Regeneration from Injury Site

o! Optimum axon regrowth =.5-1.0 inches/month o! Factors limiting effectiveness:
! Worse with increasing patient age ! Worse with increasing distance from the site of injury to the target muscle ! Worse with ongoing nerve injury (e.g.-alcohol) ! Disrupted microenvironment (scar along pathway)

Practical Use of Nerve Recovery

o! 38 yo woman with known CTS refuses surgery because a friend told her it does not work and she may end up with a paralyzed hand o! She has mild weakness of right APB muscle, mildly decreased sensation over the palmar index finger o! EMG confirms moderate demyelination and mild axonal loss in the median nerve at the wrist o! How would you explain the mechanisms of possible nerve recovery to her?

Nerve Tissue Recovery: Mechanisms

o! Remyelination-Occurs over days, weeks, and sometimes months o! Collateral sprouting with reinnervation-Begins 12-16 weeks after injury; continues up to 2 yrs o! Axonal regeneration-1 inch/mo from injury site; limited by age, scar, distance of target muscle from injury, ongoing nerve injury

Future Directions

Future Possibilities
o! Prevention-diabetes, alcoholism o! Selective trophic factors-promote accurate, timely, and functional nerve regrowth o! Better imaging of nerve tissue and muscle o! Protecting nerves during times at risk (such as chemotherapy) known to cause nerve tissue injury

Summary

Take Home Points

o! You know how to interpret the history of weakness from a patient o! You know how to recognize weakness mimics from the history and examination!such as breakaway weakness o! You know how to elicit/interpret changes in the exam for power, reflexes, and sensation from a patient with true neurologic weakness

Take Home Points

o! You know how to identify a pattern of exam findings suggestive for specific types of neuromuscular weakness o! Develop differential diagnosis once pattern recognition complete o! You know how to use the natural history of nerve recovery to inform patients and families about what recovery to expect