Diseases of Peripheral Nerve & NMJ

List the different types of Peripheral Nerve Injury

List the:

• Demyelinating neuropathies

• Axonal neuropathies

• Neuronopathies

Demyelinating Neuropathies

• Guillain-Barré syndrome

• CIDP

• CMTI

• Dejerine-Sottas disease (CMT3)

Axonal Neuropathies

• Diabetic neuropathy

• Toxic neuropathies

• Alcoholic neuropathy

• Nutritional neuropathies

• Metabolic neuropathies

• Paraneoplastic neuropathies

• CMT2

Neuronopathies

• Herpes zoster

• Paraneoplastic Sensory Neuronopathy

• Toxic Neuronopathy

• Amyotrophic Lateral Sclerosis

Describe Acute Inflammatory Demyelinating Polyradiculoneuropathy 

• AKA

• Clinical Characteristics

• Predisposing conditions

• MOA

• Treatment

• Prognosis

• AKA:

  • (Guillain- Barré Syndrome)

• Clinical Characteristics:

  • ascending paralysis -> respiratory muscles

  • Sensory & autonomic involvement

  • peripheral nerves + spinal nerve roots inflammation w/ mononuclear cells infiltration

  • foci of segmental demyelination

---

• Predisposing conditions:

  • acute flu-like illness

    • 2/3rds of cases

    •  (esp. CMV & EBV)

  • infection with certain bacterial organisms

    • Campylobacter jejuni

    • Mycoplasma pneumoniae

  • Vaccinations

• MOA:

  • Infections & vaccinations -> immune response cross reacts w/ Ags in peripheral nerve myelin 

    • (esp. gangliosides)

---

• Treatment:

  • Plasmapheresis 

• Prognosis:

  • Mortality rate is 2 - 5%

  • Up to 20% of hospitalized survivors suffer long- term disability

Describe CIDP

• STATs

• Clinical Characteristics

• Histo. Changes

• Remission Induction

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

• STATs

  • MC chronic acquired inflammatory neuropathy

• Clinical Characteristics:

  • Polyradiculoneuropathy -> chronic course w/ relapses and remissions

  • mixed sensorimotor polyneuropathy

• Histo. Changes:

  • similar to those of Guillain-Barré syndrome; 

  •  “onion bulbs”

    • Evidence of recurrent demyelination & remyelination

• Remission Induction:

  • w/ immunosuppressive Rx

    • EX: steroids, & plasmapheresis

NOTE:

• To be considered CIDP, patient has to have symptoms for at least 2 months

CIDP with Onion Bulb

Describe Diphtheria

• What is it?

• MOA

• Symptoms?

• What is it?

  • Acute necrotizing infection of URT

    • By C. diphtheriae

• MOA:

  • C. Dip -> exotoxin -> inhibits protein synthesis -> demyelinating sensorimotor neuropathy

• Symptoms:

  • paresthesias,

  • weakness, 

  • early loss of proprioception & vibratory sensation

  • Associated w/

    • prominent bulbar Dysfunction

    • respiratory muscle dysfunction

Describe Herpes zoster (Shingles)

• Pathogenesis

• Histological Findings

Herpes zoster (Shingles)

• Pathogenesis:

  • Varicella -> VZV hides in  dorsal root/Trigem ganglia  -> React. (higher age, lower immunity) -> virus spreads along sensory nerves -> painful vesicular skin eruption in the distribution of sensory dermatomes

• Histologic findings:

  • Mononuclear infiltrates + focal necrosis of Dorsal root ganglion cells

  • 2 degree degeneration of axons in peripheral nerves

Herpes Zoster (Shingles)

Describe Charcot-Marie-Tooth Disease, Type 1 (CMT1)

• STATs

• Genetics

• Clinical presentation

• Histo

Describe CMT2

• Genetics

• Symptoms

• Dif vrom CMT1

• STATs

  • MC hereditary peripheral neuropathy

• Genetics:

  • Autosomal Dominant (AD)

  • Duplication of (17p11.2-p12) (CMT1a)

    • “segmental trisomy”

  • Involves gene for PMP22 (peripheral myelin protein 22) 

  • Could also involve MPZ Gene on Chromosome 1 (CMT1b)

---

• Clinical Presentation:

  • Presents in childhood or adolescence

  • Slowly progressive w/ distal muscle weakness

  • Atrophy of calf muscles & “steppage” gait

  • Pes cavus & hammertoes

  • Stocking-glove sensory loss

  • Weakness of hand & forearm muscles

    • later

• Histo:

  • Demyelinating neuropathy with onion bulbs

    • Numerous onion bulbs = “hypertrophic” neuropathy

NOTE:

• Sensorimotor deficits and secondary orthopedic problems are usually limited in severity

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Charcot-Marie-Tooth Disease, Type 2 (CMT2)

• Genetics:

  • AD

  • genetically heterogeneous disorder

  • Mutation in MFN2 -> makes mitofusin-2

    • (CMT2A) -> early onset

• Symptoms:

  • Clinical manifestations are similar to CMTI

  • Axonal neuropathy

• Difference from CMT1

  •  No onion bulbs =  no hypertrophicneuropathy

NOTE:

• CMTI & CMT2 are the MC cause of chronic peripheral neuropathy in children

Describe Dejerine-Sottas Neuropathy (CMT3)

• Genetics

• Histo

• Clinical Presentation

Dejerine-Sottas Neuropathy (CMT3)

• Genetics:

  • AD or AR; begins in early infancy

  • Genetically heterogeneous 

    • mutations in PMP22, MPZ, et al

• Histo:

  • Demyelinating neuropath -> onion bulbs -> hypertrophic neuropathy

• Clinical Presentation:

  • Resembles CMT1, but more severe

  • Both trunk and limb muscles are involved

Describe X-linked CMT disease (CMTX)

• Stats

• Pathophysiology

• Clinical presentation

STATs

• CMT1X is the most common x-linked form

  • 15% of genetically defined cases of CMT

• Females are less severely affected than males

Pathophysiology

• Mutation in GJB1 gene -> encodes Connexin 32

  • Gap junction protein in schwann cells

Clinical Presentation

• Have features of both axonal + demyelinating neuropathy

• Progressive

Describe PERIPHERAL NEUROPATHY IN DIABETES MELLITUS

• STATs

• Types of neuropathy/MOA

• Pathophysiology

• STATS

  • Most common cause of peripheral neuropathy

• Types of neuropathy/MOA:

  • Distal symmetric sensorimotor neuropathy

    • Ischemia or metabolic derangements

  • Autonomic Neuropathy

    • Ischemia or metabolic derangements

  • Mononeuropathy or Mononeuropathy multiplex

    • Ischemia

• Pathophysiology

  • Axonal degeneration = predominant finding

  • Endoneurial arterioles -> hyaline arteriolosclerosis

Diabetic Neuropathy

Describe Toxic Neuropathies

• Causes

• Common Symptoms

Toxic Neuropathies

• Causes

  • industrial/environmental chemicals

  • biological toxins

  • therapeutic drugs

    • Most toxic

• Common Symptom:

  • distal symmetric sensorimotor neuropathy

  • axonal neuropathies

Describe Alcoholic Neuropathy

• Symptoms

• Clinical Presentation

• Causes

• MOA

• Symptoms:

  • Distal symmetric sensorimotor axonal neuropathy

  • May also have an autonomic neuropathy

• Clinical presentation

  • Symptoms begin in distal aspect of the lower extremities

  • Sensory symptoms occur before motor symptoms

---

• Causes:

  • Direct toxic effects of alcohol and its metabolites 

    • (esp. acetaldehyde)

  • Vitamin deficiencies

    • (esp. thiamine)

• MOA:

  • loss of nerve fibers due to axonal degeneration of the dying-back type

Describe Thiamine (vit. B1) deficiency

• Symptoms

• Clinical Presentation

• Associated w/?

Thiamine (vit. B1) deficiency

• Symptoms:

  • Distal symmetric sensorimotor axonal neuropathy

• Clinical Presentation:

  • Initially involves the lower extremities

  • Toe drop  -> foot drop   ->  wrist drop

• Associated w/ other manifestations of thiamine deficiency

  • Beriberi heart disease

  • Wernicke-Korsakoff syndrome

NOTE: In the US, most commonly seen in alcoholics

What are the Other vitamin deficiencies associated with axonal neuropathies

Other vitamin deficiencies associated with axonal neuropathies

• α-tocopherol (vit. E)

• Cobalamin (vit. B12)

• Folate (vit. B9)

• Pyridoxine (vit. B6)

  • Isoniazid inhibits conversion of pyridoxine to pyridoxal 5’ phosphate  -> functional pyridoxine deficiency

Describe COMPRESSION NEUROPATHY (ENTRAPMENT NEUROPATHY)

• What is Entrapment neuropathy

• What is Carpal tunnel syndrome: 

• Predisposing factors

COMPRESSION NEUROPATHY (ENTRAPMENT NEUROPATHY)

• Entrapment neuropathy 

  • nerve is compressed w/in anatomic compartment

• Carpal tunnel syndrome: 

  • compression of median nerve w/in compartment  delimited by the transverse carpal ligament

    • numbness & paresthesias of the thumb & first two fingers, pain, difficulty gripping objects

• Predisposing factors:

  • Pregnancy, hypothyroidism

  • Amyloidosis, arthritis, acromegaly

  • Excessive repetitive motion of the wrist

Describe Uremic neuropathy

• STATs

• Symptoms

• Treatment

• 
  

Uremic neuropathy

• STATs

  • ≈ 60–70% of patients with ESRD develop clinically significant peripheral neuropathy

• Symptoms:

  • Distal symmetric sensorimotor axonal neuropathy

  • Cramps, 

  • dysesthesias, 

  • restless legs syndrome

  • Decreased DTRs, 

  • sensory loss

• Treatment:

  • Hemodialysis 

  • Renal transplantation

NOTE:

• Precise cause of uremic neuropathy is not known

List the Other metabolic disorders associated with neuropathy:

Other disorders associated with neuropathy:

• Chronic liver disease

• Polycythemia

• COPD

• Acromegaly

• Hypothyroidism

List some malignancy → neuropathies due to Direct infiltration or compression of nerves

Direct infiltration or compression of nerves, e.g.

• Brachial plexopathy

• Obturator palsy

Describe these Paraneoplastic neuropathies

• Paraneoplastic sensorimotor polyneuropathy

  • STATS

  • types

  • Cause

• Paraneoplastic sensory neuronopathy

  • Preceding conditions

  • MOA

• Monoclonal gammopathies

  • Types

  • MOA

Paraneoplastic sensorimotor polyneuropathy

• STATS

  • Most common paraneoplastic neuropathy

• Type:

  • axonal neuropathy

• Cause:

  • unknown

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Paraneoplastic sensory neuronopathy

• Preceding Conditions:

  • precedes Dx of malignancy by 6 - 15 mo’s

  • small cell carcinoma of lung

• MOA:

  • anti-Hu antibodies

  • Inflammatory infiltrates w/in dorsal root ganglia

    • -> Inflammatory demyelinating polyradiculo- neuropathy

---

Monoclonal gammopathies

Types:

• MGUS

• MM & B cell lymphoproliferative disorders

MOA:

• Deposition of light-chain amyloid (AL type) in peripheral nerves

• Production of monoclonal antibody (usually IgM) against myelin-associated glycoprotein

  • (MAG) [anti-MAG neuropathy]

Describe MYASTHENIA GRAVIS

• STATs

• Pathogenesis

• Strong association w/? STATs? Why?

• Clinical Features

• Treatment

• Prognosis

STATs

• Bimodal age distribution

• F/M ratio is 2:1 in young adults

• Male predominance in older adults

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• Pathogenesis

  • 85%: autoabs against postsynaptic AChRs

  • 15%: autoabs against muscle specific receptor tyrosine kinase 

    • (anti-MuSK antibodies)

• Strong association btw anti-AChR antibodies and thymic abnormalities

  • 10% of patients have a thymoma

  • 30% of patients have thymic hyperplasia

  • WHY?

    • Thymus normally contains small numbers of myoid cells that express AChRs

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Clinical Features

• Ptosis

• Diplopia

• Generalized weakness -> fluctuates

• easy fatigability

  • muscle response decreases w/ repeated stimulation

---

• Treatment

  • Acetylcholinesterase inhibitors

  • Immunosuppressive drugs

  • Plasmapheresis

  • Thymectomy

    • Pts w/ thymoma

    • Patients w/o thymoma who

      • Have generalized MG

      • Positive for anti-AChR antibodies

      • ≤ 50 years of age

• Prognosis:

  • Overall mortality < 5%

Describe LEMS

• Preceding conditions

• Symptoms

• In contrast to MG?

• Patho?

• Treatment

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS) 

• Preceding conditions:

  • Underlying malignancy in ≈ 50% of cases

  • Symptoms may precede the Dx of cancer, sometimes by years

    • Patients w/o often have other autoimmune diseases

• Symptoms:

  • weakness + wasting of proximal limb & trunk muscles

• In contrast to Myasthenia Gravis:

  • No anti-AChR antibodies

  • Muscle strength ↑ after few seconds of muscle activity

    • Repetitive stimulation on EMG  ↑ muscle response

• Patho:

  • Autoabs against Ca++ channels -> less AcH release from pre synaptic

• Treatment

  • Drugs that ↑ acetylcholine release

  • Immunosuppressive agents