The Patient with Peripheral Nervous System Disease by ijr13051


									     The Patient with
Peripheral Nervous System
   James F. Howard, Jr., M.D.
  Caroline M. Klein, M.D., Ph.D.
     Spencer G. Weig, M.D.
   Neuromuscular Disorders Section
      Department of Neurology

To understand the components of the motor unit
To understand the differentiating features of
weakness due to central system vs. peripheral
nervous system lesions
To gain an appreciation of the neurological
syndromes due to motor unit disease
      Anatomical Localization
       of Muscle Weakness

Weakness and sensory loss are defined by:
  their pattern of abnormality
  their associated clinical signs and symptoms

As such, these findings do not stand on their
own but must be interpreted as part of the other
elements of the examination
        Anatomical Levels
      for Muscle Weakness

Cerebral Hemisphere   Spinal Root/Plexus
Brainstem             Peripheral Nerve
Spinal Cord           Neuromuscular
Anterior Horn Cell
        CNS Patterns of Weakness

   Hemi           Crossed      Quad           Para
   Cortex         Brainstem   Cervical SC   Thoracic SC
 Subcortical                                Parasaggital
High Brain Stem                                  Courtesy of Timothy Fries, M.D
PNS PATTERNS of Weakness or Sensory Loss

                                              No Sensory
                                               Loss with
                                              this pattern

Root      Mono-nerve   Stocking-Glove*         Limb-Girdle
Root       1 Nerve     Polyneuropathy            Myopathy
Plexus                                             NMJ
                        *Distal Symmetrical         Courtesy of Timothy Fries, M.D
          Anterior Horn Cell Level
Anterior Horn
                     Pattern asymmetrical
                             LE > UE, Prox > Dist
                     Tone    ↓↓
                     Bulk    ↓ ↓ late
                     DTR’s   ↓ ↓ or absent,
                             unless ALS
                     Babinski absent unless ALS
                     Sensory normal
                     Other   fasciculations
        Spinal Root / Plexus Level
Spinal Root          Pattern myotome,
                             multiple roots
                     Tone     normal or ↓
                     Bulk     ↓ ↓ very late
                     DTR’s    ↓ or absent
                     Babinski absent
                     Sensory dermatome
                     Other    mod - severe pain
          Peripheral Nerve Level
                    Pattern nerve innervation
                            distal > proximal
Peripheral Nerve
                    Tone    normal or ↓
                    Bulk    ↓ late
                    DTR’s   ↓ or absent
                    Babinski absent
                    Sensory follows nerve
                            innervation or
                    Other   pain, autonomic
Neuromuscular Junction Level
              Pattern proximal > distal
                      lids, EOM’s
              Tone     normal
              Bulk     usually normal
              DTR’s    normal
              Babinski absent
              Sensory normal
              Other    fatigable, variable
Muscle Level
     Pattern proximal > > distal
     Tone     normal (or ↓)
     Bulk     ↓ late
     DTR’s    normal (or ↓)
     Babinski absent
     Sensory normal
     Other    +/- muscle
    CNS vs PNS Differentiation
         CNS                        PNS
Reflexes increased          Reflexes decreased
(may be delayed)            (absent Babinski)
+/- Babinski present        Decreased / normal tone
May be spastic              Atrophy may be severe &
(increased tone)            focal
Atrophy is mild, regional   Fasciculations may be
No fasciculations           present
Pain: Usually head or       Limb pain common,
spine                       superficial, contact
  Other Comparative Features
Central Nervous Sys            Peripheral Nervous Sys
  Associated cortical            Absent cortical features
  findings possible                 See other column
    visual field abnormality     Movements of normal
    parietal neglect             speed
  Slowing of movements
         Motor Unit Disease
Clues from the Patient’s History
When did it begin?
What is its course / progression?

What precipitates, exacerbates or relieves
the symptoms?

Is there a family history?
        Motor Unit Disease
Clues from the Symptom Onset
  muscular dystrophy, hereditary
  MG, SMA, periodic paralysis, monomelic
  MG, polymyositis, ALS
        Motor Unit Disease
    Eliciting a Family History
Most critical in children but not limited to
Must ask specific questions REGARDING!!!
    similar weakness, sensory abnormality or
    unusual body build, e.g. pes cavus,
    scapular winging, gynecomastia,
    gastrocnemius hypertrophy
    early deaths, miscarriages
             Motor Unit Disease
 Clues from the Family History
muscular dystrophies
hereditary neuropathies
periodic paralysis (channelopathies)*
congenital / genetic myasthenic syndromes*
genetic motor neuron disease*
exceedingly rare for MS, tumor, stroke
* uncommon
           Motor Unit Disease
Clues from the Motor Examination
What is the distribution of abnormality?
  symmetrical or asymmetrical?
The Role of Electrodiagnosis (EMG-NCV)
     in the Evaluation of Weakness

 Not generally useful in CNS disease
 Can answer the following questions:
   Is there disease of nerve root, plexus,
   peripheral nerve, neuromuscular junction or
   the muscle membrane?
   What is the distribution of abnormality?
   Is the pattern diagnostic of a disease entity?
   What is the severity / prognosis?
                                               Case #1

Progressive weakness in a 55-y.o.
  A 55 year old man turned his right ankle 3
  months ago
  Trouble walking since, dragging his foot
  Two months ago he noted difficulty lifting his
  left foot
  Six weeks ago he began to have trouble
  buttoning his shirt
                                             Case #1

        Clinical examination
There was wasting of the intrinsic muscles of the
hands and feet and on the lateral aspects of the
Fasciculations were prominent in the thigh and
shoulder muscles and around the eyes
Muscle stretch reflexes were hyperactive and
there was a brisk jaw jerk
There were bilateral Babinski signs
                                            Case #1

      Laboratory evaluation

Electromyography (EMG) - fibrillation potentials
in the muscles of 3 limbs and the tongue.
Reinnervation motor unit action potentials in
these muscles.
Nerve conduction studies (NCV) - normal
conduction velocity in sensory and motor
                                              Case #1

 Amyotrophic Lateral Sclerosis

In ALS, weakness frequently begins focally
but there is usually clinical evidence of widespread
upper and lower motor neuron dysfunction early on.
EMG demonstrates widespread denervation, even
in muscles that are clinically normal
                                              Case #2

Back pain & weakness in a 58-y.o.
  A 58 year old man “wrenched” his back moving
  furniture for his family
  Abrupt and severe pain radiating from his hip
  down lateral aspect of left leg to the lateral
  border of the left foot
  Also complained of muscle spasm in low back
  Not able to get comfortable; worse when sitting
  Pain worse with cough, straining to pass stool
                                           Case #2

        Clinical examination

There was weakness of foot dorsiflexion,
extension of great toe and eversion of the left
Muscle stretch reflexes were symmetrical
There was no sensory abnormality
                                             Case #2

       Laboratory evaluation
Performed 4 weeks after onset of symptoms
 LS Spine radiographs are normal
 MR imaging demonstrates a disc bulge at L4-L5
 Nerve conduction studies (NCV) - normal in
 sensory and motor nerves.
 Electromyography (EMG) - fibrillation potentials in
 the tibialis anterior, peroneus longus, EHL, biceps
 femoris (short head), gluteus medius and L5
 paraspinal muscles (other muscles normal)
                     Case #2

    MR Imaging

R                L
                                               Case #2

      Acute L5 Radiculopathy
In many cases there is often no accompanying
neurological findings
With compression of the nerve root there may be
weakness in the distribution of different nerves but
with a common nerve root
There is no associated reflex change in L5 injury
  (L4 = knee jerk, S1 = ankle jerk)
  EHL weakness or combined weakness of ankle
  inversion and eversion are the L5 “marker”
                                           Case #3

51 y/o man who awakened approximately 1
month ago with new onset aching pain in his left
shoulder and proximal left arm.
The pain persisted for 1-2 weeks, resolved
spontaneously, and then he noticed onset of
weakness in lifting his arm and bending his
elbow on the left, with numbness and tingling
into his lateral forearm and hand. He also had
mild shortness of breath with lying down or with
physical exertion.
                                           Case #3


Moderate to severe weakness of the left arm
and shoulder including proximal shoulder girdle,
deltoid, biceps, brachioradialis, with mild
weakness of triceps. Distally, muscle strength
was normal.
Absent left Biceps reflex
Reduced sensation in the lateral arm and
forearm, thumb and index finger to pinprick
                                            Case #3

       Diagnostic Procedures
Chest X ray showed mild elevation of the left
MRI of the cervical spine was normal
EMG and nerve conduction studies showed
abnormal motor and sensory nerve conduction
studies in the left arm, with evidence of
denervation and re-innervation in the clinically
affected muscles
                                           Case #3

            Clinical Course

The patient received physical and occupational
His left arm strength gradually improved over
the next 12-18 months
His shortness of breath also improved
He had residual numbness in his arm and
occasional shortness of breath with exertion
                                          Case #3


       Parsonage-Turner Syndrome
        (Idiopathic brachial plexitis,
affecting left upper trunk and phrenic nerve)
                                              Case #4


15 y/o teenager with lifelong history of mild gait
disturbance including being “clumsy” with
walking and slower to run than others her age
The patient denies any noticeable weakness or
Her father had similar problems as a child
                                            Case #4


She is a thin teenager, with significant distal
lower extremity muscle atrophy bilaterally, high
arched feet (pes cavus) and hammertoe
Absent deep tendon reflexes throughout
Distal muscle weakness, especially with ankle
dorsiflexion, toe extension bilaterally
Mild distal loss of all sensory modalities
                                          Case #4

       Diagnostic Procedures

Abnormal nerve conduction studies, showing
marked slowing of nerve conduction velocities
Genetic testing was obtained and was
                           Case #4

Nerve Conduction Studies
                          Case #4

Athena Genetic Test Results
                                  Case #4

Inherited Peripheral Neuropathy
(HMSN type 1A, Charcot-Marie-
       Tooth Disease)
                                       Case #4

  HMSN 1--Clinical Features
Rarely present with sensory symptoms
Pes cavus and hammertoes
  Intrinsic foot muscles are weak
Abnormal gait, clumsiness in running
Loss of deep tendon reflexes
Enlarged palpably firm nerves
                                       Case #4

Inherited Peripheral Neuropathies

                  High arched feet
                  (pes cavus)
                  Hammer toe deformities
                  “Inverted champagne
                  bottle legs”
                  Dyck,PJ and Thomas, PK.
                  Peripheral Neuropathy, 3rd
                  edition, 1993.
                                   Case #4

HMSN 1A-Genetic Mechanisms

Locus on short arm chromosome 17
Duplication of 17p11.2
  60-90% of HMSN 1A

PMP gene
  Protein is membrane
  glycoprotein of compacted
  peripheral myelin
                                                  Case #5

A 22-y.o. with fluctuating weakness
  22 year old woman had intermittent slurred speech
 and trouble swallowing for 6 months
 Symptoms disappeared when she became
 Two weeks after delivery the symptoms returned
 along with intermittent double vision and drooping
 of the right eye lid
 Two years earlier the left eye lid had drooped
 intermittently for 2 weeks
                                            Case #5

There was bilateral lid ptosis which progressed
during the examination
She could not move the right eye medially
Jaw closure and neck flexion were markedly
weak; shoulder elevation and wrist extension
were weak
Pupillary light responses, sensation and muscle
stretch reflexes were normal
                                   Case #5

James F. Howard, Jr., M.D., 1984
                                              Case #5

Intravenous administration of edrophonium
produced dramatic, transient improvement in lid
ptosis and movement of the right eye
Repetitive nerve stimulation of the ulnar nerve
produced a decrementing response of the muscle
potential amplitudes; single fiber EMG shows
increased neuromuscular jitter
Acetylcholine receptor antibody levels were
15 nM/L (normal <0.02; Mayo Labs)
                                            Case #5

     Treatment and response
She had marked improvement in strength after
beginning pyridostigmine (60 mg p.o. q 4 hrs)
She improved further following a course of plasma
exchange during which prednisone, 60 mg/day
was begun
When her improvement was maximal she
underwent surgical removal of a hyperplastic
thymus gland
Prednisone was tapered slowly over the following
18 months
                                              Case #5

         Myasthenia Gravis
Weakness that varies markedly over time, even
disappearing spontaneously for prolonged
periods, is typical of myasthenia gravis
The ocular muscles and eye lids are usually
Improvement (or worsening) during pregnancy
and post-partum exacerbation are common
                                               Case #6

          A clumsy 4 year old

SD is first seen at age 4 with a CC: “he’s always
Child was a late walker at 18 months
Over the past year family thinks he has been falling
much more than his older brother & sister did at
that age
PMH & FH unremarkable
                                            Case #6

                 On exam

Delayed speech, very impulsive
Symmetric proximal weakness in both arms and
Early pseudohypertrophy of the calves
Gower’s sign present
Slow and clumsy when asked to run 25 feet in the
Pseudohypertrophy and   Case #6

  Gower’s Maneuver
                                                 Case #6

              His evaluation

CK 26,000
DNA testing for dystrophin gene mutations showed
a large multi-exon deletion causing a ‘frame shift
Frame shift mutations preclude any dystrophin
production, therefore he has DMD
Electrodiagnostic testing & muscle biopsy: not
needed for diagnosis
                         Case #6

Dystrophin complex


                                               Case #6

        Duchenne’s dystrophy
Untreated: nonambulatory by 12, death in late
Chronic corticosteroids may significantly slow down
progression but not curative
Gene-therapy: possible but technically very difficult
since dystrophin gene is one of the largest in the
human genome
Phase 1 trial of gene therapy underway
                                              Case #6

 Phase 1 Trial of Gene Therapy

6 boys with DMD
Mini-dystrophin gene inserted into adeno-
associated-virus vector (Xiao & Samulski at UNC
Gene Therapy Center)
Double blinded placebo controlled injections into
biceps of each arm
Muscle biopsies to look for dystrophin expression

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