Peripheral Neuropathy Polyneuropathy

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Peripheral NeuropathyPolyneuropathy

• Daniel L. Menkes, M.D.
• Neurology Department
• University of Connecticut

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Some important definitions

• Central Nervous System CNS
• Brain
• Spinal Cord
• Peripheral Nervous system PNS
• Any nervous tissue OUTSIDE the CNS
• Includes nerves, muscles and the NMJ

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3 main parts of the PNS

• Nerves
• Efferent nerves travel AWAY from spinal cord
• Motor nerves to muscle
• Autonomics to internal organs and skin
• Afferent nerves travel TO the spinal cord
• Sensory nerves from skin, bones, joints, tendons
• Autonomics from internal organs
• Muscle
• Neuromuscular Junction NMJ

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PNS and CNS are connected

• Symptoms what the patient notices
• Less helpful for affected site identification
• Occurs with CNS or PNS problem
• Signs what the physician observes
• Most helpful
• Allows site to be identified

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Distinguishing CNS from PNS in the motor (muscle)
system
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Distinguishing CNS from PNS in the sensory
(feeling) system
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3 important nerve structures Myelin sheath,
Vasa Nervorem, Axons

• Myelin is blue, blood vessels red, axons white

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Function of each

• Myelin allows for insulation and rapid conduction
  of nerve impulses
• Blood vessels carry nutrients to the nerves and
  waste products away from them
• Axons are the actual nerve wires that conduct
  the electrical signals

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Different nerve types

• Heavily myelinated
• Proprioceptive sensory
• Muscle spindle afferents (IA)
• Vibration and position
• Motor
• Thinly myelinated
• Autonomics
• Non-proprioceptive sensory (temperature)
• Unmyelinated
• Pinprick sensation
• Nociception

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Review of sensory afferents
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Myelin sheath

• Thickest on the outside none in the center
• Functions like tape over a bare wire
• Malfunction results in
• Weakness with little wasting
• Tingling sensations
• Lost or absent reflexes
• Fluctuations in HR and BP

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Blood vessels

• STOP at the nerve edge
• Fibers in center most at risk
• Carry oxygen and nutrients to nerve
• Carry waste products away
• Reduced blood flow leads to
• Pain in hands and feet
• Weakness and wasting

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Axons The wires themselves

• Conduct electrical signals
• Supply growth factors to muscle
• Maintain sensory receptors
• Dysfunction leads to
• Symmetric problems in areas farthest from spinal
  cord
• Starts in feet and works its way upward

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Wallerian degeneration explained

• Axon is separated from the cell body

Cell Body
Injury
Target
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Wallerian degeneration explained

• Axon dies back 2-3 nodes of Ranvier and distal
  segment degenerates in 2-3 weeks

Injury
Cell Body
Target
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Myelinopathies

• Compression (sick nerves are more liable)
• Median neuropathy at the wrist Carpal tunnel
• Ulnar neuropathy at the elbow Cubital tunnel
• Peroneal neuropathy at the fibular head
• Inherited myelinopathies
• Charcot Marie Tooth type one
• Déjèrine Sottas Disease
• Autoimmune
• Toxins

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Myelinopathies-Compression

• Stage one neuropraxia
• Wires intact but myelin not transmitting
• Acute function loss but rapidly reversible
• Stage two axontmesis
• Incomplete axon loss some wires remain
• Recovery is still possible
• Stage 3 neurontmesis
• All wires transected
• Recovery rarely occurs and is usually incomplete

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Normal and demyelinated axons
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Vasculopathies

• Secondary effects of compression
• Median neuropathy at the wrist Carpal tunnel
• Ulnar neuropathy at the elbow Cubital tunnel
• Peroneal neuropathy at the fibular head
• Nerve ischemia
• Diabetes mellitus
• Tourniquet palsies
• Autoimmune
• Vasculitis
• Hypercoaguable states

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Example of normal blood vesselToluidine Blue
stain
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Example of vasculitic neuropathyH and E stain

• Left arrow- inflammation of blood vessel
• Right arrow- subendoneurial edema

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Axonopathies

• Metabolic failure of cell bodies
• Exogenous toxins
• Medications
• Chemotherapy
• Inherited conditions
• Hereditary motor and sensory HMSN
• Hereditary sensory neuropathies HSN
• Hereditary sensory and autonomic HSAN

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Axon loss on cross sectionGomori trichrome

• Note the fascicular loss on the right

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Pathology and results
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Distinguish these clinically

• Inherited
• Signs gtgt Symptoms
• It bothers you more than it bothers them
• Usually referred by another physician
• Acquired
• Symptoms gtgt Signs
• Deterioration from a previous level of
  functioning

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Acquired neuropathiesSymmetric or Asymmetric?

• Symmetric
• Most likely to be an axonopathy
• Other causes far less likely
• Etiology is toxic/metabolic
• Asymmetric
• Think Immune mediated
• Is it a myelinopathy?
• Is it a vasculopathy?

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Asymmetric neuropathies
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Asymmetric neuropathies
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Tempo of progression

• Rapid onset and progression is an EMERGENCY
• Acute myelin failure
• Acute vasculitis
• Slower onset is less emergent

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The Guillain-Barré syndrome

• Defined as acute onset of weakness with
  diminished or absent reflexes
• Many causes are listed
• Most common variant is AIDP or Acute
  inflammatory demyelinating polyradiculoneuropathy

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The Guillain-Barré syndrome AIDP

• A case of mistaken identity
• Mild antecedent illness
• Viral upper respiratory infection most common
• Viral gastroenteritis
• Some bacteria such as campylobacter
• Viral coat uses similar constituents to myelin
• Severe immune response against myelin sheath

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Guillain-Barré syndrome-Clinical

• Acute onset of weakness
• Muscle bulk is preserved (no atrophy)
• Weakness is profound
• Acute onset of large fiber dysfunction
• Buzzing and tingling
• Pain is less common but can occur
• Reflexes diminished or absent
• Many different onset patterns occur
• NOT always an ascending paralysis

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Diagnosis

• High index of suspicion
• Early recognition is key
• The other tests may be normal
• CSF albuminocytologic dissociation
• High protein (gt45 mg/dl)
• Fewer than 5 WBCs per cubic mm
• If due to HIV, the value is lt 50 WBCs/cu mm
• EMG and nerve conduction studies
• Prolonged or absent late responses

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Treatment

• Admit to hospital for close observation
• Intubate before respiratory compromise
• Address immune reaction with EITHER
• Intravenous immune globulin (IvIg) OR
• Plasma exchange
• There is NO ROLE FOR STEROIDS!
• Treat any complications that arise
• Physical therapy

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Non-emergent neuropathies

• If symmetric by history and exam
• Toxic-metabolic is the likely cause
• Find the cause and fix it whenever possible
• Example Other organ dysfunction
• If asymmetric by history and exam
• Autoimmune is likely
• Find the cause and fix it whenever possible
• Immunosuppression if no cause is found

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Treatable (reversible) causes of axonal
neuropathies

• Nutritional problems (rare)
• Toxins (rare)
• NERVES DONT WORK WELL WHEN OTHER ORGANS DONT
  WORK WELL!
• Diabetes mellitus
• Thyroid disease
• Kidney disease
• Low blood flow to nerves
• Peripheral vascular disease from smoking

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Evaluation of neuropathies- The minimum number
of studies

• CBC evaluate for infection
• CMP evaluate for liver or kidney abnormalities
• TSH evaluate for thyroid abnormalities
• Fasting blood sugar Diabetes mellitus?
• Paraproteins Immune dysfunction?
• SPEP, Urine Protein Electrophoresis
• ESR Vasculitis?
• B12 Does not cause a neuropathy but old habits
  die hard

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Neuropathy evaluation- by EMG

• Nerve conduction studies
• Evaluates for asymmetry
• Objective measurement of sensory and motor
  function
• EMG
• Resting activity (should be quiet)
• Injury potentials indicate discontinuity of motor
  axons to muscle membrane
• Voluntary activity

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Common mistakes in neuropathy

• Your neuropathy is due to diabetes
• Mean of 10 years diabetes before neuropathy
• Does not occur in every diabetic patient
• Having 1 disease does not exempt you from all
  others
• I see nothing on your exam
• Symptoms ALWAYS have a cause
• Signs may not be present
• Your neuropathy is from alcohol
• Only seen with concomitant nutritional deficiency

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Common mistakes in neuropathy Low yield
evaluations

• 24 hour urine for heavy metals
• An exposure history is key
• Usually preceded by severe gastroenteritis
• Nerve and muscle biopsy
• Only for progressive asymmetric neuropathies when
  pathophysiology is unknown
• Sural nerve and adjacent muscle usually biopsied
• Most useful for vasculitic neuropathies

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Conclusions

• Suspect a peripheral neuropathy
• Inherited?
• Acquired?
• Define its distribution by
• History
• Examination
• EMG studies
• Attempt to identify the cause
• Treat the cause whether explicit or implicit

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Supplemental material

• These case histories illustrate these concepts
• These slides are considered optional

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Case 1- History

• 38 year old man who reports that he has been
  experiencing progressive weakness over the past 5
  days
• He has difficulty standing up off the commode and
  getting in and out of his sports car
• He also notes that he is breathing much more
  heavily when walking up stairs
• What other history would be helpful?

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Additional history

• Past medical history?
• Recent infection?
• Medications?
• Used any non-prescription drugs?
• Travel outside the USA?
• Received any vaccines recently?
• History of a blood transfusion?

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Case 1-Additional history

• He reports that he had asthma as a child that he
  outgrew
• He is taking no medications of any kind
• He only traveled abroad to Cancun on his
  honeymoon 9 months ago
• No recent illness or vaccines
• He never had a blood transfusion
• He works as an accountant-no toxic exposures

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Case 1-Examination

• Vitals- T 100 F, BP 120/68, HR 50, RR 23
• General physical examination is normal
• Neurological examination
• CN- mild infranuclear facial weakness
• Motor demonstrates 4/5 strength in proximal and
  distal muscles with no atrophy
• All reflexes are absent
• Vibratory loss at ankles bilaterally

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Case 1- Diagnosis

• Inherited or acquired neuropathy?
• No family history
• Rapid onset
• Myelinopathy or axonopathy
• Normal bulk and tone with weakness
• Face is involved
• Reflexes lost early
• What should you do?

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Case 1- Course of Action

• Admit to hospital NOW
• Facial weakness may signal incipient respiratory
  failure
• This is GBS until proven otherwise
• Determine forced vital capacity FVC
• If less than 15 ml/kg then INTUBATE
• If not, obtain FVC every 8 hours
• What would you do to confirm diagnosis?

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Case 1-Confirm diagnosis

• EMG and NCVs
• Motor and sensory studies are normal
• All F waves are absent
• CSF examination
• WBCs 40 per cu mm with 0 RBCs
• Protein 75 mg/dl
• Glucose 60 mg/dl serum glucose of 80 mg/dl
• Gram stain negative
• What other studies would you obtain?

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Case 1-Additional tests

• CBC is normal
• WBC count is 5.6 with normal differential
• Hgb is 15 with an Hct of 45
• Platelets are normal at 250,000
• CMP is normal
• Hepatitis profile is normal
• SIEP demonstrates a normal pattern
• A diagnostic test was performed

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Diagnostic Test- HIV

• HIV is positive by ELISA and Western blot
• CD4 count is normal at 600
• Final diagnosis is HIV associated GBS

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Why this test is crucial

• Early treatment for HIV prolongs survival and
  quality of life
• His spouse may want to be tested
• He should be educated about HIV and related
  illnesses

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Case 2-History

• 54 year old woman with sudden onset of severe
  pain and sensory loss in the fingertips of her
  right hand 3 weeks ago
• 1 week ago she had acute onset of pain in her
  left foot followed 3 days ago by pain in her
  right foot
• She presents with 24 hours of fever and nausea
• What else would you ask her?

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Case 2-Other history

• What diseases has she had in the past?
• Lupus?
• Sarcoid?
• What medicines is she using?
• Used any non-prescription drugs?
• Travel outside the USA?
• Received any vaccines recently?
• History of a blood transfusion?

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Case 2-Exam

• Vitals T 101 F, BP 120/80, HR 88, RR16
• General physical examination
• Reddish purple skin discoloration of fingers and
  toes
• 2/6 systolic ejection murmur (old)
• Neurological examination
• 4/5 weakness in toe plantar flexors bilaterally
• Decreased pin sensation from mid shin distally
  and in the distal segments of all right hand
  digits
• Ankle reflexes absent bilaterally

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Categorize neuropathy

• Hereditary or acquired?
• Why is this clearly acquired?
• Symmetric or asymmetric?
• Left versus right?
• Distal symmetric or not?
• Pathophysiology?
• Myelinopathy?
• Axonopathy?

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Confirm by EMG/NCV

• Sural SNAPs
• Absent on the right
• 1 microvolt but present on the left
• Right median SNAP is absent but left is present
• Motor and F waves studies are normal
• Needle EMG demonstrates spontaneous activity in
  both feet
• Diagnosis Asymmetric Axonopathy

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Asymmetric axonopathy-Vasculopathy

• Inflammatory or purely ischemic?
• Why is this inflammatory?
• How would ischemic neuropathy differ?
• Causes of inflammation
• Systemic disease associated?
• Autoimmune?
• Idiopathic
• Antigen-related

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History and exam drive appropriate diagnostic
testing

• She denies any PMH, medications, allergies,
  recent vaccines or travel abroad
• There is no family history
• She denies the use of illegal substances or
  homeopathic medications
• How would you proceed?

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Approach to Testing

• Fever demands a CBC and an ESR
• Inflammation suggests evaluation of
• RF, ANA, complement, serum cryoglobulins
• Serum immunoelectrophoresis
• Urine protein electrophoresis
• CPK to determine extent of muscle involvement

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Testing results

• CPK elevated at 350 normal 150-300
• All other tests are normal
• How would you proceed?

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Nerve and muscle biopsy

• Left sural is sampled
• Low amplitude guarantees some normal fascicles
• AVOID biopsy of a normal sural nerve
• Left lateral gastrocnemius muscle as well
• Increases yield of diagnosing vasculitis
• Characterizes extent of disease process

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Nerve and muscle biopsy

• Muscle biopsy demonstrates perivascular cuffing
  and inflammation of arterioles and venules
• Sural nerve demonstrates cellular infiltrate of
  vasa nervorem with evidence of Wallerian
  degeneration of unmyelinated more than myelinated
  fibers
• Diagnosis Polyarteritis nodosa

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Treatment

• Present risks and benefits of immunosuppression
  to the patient
• The patient should choose their treatment
• Prednisone
• MTX
• Cyclophosphamide
• Follow closely for efficacy