ABSTRACT
A. Brachial Plexus: basic neuroanatomy (Fig. 21-1) 1. Formed from spinal roots (ventral primary rami) of
C5-T1 2. Dorsal scapular nerve arises from C5 nerve root and
supplies the major and minor rhomboid muscles 3. Long thoracic nerve arises from C5-C7 roots and
supplies the serratus anterior muscle 4. Upper trunk
a. Formed from C5 and C6 roots b. Provides an anterior division to the lateral cord and
posterior division to the posterior cord (contributes to all the peripheral nerves arising from the cords except the ulnar nerve)
c. Suprascapular nerve arises from upper trunk and supplies the supraspinatus and infraspinatus muscles
d. The nerve to the subclavius muscle also arises from the upper trunk
5. Middle trunk a. Formed from C7 root b. Provides an anterior division to the lateral cord and
posterior division to the posterior cord (contributes to all peripheral nerves arising from the cords except the ulnar nerve)
6. Lower trunk: provides an anterior division to the medial cord and posterior division to the posterior cord (contributes to all peripheral nerves arising from the cords except the musculocutaneous nerve)
7. Lateral cord a. Gives rise to the musculocutaneous nerve and con-
tributes to the median nerve
b. Lateral pectoral nerve arises from the lateral cord and supplies the pectoralis major muscle
8. Posterior cord a. Gives rise to the axillary and radial nerves b. Upper scapular nerve arises from the posterior cord and
supplies the subscapularis muscle c. Thoracodorsal nerve arises from the posterior cord and
supplies the latissimus dorsi muscle d. Lower scapular nerve arises from the posterior cord and
supplies the subscapularis and teres major muscles 9. Medial cord
a. Gives rise to the ulnar nerve and contributes to the median nerve
b. Medial pectoral nerve arises from the medial cord and supplies the pectoralis major and minor muscles
c. Medial brachial cutaneous and medial antebrachial cutaneous nerves also arise from the medial cord
B. Peripheral Nerves of the Arm and the Related Entrapment Neuropathies
1. Treatment for all entrapment neuropathies a. Depends mainly on the cause b. Anticonvulsants and tricyclic antidepressants may be
used to treat neuropathic pain 2. Axillary nerve
a. Supplies the teres minor muscle and then deltoid muscle as it curves around the humerus
b. Gives rise to lateral brachial cutaneous sensory nerve to lateral aspect of the arm
3. Musculocutaneous nerve a. Supplies the coracobrachialis, biceps brachii (short head
and long head), and brachialis muscles b. Gives rise to lateral antebrachial cutaneous nerve
4. Median nerve a. Anatomic landmarks in order of occurrence
1) In some persons, the median nerve travels inside a foramen created by a tendinous band that runs between the humerus and the medial epicondyle
(ligament of Struthers) 2) After entering the forearm, the median nerve passes
underneath a fibrous aponeurotic band that runs from the tendon of the biceps brachii to forearm flexors (lacertus fibrosus)
3) Runs between the two heads of the pronator teres and innervates that muscle and the flexor carpi radialis (both C6, C7) and the palmaris longus and flexor digitorum superficialis (both primarily C8)
4) Gives rise to anterior interosseous nerve, which supplies innervation to flexor digitorum profundus I and II, flexor pollicis longus, and, most distally, pronator quadratus (all of which are primarily C8)
5) Travels in the forearm and passes deep to flexor digitorum superficialis muscle and the fibrous aponeurotic arch attached to it
6) Gives rise to the palmar cutaneous sensory branch distally to supply the area over the thenar eminence and then dives inside the flexor retinaculum (whereas the palmar sensory branch travels over the ligament)
7) Innervates abductor pollicis brevis, opponens pollicis, first and second lumbricals, and partially innervates flexor pollicis brevis (with the ulnar nerve)
b. Median neuropathy at the wrist: carpal tunnel syndrome (CTS) 1) Wrist pain and hand pain and paresthesias in median
nerve distribution, sometimes radiating to the forearm and arm, episodic pain and paresthesias worse at night
2) Symptoms often provoked with extended wrist posture, such as driving or holding a book
3) Sensory fibers are affected early, motor fibers in advanced cases
4) Patients may complain of weakness of thumb abduction and opposition, followed by atrophy of thenar eminence
5) Sensation is spared over thenar eminence because the palmar cutaneous sensory branch is spared
6) Tinel’s sign (induced by tapping over median nerve at the wrist) and Phalen’s maneuver (passive flexion of wrist producing paresthesia)
7) Associated and predisposing conditions a) Hereditary neuropathy with liability to pressure
palsies b) Diabetic neuropathy, other polyneuropathies c) Pregnancy d) Hypothyroidism e) Acromegaly f) Amyloidosis g) Renal failure
8) Nerve conduction studies
a) Palmar orthodromic technique is most sensitive for demonstrating focal slowing across wrist because of shorter distance; the antidromic technique is an alternative for moderate to severe neuropathy
b) Mild CTS: prolonged median sensory or mixed nerve action potential distal latency (orthodromic or antidromic, respectively), sensory nerve action potential (SNAP) amplitude may be reduced
c) Moderate CTS: prolonged distal latencies of both median motor and sensory responses, SNAP amplitude may be reduced
d) Severe CTS: prolonged distal latencies of both median motor and sensory distal latencies and either absent SNAP or mixed nerve action potential or low-amplitude thenar compound muscle action potential (CMAP)
e) Very severe CTS: no thenar motor or sensory palmar nerve action potential
c. Anterior interosseous nerve syndrome 1) Isolated neuropathy involving anterior interosseous
nerve a) In the setting of immune-mediated brachial plexus
neuropathy (Parsonage-Turner syndrome) b) Less commonly, in the setting of hereditary
neuropathy with liability to pressure palsy or possibly compression of anterior interosseous nerve by fibrous bands attached to flexor digitorum superficialis muscle
2) Weakness of pronation (pronator quadratus), weakness of flexion of thumb (flexor pollicis longus), and weakness of flexion of distal phalanx of the fingers (flexor digitorum profundus I and II)
3) Weakness of distal interphalangeal joints of thumb and index finger creates hyperextension at these joints when making the “OK” sign
d. Pronator syndrome 1) Compression of median nerve by the two heads of
pronator teres muscle, lacertus fibrosus, and the aponeurotic fibrous arch attached to flexor digitorum superficialis muscle
2) Entrapment results from repetitive pronation 3) Variable extent of weakness (usually mild) of flexor
pollicis longus, abductor pollicis brevis, and other distal median-innervated muscles
e. Entrapment at the ligament of Struthers 1) Variable degrees of weakness and sensory symptoms
in distribution of median nerve 2) Paresthesias in the median nerve distribution,
produced by supination of the forearm and extension at the elbow
3) Brachial artery also passes through the foramen produced by ligament of Struthers. There may be reduced radial pulses with this condition
5. Radial nerve a. Anatomic landmarks in order of occurrence
1) Innervates the three heads of triceps brachii (long, medial, and lateral heads) and anconeus muscle, gives rise to posterior brachial cutaneous nerve as it passes along lateral wall of the axilla toward the spiral groove of the humerus
2) Gives rise to lower lateral brachial cutaneous and posterior antebrachial cutaneous nerves as it passes through the spiral groove
3) As radial nerve curves around the humerus, it supplies brachioradialis (C5, C6) and extensor carpi radialis longus (C6, C7) muscles
4) Further down, it gives rise to superficial (dorsal) radial sensory branch
5) Becomes the posterior interosseous nerve, which provides innervation to extensor carpi radialis brevis (C6, C7) and supinator (C5, C6) muscles and then dives into supinator muscle (arch of Frohse)
6) Innervates rest of the digit extensors, including extensor carpi ulnaris muscle, and abductor pollicis longus muscle
b. Lesion at the axilla 1) May result from prolonged compression, which may
occur in patients who use crutches incorrectly, applying excess pressure on the axilla
2) Results in weakness of all radial-innervated muscles and sensory deficits involving entire radial nerve distribution (posterior arm and forearm and lateral aspect and dorsum of hand)
c. Lesion at spiral groove at mid-arm (Fig. 21-2) 1) “Saturday night palsy”: compression at the spiral
groove, as with compressing the nerve while sleeping (especially after intoxication)
2) May also result from fracture of the humerus, multifocal motor neuropathy with conduction block, or another immune-mediated process
3) Clinical features similar to those of axillary lesions, but with sparing of most of triceps brachii and sensation to posterior arm
d. Posterior interosseous neuropathy 1) Clinical features similar to those of spiral groove
lesion, but also with sparing of extensor carpi radialis longus, brachioradialis, anconeus, and triceps brachii as well as any sensory deficits (purely a motor branch)
2) Patients present with “finger drop” and supinator weakness
e. Superficial radial sensory neuropathy (cheiralgia paresthetica) 1) Sensory deficits involving the lateral aspect and dor-
sum of hands and fingers (no motor deficits) 2) Occurs with tight handcuffs, bands, watches
6. Ulnar nerve a. Anatomic landmarks in order of occurrence
1) Passes in retrocondylar groove and then in cubital tunnel formed by the medial ligament of the elbow joint and aponeurosis of flexor carpi ulnaris muscle
2) As the ulnar nerve enters the forearm, it supplies flexor carpi ulnaris and flexor digitorum profundus III and IV and travels in forearm
3) In distal aspect of forearm, it gives rise to dorsal ulnar cutaneous and palmar cutaneous sensory nerves responsible for sensation of hypothenar eminence
4) At the wrist, it gives off the digital sensory branch that supplies the fifth digit and medial half of the fourth digit
5) Supplies hypothenar muscles and immediately enters Guyon’s canal formed by the pisiform bone and hook of the hamate
6) After entering Guyon’s canal, the ulnar nerve ends as the deep palmar motor branch to supply interossei muscles, including first dorsal interosseous [FDI]), third and fourth lumbricals, adductor pollicis, and half the innervation to flexor pollicis brevis
b. Ulnar neuropathy at the elbow 1) Chronic mechanical compression due to repeated
trauma, arthritis, and other factors causing tardive ulnar palsy
2) Ulnar palsy at the groove may also occur with mechanical compression (e.g., during general anesthesia or coma)
3) Ulnar nerve prolapse: a condition in which the ulnar nerve is displaced from the groove and predisposed to trauma
4) Ulnar compression at the cubital tunnel or the groove may occur with repeated flexion at the elbow causing chronic, minor trauma and compression
5) Some people have congenitally tight cubital tunnels and a predisposition for development of ulnar neuropathy at the cubital tunnel
6) In addition to repetitive trauma and arthritic changes, causes include tumors, fibrous bands, accessory muscles
7) Symptoms a) Weakness of ulnar-innervated intrinsic hand
muscles and atrophy in chronic cases b) Sensory symptoms (paresthesias and dysesthesias)
involve the volar and dorsal aspects of the fifth and medial aspect of the fourth digits and hand
8) Benediction posture (“clawing” of the hand): due primarily to weakness of third and fourth lumbricals causing hyperextension at metacarpophalangeal joints and flexion of proximal and distal interphalangeal joints (Fig. 21-3)
9) Wartenberg’s sign: abduction of fifth digit due to weak adduction from weakness of third palmar interosseous muscle (Fig. 21-3)
10) Froment’s sign: a) Due to weakness of pinch as result of weak ulnar-
innervated adductor pollicis, interossei, and flexor pollicis brevis (partially)
b) Median-innervated flexor pollicis longus and the flexor digitorum profundus I and II and superficialis are instead activated and used to pinch
11) Treatment: primarily surgical (decompression of cubital tunnel, medial epicondylectomy, and submuscular transposition of ulnar nerve) after conservative management fails (physical therapy, avoidance of leaning on elbow, or use of elbow pad)
c. Electrophysiologic evaluation for suspected ulnar neuropathy at the elbow 1) Extended elbow position may underestimate length
of the nerve, and conduction velocity may seem slow across the elbow
2) More accurate measurement with the elbow flexed 3) Inching technique is often used to better localize the
conduction block or slowing 4) Focal slowing
a) Abrupt drop in conduction velocities (above the elbow [AE]-to-below the elbow [BE] segment >10 m/s slower than the BE-to-wrist [W] segment)
b) Lack of adequate data in the literature for this 5) Partial conduction block or temporal dispersion (focal
demyelination) a) More than 20% decrease in amplitude of CMAP
(negative peak) across elbow (10 cm), as per AAEM practice guidelines
b) This presumes absence of anomalies of innervation (i.e., Martin-Gruber anastomosis)
c) Some authorities regard more than 10% slowing across elbow as significant
d) Normal subjects may have slowing up to 10% across elbow
6) Routinely, motor conduction studies can be obtained by recording at abductor digiti minimi
7) Because entrapment neuropathies of ulnar nerve are often fascicular, additional recording at first dorsal interosseous may increase the sensitivity
8) Dorsal ulnar cutaneous sensory conduction study may also be an important adjunct
9) Both ulnar antidromic sensory (recording at fifth digit) and dorsal ulnar cutaneous sensory studies may be abnormal in lesions at level of the elbow, whereas a dorsal ulnar cutaneous sensory study is often normal with ulnar neuropathy at the wrist because the dorsal ulnar sensory branch takes off proximal to the wrist
10) Note: ulnar neuropathies at elbow are often fascicular and may spare the dorsal sensory branch
11) Needle examination: muscles innervated by the deep palmar motor and hypothenar branches are often affected more than more proximally innervated muscles
d. Ulnar neuropathy at the wrist 1) Motor and sensory involvement: lesion proximal to
sensory and motor branches 2) Pure sensory involvement: lesion of digital sensory
branch only (rare) 3) Pure motor involvement: lesion after the sensory
branch, affecting all ulnar-innervated intrinsic hand muscles (sparing sensation of hypothenar eminence)
4) Pure motor involvement of intrinsic hand muscles, sparing hypothenar muscles: lesion after Guyon’s canal, sparing hypothenar sensory and motor function, but causing weakness of the muscles supplied by deep palmar motor branch
e. Electrophysiologic evaluation for suspected ulnar neuropathy at the wrist 1) Nerve conduction studies must include recording at
the FDI 2) CMAP amplitudes and latencies recorded at adductor
digiti minimi are expected to be normal, with lesions at Guyon’s canal affecting only the deep palmar motor branch (common)
3) Lesions distal to the dorsal ulnar cutaneous branch spare the dorsal ulnar cutaneous SNAP and cause an abnormal ulnar sensory antidromic SNAP recorded at the fifth digit
4) If ulnar neuropathy is expected at the wrist, the distal latencies of responses obtained by stimulating ulnar and median nerves and recording at interossei and lumbrical muscles, respectively, should be performed, and inching across the wrist must be attempted
5) Needle examination: muscles innervated by deep palmar motor branches are often most affected
C. Lumbosacral Plexus: basic neuroanatomy 1. Anatomically divided into lumbar plexus and sacral
plexus 2. Lumbar plexus
a. Formed within psoas major muscle b. L1: gives rise to ilioinguinal, iliohypogastric, and
genitofemoral nerves (the latter two also receive innervation from T12 and L2)
c. L2, L3, L4 anterior divisions: give rise to obturator nerve d. L2, L3, L4 posterior divisions: give rise to femoral nerve e. L2, L3 posterior divisions: give rise to lateral cutaneous
nerve of the thigh 3. Sacral plexus
a. Connects with lumbar plexus via lumbosacral trunk (anterior division of L4 and L5), other primary rami forming the sacral plexus are S1, S2, S3
b. L4 to S3 anterior divisions: give rise to tibial and posterior divisions of the common peroneal portions of the sciatic nerve
c. S1, S2, S3 anterior divisions: give rise to posterior cutaneous nerve of the thigh
d. S2, S3, S4 anterior divisions: give rise to pudendal nerve (“S2, 3, 4 keep your pelvis off the floor”)
D. Peripheral Nerves of the Leg and Related Entrapment Neuropathies
1. Peroneal nerve anatomy: anatomic landmarks in order of occurrence (Fig. 21-4) a. Common peroneal nerve travels with tibial nerve in the
nerve bundle of sciatic nerve, the two nerves share a sheath but remain separated
b. First branch of common peroneal nerve: innervation to the short head of biceps femoris muscle
c. Common peroneal nerve then separates completely from tibial nerve
d. Once peroneal nerve reaches popliteal fossa, it gives rise to lateral cutaneous nerve of the calf (supplying lateral proximal portion of the calf) and the sural communicating branch, which joins sural nerve (both sensory), and continues on for a short distance and wraps around the fibular neck and continues into the fibular tunnel (formed from the tendinous portion of peroneus longus and fibula)
e. After this, it divides into superficial and deep peroneal nerves
f. Superficial peroneal nerve gives rise to innervation to peroneus longus and brevis muscles, and then superficial peroneal sensory branch, which divides into medial and lateral branches to supply the distal aspect of lateral calf and dorsum of the foot, sparing the web space between first and second toes
g. Deep peroneal nerve is primarily motor and supplies innervation to tibialis anterior, extensor digitorum longus, extensor hallucis longus, peroneus tertius, and extensor digitorum brevis (EDB) muscles
h. Deep peroneal nerve continues on as dorsal digital cutaneous nerve to supply sensory innervation to the web space between first and second toes
2. Common peroneal neuropathy at fibular neck a. Predisposed to compression and nerve trauma at fibular
neck
b. Fascicles of the deep peroneal branch usually are more affected
c. Predisposing factors and etiologic circumstances: habitual leg crossing, intraoperative compression, prolonged bed rest and prolonged hospitalization, coma, casts, pneumatic compression devices, excessive weight loss with loss of supportive surrounding fat, diabetes mellitus
d. Other causes of compression may include: ganglion cysts, Baker’s cyst, hematomas, tumors
e. Acute or subacute onset of partial or complete footdrop (with steppage gait), which may be related temporally to the cause (if there is one, e.g., intraoperative compression)
f. Hyperesthesia, paresthesias, and sensory deficits in peroneal nerve distribution
g. Tinel’s sign at the fibular neck h. Electrodiagnostic evaluation important to define exactly
the localization, rule out other possible localization such as L5 radiculopathy, determination of prognosis, determination of presence and extent of denervation and reinnervation
i. Nerve conduction studies for suspected common peroneal neuropathy at fibular head: 1) CMAP obtained by stimulating deep peroneal nerve
at the ankle and stimulating common peroneal nerve above and below fibular head
2) Superficial peroneal sensory conduction: often normal, but may be absent or of low amplitude if there is enough axonal injury
3) Isolated denervation of EDB from local trauma or chronically wearing tight shoes: can cause absent responses recorded at EDB in absence of a peroneal neuropathy
4) Otherwise, some degree of atrophy and denervation of EDB may suggest severe axonal injury in presence of a peroneal neuropathy
5) Recording of the response at anterior tibialis muscle may reflect more accurately the degree of axonal injury and prognosis and better define the extent of the peroneal neuropathy given the commonly fascicular involvement
6) An accessory deep peroneal nerve may be present, which should be suspected if the CMAP amplitude obtained at the knee is larger than that at the ankle
7) Pathophysiology: primarily axonal loss a) Level of the lesion may not be accurately
determined b) Sensory and motor responses may be reduced
(SNAPs may be absent with severe axonal loss), and there may be mild slowing when advanced axonal injury involves the fastest fibers
8) Primarily demyelinating disease: presence of conduction block or focal slowing determines the localization
j. Needle electromyography (EMG) 1) Required for localization of peroneal neuropathy in
the absence of definite, localizing conduction block 2) Short head of the biceps is the only muscle innervated
by the peroneal portion of the sciatic nerve proximal to common peroneal nerve and must be examined; if abnormal, sciatic neuropathy becomes a consideration and other sciatic-innervated muscles must be examined
3. Sciatic neuropathy a. Often occurs at hip because of proximity to hip joint b. Most common causes: hip dislocation, fracture, periop-
erative associated, femur fracture, idiopathic (possibly inflammatory, less identified)
c. Other causes: external compression by prolonged sitting or lying, typically across narrow hard surfaces (including toilet seats), mass lesions in buttock (e.g., prominent vascular loop), tumors, enlargement of lesser trochanter, and, rarely, inferior gluteal venous varicosities
d. Common peroneal nerve is more predisposed to injury than the tibial portion
e. Sciatic mononeuropathy may occur with greater involvement of common peroneal portion, with subtle signs of tibial nerve involvement often present
f. Clinical signs and symptoms: variable degrees of pain, paresthesias, and weakness (often involving peroneal distribution)
g. Preferential involvement of the peroneal portion explains prominent dorsiflexion weakness and footdrop seen with milder forms
h. Prominent, concurrent weakness of tibial-innervated muscles and a flail foot may occur with severe sciatic neuropathies
i. Electrodiagnostic evaluation for suspected sciatic neuropathy 1) Nerve conduction studies: often suggest a common
peroneal neuropathy (abnormal peroneal motor response)
2) Bilateral sural SNAP, H reflex, and tibial motor responses would need to be obtained for comparison
3) Asymmetry in any of these responses in addition to abnormal peroneal motor response is clue to sciatic nerve involvement
j. Tibial nerve-anatomic landmarks in order of occurrence (Fig. 21-5) 1) While in the sciatic nerve bundle, it innervates all
hamstring muscles (except for short head of biceps femoris muscle) and adductor magnus (also innervated by obturator nerve)
2) First branch after separation from common peroneal nerve in the sciatic nerve bundle: sural nerve (which also receives a communicating branch from common peroneal nerve as mentioned above and supplies sensory innervation to lateral portion of the foot)
3) Dives under tendinous arch of soleus muscle and innervates soleus, gastrocnemius, tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles
4) Travels posterior to medial malleolus through tarsal tunnel to enter foot
5) Divides into three terminal branches as it runs through the tarsal tunnel underneath the flexor retinaculum a) First terminal branch: bundle of pure sensory
nerves (calcaneal branches) supplying sensation to sole of the heel
b) Medial plantar nerve: innervates abductor hallucis, flexor digitorum brevis, and flexor hallucis brevis muscles
c) Lateral plantar nerve: innervates abductor digiti minimi, flexor digiti minimi, adductor hallucis, and interossei muscles
k. Tibial neuropathy proximal to the ankle 1) May be caused by a compressive lesion (e.g., synovial
cyst [Baker’s cyst], fibrotic arch of soleus muscle, nerve sheath tumors)
2) Presentation: foot pain, tenderness at the popliteal fossa or Tinel’s sign, possibly weakness in more severe cases (ankle inversion, plantar flexion, and toe flexion), and absence of ankle jerks
l. Tibial neuropathy at the ankle (tarsal tunnel syndrome) 1) Rare 2) Caused by compression of tibial nerve or its three
terminal branches as they run through the tarsal tunnel, underneath the flexor retinaculum
3) Possible causes: idiopathic, repetitive trauma (sprains, fractures), arthritis, nerve sheath tumors, other mass lesions
4) Possible predisposing conditions: diabetes mellitus, acromegaly, hypothyroidism
5) Most common clinical feature: burning foot pain at the sole and ankle, often worse with weight bearing or at nighttime, and possibly paresthesias and sensory loss at sole of the foot
6) Nerve conduction studies a) Tibial motor conductions recording at abductor
hallucis and abductor digiti quinti may be helpful but is not sensitive (often negative)
b) Medial and lateral plantar sensory orthodromic responses: most useful when compared with the asymptomatic side, but often normally absent
7) Needle EMG a) Is used to define localization, severity b) Used to rule out other possibilities, such as a more
proximal tibial or sciatic neuropathy c) Presence of occasional fibrillation potentials in
intrinsic foot muscles may be normal finding and should be interpreted with caution
m. Femoral nerve-anatomic landmarks in order of occurrence (Fig. 21-6)
1) Originates predominantly from primary ventral rami of L2, L3, L4
2) Innervates psoas and iliacus muscles, runs in between these two muscles and then underneath inguinal ligament
3) Innervates all portions of quadriceps and sartorius muscles 4) Gives off three sensory branches (medial and interme-
diate cutaneous nerves of thigh and saphenous nerve), together supplying the medial aspect of the leg
n. Femoral neuropathy causes 1) Most common: inflammatory (e.g., diabetic
amyotrophy)
2) Other: isolated iatrogenic, often after abdominal and gynecologic operations, especially ones involving use of self-retracting blades, compressing the nerve between the pelvic wall and retractor
3) Lithotomy positioning, as with vaginal delivery, hysterectomy, and other surgical procedures, predisposes to unilateral or bilateral compression of femoral nerve by inguinal ligament
o. Obturator nerve-anatomic landmarks in order of occurrence 1) Originates from anterior divisions of ventral primary
rami of L2, L3, L4 2) Passes in between iliacus and psoas muscles for short
distance and then on the medial aspect of psoas muscle (on the edge of superior pubic ramus) and then into the obturator groove of the pubis
3) Dives into obturator foramen 4) Innervates thigh adductors (adductor magnus also has
innervation from tibial division of the sciatic nerve) and gives off a sensory branch to upper medial aspect of the thigh
p. Obturator neuropathy 1) Causes: trauma, genitourinary or abdominal
procedures, or vaginal delivery (especially with use of forceps)
2) Clinical features: pain in medial thigh exacerbated with exercise, weakness of thigh adduction, sometimes causing circumduction of gait
q. Lateral femoral cutaneous nerve-anatomic landmarks in order of occurrence 1) Originates from L2, 3 rami, passes over iliac crest and
anterior to iliacus muscle 2) Dives under inguinal ligament (medial to anterior
superior iliac spine) and enters the thigh to supply sensory innervation over lateral aspect of the thigh, not extending below the knee
r. Lateral femoral cutaneous neuropathy (meralgia paresthetica) 1) Usually caused by compression of the nerve by
inguinal ligament 2) Predisposing factors: truncal obesity, diabetes mellitus,
pregnancy 3) Clinical features: neuralgic pain, numbness, and
paresthesias involving distribution of the nerve, often exacerbated with walking or standing
4) Pain may be widely distributed and may include lower back, buttock, lateral aspect of the knee, and anterolateral portion of the thigh
5) Paresthesias are usually more localized than pain to anterolateral thigh, in the distribution of lateral femoral cutaneous nerve
6) Main goal of electrodiagnosis: rule out L3 radiculopathy or femoral neuropathy, which may potentially mimic the symptoms
7) Treatment: symptomatic treatment of neuralgic pain, local corticosteroid injection, and, when intractable pain, surgical decompression of the nerve or neurolysis
s. Ilioinguinal, iliohypogastric, and genitofemoral nervesanatomic landmarks and neuropathies 1) All predominantly arise from L1 ventral primary rami 2) Iliohypogastric and genitofemoral nerves also receive
contributions from T12 and L2 rami 3) Iliohypogastric and ilioinguinal nerves pass anterior to
quadratus lumborum muscle and then medial to anterior superior iliac spine and innervate lower abdominal muscles
4) Genitofemoral nerve a) Runs over psoas muscle b) Supplies sensory innervation over a small area on
anterior aspect of proximal thigh, scrotum, and labia
c) Innervates cremasteric muscle: it is the afferent arm of the cremasteric reflex
5) Neuropathy involving these nerves a) Most commonly the result of iatrogenic injury
from genitourinary and abdominal operations (e.g., hernia repair, appendectomy)
b) Rare causes: tumors, psoas abscess (compressing genitofemoral nerve), other compressive lesions
c) Clinical features: burning pain and paresthesias in groin, scrotum, labia, and lower abdomen and bulging of lower abdomen
t. Notalgia paresthetica 1) Sensory neuropathy affecting dorsal primary rami
branches of spinal nerves 2) Pain, paresthesias, hyperesthesias, pruritis in the back,
sometimes resulting in well-circumscribed hyperpigmented patch in symptomatic area
3) Associated with degenerative spine disease
A. Radiculopathy 1. Term generally applied to derangement of a ventral or
dorsal spinal root or the immediate proximal spinal nerve formed by their combination
2. Synonymous with monoradiculopathy because there are alternative terms applied to disorders affecting more than one root level or more distal neural components
B. Dermatome: cutaneous innervation by a root segment
C. Myotome: muscular innervation by a root segment 1. All spinal roots have a motor component (and all but
C1 have a sensory component) 2. Myotomes described in this section refer to the motor
destination of each root’s destination in the limbs, with emphasis on muscles easily assessed clinically or electrophysiologically
3. These muscles are innervated by ventral primary rami; dorsal primary rami innervate paraspinal muscles a. Cervical: Table 21-1 b. Thoracic: except for T1, which often innervates several
small muscles of the hand, ventral rami of thoracic roots primarily innervate intercostal muscles and abdominal oblique and rectus muscles according to their level in the thoracic spine
c. Lumbosacral: Table 21-2 4. Commonly elicited muscle stretch reflexes
a. Cervical: Table 21-3 b. Thoracic: deep abdominal reflexes are mediated via
thoracic levels T8-T12 and may be difficult to obtain in obese or multiparous patients
c. Lumbosacral: Table 21-4
D. Clinical Presentations 1. Onset of symptoms may be spontaneous or associated
with a precipitating event (e.g., heavy lifting) 2. Pain: most frequently the initial symptom prompting
medical attention (but not always present) a. Pattern and progression may not be predictable b. Temporal profile: acute, subacute, or insidious onset c. Location may be variable, ranging from localized axial
pain to classic radiating pain within a dermatome d. A specific (though not sensitive) feature of radiating pain
due to a compressive lesion: worsening with cough, sneeze, or the Valsalva maneuver
e. Cervical root pain due to compressive lesions may be alleviated with shoulder abduction and lifting hand above head
The suboccipital nerve (C1) usually has no sensory dermatomal innervation (pure motor) and innervates the deep muscles with insertions at the occiput (e.g., rectus capitis posterior and obliquus capitis muscles)
Table 21-2. Lumbosacral Myotomes: Common Root Innervations of the Most Commonly Examined Lower Limb Muscles
Root Muscle L2 L3 L4 L5 S1 S2 S3 S4
Table 21-1. Cervical Myotomes: Common Root Innervations of the Most Commonly Examined Upper Limb Muscles
Root Muscle C3 C4 C5 C6 C7 C8 T1
3. Paresthesias and sensory loss a. Less common than pain b. Classically (not always): pain precedes paresthesias,
paresthesias precede anesthesia 4. Weakness
a. May develop in any radiculopathy sufficiently severe to affect motor axons
b. May develop early or late in the course c. Important to recognize because of the potential for dis-
ability or prolonged convalescence after treatment of the cause
5. Recreation of compressive symptoms with a. Straight leg raising for lower lumbosacral radiculopathies b. Reverse straight leg raising for upper lumbosacral radicu-
lopathies c. Spurling’s maneuver: axial compression in lateral neck
flexion
E. Causes of Radiculopathy 1. Degeneration and structural compression
a. Spondylosis: arthropathy of facet joints and disks, associated with vertebral body osteophytes, Schmorl’s nodes, synovial cysts, and extension of nucleus pulposus into the vertebral bodies
b. Spondylolysis 1) Separation of facet joints by a fibrous cleft at vertebral
pars articularis, causing instability of facet joints, and may cause spondylolisthesis (most commonly at L4S1 segments)
2) May be congenital or traumatic c. Spondylolisthesis
1) Anterior subluxation of one vertebral body on another, usually L5 on S1
2) Often due to spondylotic disruption of facet joints 3) May cause spinal stenosis if severe enough, requiring
decompression surgery d. Disk bulges
1) Symmetric, diffuse and circumferential bulging of disks beyond vertebral bodies
2) Due to loss of water content from the nucleus pulposus e. Protrusion or extrusion of the intervertebral disk
1) Extension of nucleus pulposus through an anular tear or fissure
2) Most common cause of radiculopathy 3) Collectively referred to as “disk herniation” 4) Most common cervical roots affected: C5, C6, C7 5) Most common lumbar roots affected: L5 and S1 6) Location
a) Most common: lateral and intradural (inside spinal canal)
b) Infrequent: intradural and into nerve root sleeve or extreme lateral (transforaminal) (Fig. 21-7)
7) Lateral protrusion of disks usually affects the nerve root exiting below the disk a) Example: L5-S1 disk affects the S1 root b) Extreme lateral protrusions may involve the root
exiting above the disk, sometimes in combination with other factors such as facet arthropathy
f. Contributing degenerative changes 1) Facet arthropathy: enlargement of vertebral facet
joints due to arthritis, which may result in dorsal encroachment on the root in the intervertebral foramen or medially
2) Juxtafacet cysts (synovial cysts and ganglion cysts): formed by extrusion of synovial fluid or cystic degeneration of collagenous connective tissue or by other mechanisms (Fig. 21-8)
3) Osteophytic spurs 4) Ligamentum flavum hypertrophy 5) Ossification of posterior longitudinal ligament 6) Congenitally short vertebral pedicles 7) Congenitally narrow central spinal canal
g. Cervical spinal stenosis (cervical spondylotic myelopathy) (Fig. 21-9)
Table 21-3. Common Deep Tendon Reflexes of the Upper Limb and the Corresponding Roots
Root Reflex C5 C6 C7 C8 T1
Table 21-4. Common Deep Tendon Reflexes of the Lower Limb and the Corresponding Roots
Root Reflex L2 L3 L4 L5 S1
1) May present with symptoms of cervical nerve root compression or irritation and/or cervical cord compression (myelopathy)
2) Usually caused by more than one aforementioned degenerative mechanism
3) Temporal profile: variable a) Precipitous onset (especially with trauma) b) Gradual onset c) Gradual, stepwise progression d) No progression, stable deficits
4) Upper motor neuron signs of spasticity and hyperreflexia below the segment of the lesion
5) Lower motor neuron findings at the segment of the lesion (reduced or absent reflexes or other sensory or motor symptoms indicative of root involvement)
6) Some patients may have Lhermitte’s sign h. Lumbar spinal stenosis
1) May be caused by a combination of compressive lesions, including disk bulges and herniation, hypertrophy of the ligamentum flavum, facet arthropathy, and other degenerative changes discussed above
2) Uncommon in people younger than 40 years 3) May be asymptomatic 4) Insidious onset of lower back pain and lower limb
pain, symptoms of neurogenic claudication-
important to distinguish from vascular claudication (Table 21-5)
5) Most patients do not have signs of nerve root damage 6) Bladder function often not affected 7) Lateral recess syndrome
a) Refers to compression of nerve roots immediately before entrance into the foramina
b) Presents with chronic, gradually progressive unilateral or bilateral symptoms of neurogenic claudication
i. Acute cauda equina syndrome (typical features) 1) Early unilateral or asymmetric bilateral lower limb
radicular pain in distribution of compressed roots 2) With more severe involvement: asymmetric hypo-
tonic, flaccid, areflexic weakness in myotomal distribution and sensory loss in dermatomal distribution
3) Asymmetric saddle anesthesia 4) Sphincter changes tend to be late in course of disease
j. Conus medullaris syndrome: typical features 1) Symmetric flaccid weakness, areflexia, and sensory loss 2) Symmetric saddle anesthesia 3) Pain uncommon and not severe when present 4) Sphincter changes tend to be early in the course of
disease k. Electrophysiologic testing (see Chapter 5)
1) Nerve conduction studies a) Sensory conduction studies: normal SNAPs given
the usual preganglionic localization b) Rare exception to the above: dorsal root ganglia in
L5 and S1 segments may be located within the spinal canal and a far lateral disk herniation could potentially involve the ganglia or the postganglionic segment, and in this case, SNAPs may be affected, but this occurs much less frequently than expected
c) CMAPs corresponding to affected nerve root may be of low amplitude
2) Needle EMG: most useful in identifying localization and severity, and denervation in otherwise clinically asymptomatic muscles
l. MRI 1) In normal child
a) Very high T2 signal of both nucleus pulposus and anulus fibrosus
b) This is gradually lost with age 2) Anular tear: high T2 signal with or without enhance-
ment, may be concentric, radial, or transforaminal 3) Disk herniation: focal extension of disk material
beyond the anulus, often associated with anular tear (high T2 signal in posterior anulus)
4) Facet hypertrophy and synovial cyst: variable T2 signal intensity (Fig. 21-8)
m. Treatment is determined by severity of the clinical syndrome, with more invasive therapy being appropriate in setting of refractory pain or progressing deficit 1) Medications such as tricyclic antidepressants or anti-
convulsants useful for neuropathic pain 2) Epidural injection of anesthetics and anti-inflamma-
tory medications 3) Open surgical correction with laminectomy,
Table 21-5. Comparison of Neurogenic Claudication From Lumbar Canal Stenosis and Vascular Claudication
Neurogenic claudication
Clinical (pseudo-Vascular feature claudication) claudication
foraminotomy, or diskectomy, as indicated by structural derangement
2. Autoimmune and infectious inflammatory a. Inflammatory causes of diffuse polyradiculopathy (see
below, Section IV. Polyradiculopathies and Polyradiculoneuropathies) may occasionally present with spatially restricted disease limited to a single spinal root or segment
b. Should be considered in absence of a structural cause on imaging
c. Varicella zoster reactivation 1) Most common recognized cause of infectious mono-
radiculopathy 2) Should be considered in presence of a dermatomal
vesicular rash d. Diabetic monoradiculitis is likely the most common
inflammatory/autoimmune monoradiculopathy 3. Traumatic
a. Acute radiculopathy in the setting of trauma is most often associated with other injuries
b. The force required to cause traumatic radiculopathy often injures contiguous peripheral nerves or plexi, creating difficulty in localization
c. The most severe traumatic radiculopathies result from root avulsion, for which the prognosis of spontaneous recovery is poor (discussed below)
d. EMG is useful in this setting 1) Needle EMG: paraspinal muscles generally show evi-
dence of denervation 2) In nerve root avulsion without plexus or nerve injury,
sensory nerve action potentials are preserved 4. Neoplastic
a. Compression of nerve roots by extraneural tumors is more common than by intrinsic neural tumors
b. Neoplastic monoradiculopathies: typically insidious in onset and progression
c. “Intrinsic” causes of radiculopathy 1) Schwannoma 2) Neurofibroma 3) Meningioma 4) Ependymoma 5) Paraganglioma 6) Primitive neuroectodermal tumors
d. Metastatic or “extrinsic” causes of radiculopathy, often from invasion of structures adjacent to the root 1) Lymphoma 2) Breast carcinoma 3) Lung carcinoma 4) Prostate carcinoma 5) Colon carcinoma
6) Melanoma e. Diagnosis: imaging characteristics, cerebrospinal fluid
analysis (CSF) (nonspecifically abnormal in any leptomeningeal disease, but cytology may help identify type), ultimately biopsy
A. Introduction 1. Polyradiculopathy: any disease process affecting multi-
ple spinal roots 2. Polyradiculoneuropathy: any disease process affecting
multiple spinal nerve roots and ganglionic or postganglionic segments of the nerves
3. Causal overlap between polyradiculoneuropathies and some causes of both radiculopathy and peripheral neuropathy
4. Severe length-dependent neuropathies that extend to proximal components of peripheral nerves may be clinically and electrophysiologically indistinguishable from polyradiculopathies; understanding the history of progression in these patients is crucial
B. Clinical Presentation 1. Sensory changes and motor dysfunction suggestive of a
lower motor neuron process involving more than a single spinal nerve root, often more than a single limb
2. The following disorders may present with similar syndromes: a. Motor neuron disease: should not have sensory
disturbance b. Proximal, distal, and diffuse myopathies: should not
have sensory disturbance c. Myelopathy: associated with upper motor neuron signs
and a sensory level d. Brachial or lumbosacral plexopathies (although there is
often a clinical and pathologic overlap between plexopathies and polyradiculoneuropathies, particularly among inflammatory causes)
e. Multiple mononeuropathies, inflammatory or noninflammatory
f. Severe disorders of neuromuscular transmission may also present in a similar fashion: suggested by absence of sensory complaints
C. Laboratory Findings 1. Imaging
a. Multilevel spondylotic disease readily identified with
magnetic resonance imaging (MRI) or conventional or computed tomographic (CT) myelography
b. MRI: focal contrast enhancement of nerve roots affected by inflammatory process or diffuse leptomeningeal enhancement in meningeal metastasis
2. Serum a. Immune markers, suggesting multisystem or nerve-
specific autoimmunity (e.g., antinuclear antibodies, antibodies to extractable nuclear antigens, rheumatoid factor, and antineutrophil cytoplasmic antibodies [ANCAs])
b. Nerve-specific antibodies (e.g., anti-GM1 seen in multifocal motor neuropathy with conduction block, antiGQ1b, and other ganglioside antibodies; anti-MAG (myelin-associated glycoprotein) antibodies, anti-sulfatide antibodies, and any of several paraneoplastic antibodies (particularly anti-Hu/ANNA-1 [antineuronal nuclear antibody] antibodies) 1) Serum protein electrophoresis with immunofixation is
critical for identifying nonspecific monoclonal proteins
c. Metabolic testing for systemic disorders such as diabetes mellitus or sarcoidosis
d. Antibodies to viruses (such as human immunodeficiency virus [HIV], cytomegalovirus [CMV], varicella-zoster virus [VZV]) and bacteria (such as Borrelia burgdorferi)
3. CSF a. A nonspecific inflammatory response consisting of ele-
vated total protein with or without an associated cellular response 1) Acute and chronic inflammatory polyradiculo-
neuropathies are notable for the “dissociated” elevation in protein without a prominent cellular response
b. As with serum testing, antibodies suggesting infection or autoimmunity may be tested for with various degrees of sensitivity; for infections, CSF testing has added benefit of polymerase chain reaction (PCR) testing for specific entities, which may increase sensitivity in their detection
c. Though less sensitive, cultures for viruses or atypical bacteria may be helpful if positive
D. Electrophysiologic Findings 1. Nerve conduction studies (NCSs)
a. Polyradiculopathy 1) Low-amplitude CMAPs in affected segments, with
prolonged or F wave latencies 2) Preganglionic sensory involvement: normal SNAPs
b. Polyradiculoneuropathy 1) Above plus slowing of conduction velocities and
prolongation of distal latencies, mild in disorders primarily affecting axons and more prominent in
demyelinating processes (both motor and sensory) 2) Temporal dispersion and focal conduction blocks in
acquired demyelinating polyradiculoneuropathies 2. Needle EMG
a. Identify degree of axonal damage b. Identify subclinical proximal denervation in patients pre-
senting with clinical phenotype of length-dependent sensorimotor peripheral neuropathy
c. Fibrillation potentials and reduced recruitment of large, complex motor unit potentials: indicative of axonal involvement
d. Fasciculation potentials e. Myokymic discharges: may be seen in poly-
radiculopathies associated with radiation treatment or exposure (but not exclusively)
3. Normal EMG and NCS in polyradiculopathies restricted to sensory roots proximal to dorsal root ganglia (chronic immune sensory polyradiculopathy [CISP]) a. Electrophysiologic abnormalities are noted only in
somatosensory evoked potentials b. Spinal MRI with gadolinium contrast may be needed
E. Causes of Polyradiculopathy and Polyradiculoneuropathy
1. Most common causes: multilevel spondylotic disease of spine; less frequently, metastatic neoplastic disease
2. Autoimmune inflammatory (discussed below) a. Acute inflammatory polyradiculoneuropathy b. Chronic inflammatory polyradiculoneuropathy c. Sarcoidosis d. Paraproteinemias e. Diabetic polyradiculoneuropathies: very likely immune
mediated f. CISP
1) Predominantly demyelinating, immune-mediated process involving dorsal roots proximal to dorsal root ganglia
2) Unlike in sensory polyganglionopathy, SNAPs are preserved because lesion (typically demyelinating) is preganglionic
3) Thickened nerve roots may be demonstrated on highresolution MRI
4) Elevated CSF proteins 5) Response to immune-mediated treatment: intravenous
immunoglobulin, corticosteroids 3. Infectious inflammatory
a. Viruses 1) VZV 2) CMV
3) HIV 4) Epstein-Barr virus (EBV) 5) Herpes simplex virus types 1 and 2
b. Bacteria 1) Borrelia burgdorferi 2) Treponema pallidum 3) Corynebacterium diphtheriae infection does not directly
cause polyradiculoneuropathy, but exotoxin secreted by the bacteria does; may respond to antitoxin
4) In immunocompromised patients, syphilis, toxoplasmosis, or mycobacterial infections may present with polyradiculoneuropathy
5) Rarely, Listeria monocytogenes, Chlamydia pneumoniae, or Brucella species
4. Degenerative (structural): multilevel spondylotic disease of the spine a. Likely the most common cause of polyradiculopathy b. Usually results from multiple degenerative processes c. May be associated with myelopathy
5. Neoplastic a. Tumors of peripheral nerve origin: multiple and plexi-
form neurofibromas; less commonly, schwannomas, perineuromas
b. Metastatic disease 1) Diffuse leptomeningeal metastasis or focal involve-
ment of individual roots 2) Sources of metastasis commonly include
a) Lymphoma (may rarely present primarily in the root)
b) Breast carcinoma c) Lung carcinoma d) Prostate carcinoma e) Colon carcinoma f) Melanoma g) Primitive neuroectodermal tumors with intraxial
metastasis
A. Overview 1. Predominant insult at level of dorsal root ganglion 2. Different causes clinically indistinguishable (serologic
testing may be helpful)
B. Etiology 1. Paraneoplastic 2. Nonmalignant inflammatory 3. Toxic: pyridoxine, cisplatin, paclitaxel 4. Idiopathic
C. General Clinical Manifestations (heterogeneous, variable)
1. Subacute or chronic onset of sensory symptoms 2. Three different patterns of fiber type involvement
a. Patchy, painful dysesthesias becoming widespread in distribution
b. Prominent proprioceptive loss 1) Sensory ataxia (exacerbated in the dark) 2) “Pseudoathetosis” of the hands
c. Combination of the above 3. Generalized areflexia 4. Variable degree of autonomic impairment, which may
be asymptomatic 5. Preserved strength unless more widespread nervous
system involvement
D. Nerve Conduction Studies 1. Widespread absence or severe reduction of SNAP
amplitudes 2. Relatively normal motor conduction studies and EMG
E. Paraneoplastic 1. Associated cancers
a. Most common: small cell lung cancer b. Also common: breast, prostate, ovary, neuroblastoma,
and germ cell tumors 2. Antibodies
a. ANNA-1 (anti-Hu) neuronal antibodies in serum ± CSF b. Frequently occurs in association with other paraneo-
plastic syndromes: encephalomyelitis, autonomic neuropathy, cerebellar degeneration
F. Nonmalignant Inflammatory 1. Associated with Sjögren’s syndrome and other autoim-
mune disorders and paraproteinemias (Fig. 21-10) 2. Key features of Sjögren’s syndrome-related cases
a. Dry eyes, dry mouth b. Positive Schirmer’s test c. Antibodies to extractable nuclear antigens (anti-Ro/SSA
or anti-La/SSB) d. Lymphocytic infiltrates on minor salivary gland biopsy
G. Differential Diagnosis 1. Features favoring paraneoplastic cause
a. Subacute presentation and rapidly progressive course b. Coexistent multifocal nervous system involvement
(autonomic, cerebral cortex, spinal cord, cerebellum) c. High CSF protein and/or lymphocytosis d. Paraneoplastic serologic tests
1) Highly associated with cancer
2) Initially, cancer may not be detectable, and specific neurologic syndrome or antibody may not predict specific primary cancer
2. Other ataxic sensory syndromes a. Vitamin B12 deficiency b. Tabes dorsalis c. Spinocerebellar ataxia d. CISP
H. Treatment and Prognosis 1. Prognosis for recovery tends to be poor, given absence
of effective regeneration of sensory ganglion cells after destruction
2. Primary aim of treatment: prevent further ganglion cell loss
3. Paraneoplastic: antitumor therapy is more effective than immune-modulating therapy
4. Inflammatory a. No randomized controlled data b. Anecdotal reports of benefit with various immune-
mediated treatments
A. Traumatic Plexopathies (and root avulsions) 1. Result of direct trauma (open or closed, shear injury to
nerves), secondary to injury of surrounding structures,
and iatrogenic 2. Upper plexus traumatic lesions (sometimes called Erb-
Duchenne palsy) a. Often associated with C5 and C6 root avulsions b. Present with internally rotated arm, extended at elbow
3. Lower plexus traumatic lesions (sometimes called Dejerine-Klumpke palsy) a. Often associated with C8 and T1 root avulsions b. Present with intrinsic hand muscle weakness and atrophy
(“claw hand” deformity) 4. Supraclavicular plexopathies: more common and more
severe than infraclavicular plexopathies 5. Traction injuries occur when heavy objects fall on the
shoulder or when patient falls on the shoulder, causing a supraclavicular traumatic plexopathy (more frequent than infraclavicular); upper plexus is most often damaged with closed traction injuries
6. There may be associated nerve root avulsion a. Worse prognosis: persistent, irreversible loss of function
and intractable pain, often within 2 weeks after insult b. C8 and T1 roots are likely more vulnerable to avulsion
injury (C5 and C6 roots are protected by fascia and bone as they exit the foramina, despite vulnerability of the upper plexus to traumatic injury)
c. Nerve root avulsions usually cause severe deficits and pain in distribution of affected nerve
d. Features suggestive of nerve root avulsions: complete plexopathy, intractable and severe burning pain in the hand, ipsilateral hemidiaphragm paralysis, traumatic meningocele or absence of nerve roots on neuroimaging, paraspinal fibrillation potentials and normal SNAPs, with low-amplitude or absent CMAPs
7. The primary roots are vulnerable to avulsion from traction injury because they are short and lack epineural and perineural sheaths that protect the nerves
8. Classic postoperative paralysis a. Often results from brachial plexus traction during sur-
gery under general anesthesia b. Usually affects the upper plexus more severely c. Symptoms often present immediately after the operation
9. Obstetric paralysis: brachial plexus traction injuries of infants sustained during birth a. Occurs more frequently with complicated deliveries
requiring instrumentation or those with less desirable fetal presentations (e.g., breech presentation)
b. Predisposing risk factors: fetal macrosomia and maternal obesity and diabetes
c. Mechanism of injury: possibly traction injury on the plexus
d. Most often involves the upper plexus (Erb-Duchenne
palsy); less commonly, lower plexus (Dejerine-Klumpke palsy) or entire plexus
10. Burner syndrome: traumatic plexopathy caused by sudden forceful depression of shoulder and head, almost always due to certain contact sports a. Symptoms: acute-onset dysesthetic pain and weakness,
often involving entire upper limb (unilateral), usually short duration
b. Attacks typically resolve promptly and completely c. Residual weakness if attacks are unusually severe and/or
numerous d. Almost all patients have neurogenic changes on needle
EMG e. Clinical abnormalities are almost always restricted to
upper plexus 11. Pack palsy (rucksack paralysis): weakness and pares-
thesias involving upper plexus, attributed to compression of upper plexus by backpack straps
B. Neoplastic Plexopathy 1. Secondary
a. Lymphatic spread (most common mechanism): metastasis involving lymph nodes adjacent to the lower portion of plexus and nerves (most often lung or breast cancer)
b. Direct extension of primary tumor (e.g., non-small cell bronchogenic carcinoma involving lung apex)
c. Pancoast’s syndrome 1) Symptom complex referring to tumors involving lung
apex 2) These tumors most often affect lower brachial plexus
(C8, T1 distribution) 3) Presentation: pain and paresthesias in C8, T1 der-
matomal distribution, Horner’s syndrome, and motor involvement (weakness and atrophy of intrinsic hand muscles, thenar and hypothenar muscle groups)
d. Treatment: often perioperative radiotherapy and resection 2. Primary: nerve sheath tumors (most common)
a. Most often involve upper brachial plexus (C5, C6 distribution) and supraclavicular in location
b. Primary neoplasms often cause limb pain, dysesthesias, and palpable mass; symptoms are often reproduced with palpation of the superficial tumor
c. Most common: benign neurofibromas; more common in women (than men) and adults (than children)
d. Next most common primary tumor: benign schwannoma
3. Radiation-induced plexopathy is main differential diagnostic consideration in patients who have received radiotherapy
C. Radiation Plexopathy 1. Typically, slowly progressive, long duration 2. Predominant symptom of paresthesias (much less pain
than neoplastic or compressive etiology) and painless weakness
3. Primarily in distribution of upper brachial plexus 4. Features suggestive of radiation-induced plexopathy:
predominance of paresthesias, slowly progressive history with presence of myokymia on EMG examination
5. Features suggestive of a cause other than radiation: rapidly progressive painful syndrome with onset of symptoms less than 6 months after radiotherapy
6. Three different presentations a. Onset within a few days after radiation: permanent,
painless weakness and sensory loss from radiationinduced ischemic injury and occlusion of subclavian artery
b. Reversible sensory symptoms, often paresthesias (often resolving in 6-12 months)
c. Delayed onset of progressive and permanent motor and sensory loss from radiation-induced fibrosis (onset of symptoms may vary from several weeks to >30 years), slow progression throughout several years (radiotherapy induces primary demyelination, followed by axonal loss after several years)
7. Relative sparing of lower plexus may be explained partly by “protective” effects of the clavicle
8. Pancoast’s tumor tends to involve lower brachial plexus, whereas radiation-induced plexopathy is primarily an upper brachial plexus syndrome
9. Pathophysiology: vascular endothelial thickening and resultant obliteration of microvasculature, and radiation-induced endoneural and perineural fibrosis
10. Electrophysiology a. Reduced SNAP and CMAP amplitudes b. SNAPs are usually most sensitive, show earliest abnor-
malities, and may be unobtainable when the process is advanced
c. Supraclavicular stimulation may show conduction block d. Needle EMG examination often shows denervation,
neuropathic changes, and possibly myokymic discharges 11. 3-T MRI may be helpful in differentiating infiltrative,
expansile neoplastic (recurrence) plexopathy from postradiation changes: the latter often have nonexpansile, isolated T2 signal change, or may be normal
12. Poor prognosis: progressive course, no treatment
D. Immune-Mediated Brachial Plexus Neuropathy (also called neuralgic amyotrophy, Parsonage-Turner syndrome, idiopathic brachial plexus neuropathy)
1. Sporadic, immune-mediated (hereditary brachial plexus neuropathy is described below)
2. Males affected more frequently than females 3. Multiple episodes often occur with familial brachial
plexus neuropathies, whereas sporadic brachial plexus neuropathies are often monophasic and unilateral
4. Clinical features a. Abrupt onset of severe pain (with tendency to occur at
night and wake patient from sleep), which often lasts several days to weeks
b. Patients tend to immobilize the arm but do not experience exacerbation of pain with the Valsalva maneuver
c. Absence of pain (although atypical) does not rule out this diagnosis: reports of patients with painless ParsonageTurner syndrome
d. Pain is less frequent in pediatric patients with this condition
e. Weakness becomes apparent after pain subsides, usually present after the third week
f. Atrophy of affected muscle groups becomes evident later 5. Distribution of involvement
a. Often patchy b. Tendency to affect pure motor nerves: long thoracic,
anterior interosseous, posterior interosseous, suprascapular, axillary nerves
c. Also reported: fascicular involvement of musculocutaneous nerve
d. Some nerves that do not arise from brachial plexus may also be involved (e.g., phrenic and spinal accessory nerves)
e. Bilateral phrenic nerve involvement often causes dyspnea and orthopnea
6. Antecedent conditions: flulike syndrome or upper respiratory infection, postoperative (surgery at a distant site), immunization (e.g., hepatitis B vaccine), medications (interferons, lamotrigine, botulinum toxin), pregnancy, systemic vasculitis (e.g., giant cell arteritis, systemic lupus erythematosus, rheumatoid arthritis)
7. Electrodiagnosis: multifocal or patchy evidence of axonal loss on EMG and NCS
8. Pathology a. Not well understood b. Reports of epineural and endoneural mononuclear
inflammatory infiltrates, microvasculitis 9. Neuroimaging (MRI)
a. Helpful to exclude structural causes b. May show increased T2 signal of plexus or denervated
skeletal muscles 10. CSF: often normal, may show elevated protein
11. Treatment a. Corticosteroids, intravenous immunoglobulin, or
plasmapheresis may be tried in acute stage b. Improvement in pain with corticosteroids in several large
open series is noted and appears dose-related c. Other outcomes (strength, sensory loss, length) are not
established with either corticosteroids or other immune therapies
12. Prognosis a. Good prognosis for recovery: 89% in 3 years b. Resolution of pain: usually in several weeks c. Recovery of weakness and atrophy: depends on extent of
involvement (patients with upper trunk lesions recover sooner, partly because proximal muscles are reinnervated sooner)
d. Recovery of phrenic nerve involvement (and diaphragmatic weakness): usually late, tends to be incomplete (given the longer distance)
E. True Neurogenic Thoracic Outlet Syndrome (cervical rib and band syndrome)
1. Rare nontraumatic cause of supraclavicular plexopathy caused by a bony defect (a rudimentary cervical rib arising from C7 vertebra or elongated C7 transverse process)
2. Fibrous band may extend from the bony anomaly to first thoracic rib, often compressing T1 ventral primary rami or lower plexus
3. Symptoms involve lower brachial plexus: paresthesias and mild discomfort involving medial aspect of upper extremity, usually present with atrophy and weakness of thenar and intrinsic hand muscles
4. Plain film of neck: often adequate for diagnosis of the cervical rib
5. Fibrous band: usually not seen on plain films and frequently missed on CT or MRI
F. Lumbosacral Plexopathies 1. Neoplastic plexopathy
a. Uncommon cause of lumbosacral plexopathy b. Caused by direct invasion or compression of plexus by
tumor c. Colorectal, genitourinary (ovary, uterus, prostate), breast,
lymphoma are most common types of secondary tumors to cause this condition (most common is locally invasive colorectal carcinoma)
d. Unilateral more than bilateral plexus involvement e. Severe pain, followed by weakness and sensory loss f. Diagnosis: usually made with MRI or CT g. Therapy
1) Depends on lesion 2) Local radiotherapy is variably effective for pain
2. Retroperitoneal hemorrhage a. Often associated with therapeutic anticoagulation,
trauma, or pelvic fracture b. Hematoma of iliacus muscle
1) Causes intrapelvic femoral nerve compression 2) Presents with pain in groin or lower iliac fossa radiat-
ing to anterior thigh and medial lower leg c. Hematoma of the psoas muscle
1) Produces intrapelvic lumbar plexus compression 2) Deficits in the distributions of femoral and obturator
nerves d. Patients may assume a flexed posture to decrease pain by
flexing and externally rotating the hip e. Diagnosis: CT of abdomen and pelvis
3. Pregnancy-related a. Presentation: usually postpartum from direct compres-
sion of the plexus on one or both sides by infant’s head during its decent
b. May also occur during latter part of third trimester, especially if a mass such as uterine leiomyoma compresses lumbosacral plexus
c. Primigravida women of short stature are at risk d. Other risk factors: infant macrosomia, protracted labor,
midpelvic forceps delivery, cephalopelvic disproportion e. Symptoms: commonly present with footdrop, with
sensory loss often in lateral aspect of distal lower extremity and dorsum of the foot; bilateral in one-fourth of cases
f. Prognosis: good, complete recovery is expected (usually within 3 months)
4. Radiation-induced a. Typically presents about 5 years (range ,1-31 years) after
the radiotherapy b. Typical presentation: slow, progressive leg weakness
(often bilateral); less often, paresthesias and numbness c. May be associated with mild pain (severe pain experi-
enced with plexopathies related to malignant infiltration is atypical)
d. Symptoms typically start in distal aspect of affected lower limb(s) (as compared with plexopathies due to neoplastic infiltration, which are typically proximal in distribution)
e. Electrophysiologic characteristics mimic those of radiation-induced brachial plexopathy discussed above, including presence of myokymia
f. CSF: protein may be elevated g. Imaging and potentially site-directed biopsy: may help
distinguish between infiltrative and radiation-induced changes
5. Traumatic a. Uncommon; caused by falls or motor vehicle accidents b. Mostly caused by double vertical fracture-dislocations of
bony pelvic ring, also with fracture-dislocation of hip joint and acetabulum
c. May be associated with root avulsions d. Weakness commonly affecting lumbosacral trunk (L5-
and S1-innervated muscles); may also affect obturator and superior gluteal nerves and ventral primary rami of L5 and sacral roots
e. The weakness may be overshadowed by pelvic pain, but this diagnosis needs to be considered in patients with persistent leg weakness following pelvic fracture
6. Immune-mediated nondiabetic lumbosacral plexus neuropathy a. The “leg equivalent” of neuralgic brachial amyotrophy b. Subacute to acute onset of pain: may be anterior thigh
with lumbar predominance or posterior thigh and buttock area with sacral predominance, may mimic disk because of distribution and rapidity of onset
c. Weakness becomes apparent as pain disappears d. Pathology: microvasculitis and local nerve ischemic
injury, similar to changes seen in diabetic amyotrophy (described below)
e. Acute painful plexopathy with stepwise progression may be seen in systemic vasculitis
f. There is often associated weight loss and sometimes increased erythrocyte sedimentation rate (ESR), in the absence of other rheumatologic markers
g. Adequate data for treatment are lacking, but open trials with intravenous methylprednisolone reduced progression and helped pain
h. Intravenous immunoglobulin may also be helpful 7. Diabetic lumbosacral plexus neuropathy (diabetic
amyotrophy) (see Part B of this chapter)
A. Overview 1. Inherited neuropathies include disorders that primarily
affect the PNS only (e.g., Charcot-Marie-Tooth disease, hereditary motor and sensory neuropathy), the PNS and CNS (e.g., spinocerebellar ataxia) and disorders that have systemic organ involvement (e.g., Fabry’s disease) (Table 21-6)
2. Classification schemes
a. Hereditary motor and sensory neuropathy (HMSN), also called Charcot-Marie-Tooth (CMT) disease: motor predominant sensory and motor-length dependent peripheral neuropathy
b. Hereditary sensory and autonomic neuropathy (HSAN): small-fiber sensory neuropathy with variable degree of autonomic neuropathy
c. Spinocerebellar ataxia (SCA): autosomal dominant inherited cerebellar ataxia with variable degree of peripheral neuropathy
Table 21-6. Summary of Inherited Neuropathies
Condition Inheritance Gene(s) Nerve conduction study Other
d. Spinal muscular atrophy (SMA), also called hereditary motor neuronopathy (HMN): autosomal recessive lower motor neuronopathy
2. Important additional individual inherited neuropathies include a. Hereditary neuropathy with liability to pressure palsies
(HNPP) b. Hereditary brachial plexitis c. Friedreich’s ataxia d. Kennedy’s disease e. Transthyretin amyloidosis
3. Many inherited metabolic multisystem disorders may also cause neuropathy a. Lipid metabolism disorders (Krabbe’s disease, metachro-
matic leukodystrophy) b. Lipoprotein deficiency (Tangier disease, cerebrotendi-
nous xanthomatosis) c. Peroxisomal disorders (Fabry’s disease) d. Mitochondrial disorders (Kearns-Sayre syndrome) e. Defective DNA maintenance (xeroderma pigmentosum,
ataxia-telangiectasia) f. Porphyrias (acute intermittent)
B. General Principles 1. Most common pattern of inheritance is autosomal
dominant-exceptions are a. X-Linked
1) HMSN X 2) Fabry’s disease 3) Kennedy’s disease
b. Autosomal recessive 1) Most of the metabolic disorders 2) HMSN IV 3) HSAN II-V 4) Friedreich’s ataxia
2. In assessing an apparently sporadic idiopathic neuropathy: evaluation of asymptomatic family members may show subclinical neuropathy confirming the inherited etiology
3. Phenotypic variability: considerable within each condition and even within individual kinships
4. Phenotypic overlap (within and between classification schemes): an example is HMSN II and HSAN I, between which it may be difficult to distinguish
5. Clues to inherited etiology a. Family history
1) May be lacking in autosomal recessive or X-linked recessive conditions
2) May be subclinical in other family members (because of variable expression)
Molecular Genetics Peripheral myelin protein 22 (PMP22)
Compact myelin Duplicated in CMT 1a, deleted in HNPP
Myelin protein zero (MPZ, P0) Compact myelin Adhesion molecule Point mutation of P0 in CMT 1B, some cases of CMT 2
Connexin 32 (Cx32 or GJB1) Uncompacted paranodal myelin Gap junction protein CMT X
Transthyretin (TTR) Familial amyloidosis
IKBKAP Essentially all cases of HSAN III with full penetrance Important for carrier detection and egg selection
SMN1 Commonly deleted in patients with SMA1-3 Involvement of additional genes (SMN2, NAIP) responsible for variable expression
Trinucleotide repeat diseases of peripheral nerve Frataxin (Freidreich’s ataxia) GAA Polyglutamine diseases (CAG)
Androgen receptor (Kennedy’s disease) Ataxin (SCA 1,2,3)
3) Male-to-male inheritance: excludes X-linked recessive conditions (may partially manifest in females and mimic autosomal dominant pattern) and also inherited mitochondrial DNA mutations (caveat: nuclear DNA encodes some mitochondrial proteins)
b. Pes cavus (Fig. 21-11) c. Insidious onset, very slow progression over years to
decades d. Usually symmetric, length-dependent pattern e. General lack of positive sensory symptoms
1) Prominent paresthesias more common in acquired neuropathy
2) Common finding: marked sensory loss on examination to which the patient is symptomatically unaware,
sometimes with dire consequences (e.g., acral mutilation)
3) Exception: spontaneous neuropathic pain of HSAN 6. Most common conditions
a. Demyelinating motor predominant neuropathy: HMSN I
b. Axonal motor predominant neuropathy: HMSN II c. Small-fiber sensory predominant: HSAN I
7. Demyelinating inherited neuropathies a. HMSN I b. Dejerine-Sottas neuropathy c. HMSN IV d. HMSN X e. Refsum’s disease f. Metachromatic leukodystrophy g. Globoid cell leukodystrophy (Krabbe’s disease) h. Adrenomyeloneuropathy i. Mitochondrial neurogastrointestinal encephalopathy
(MNGIE), also called myopathy, neuropathy, gastrointestinal encephalopathy
j. Leigh disease k. Caveat
1) Many patients with a long-standing inherited demyelinating neuropathy develop axon loss
2) Low-amplitude sensory and motor responses on NCSs and long-duration motor unit potentials on needle EMG are indicative of axonal loss (fibrillation potentials are relatively mild or absent)
8. Inherited neuropathies with specific treatments a. Fabry’s disease: enzyme replacement b. Transthyretin amyloidosis: liver transplantation c. Refsum’s disease: phytanic acid-free diet d. Kennedy’s disease: possible role for antiandrogen therapy
C. Hereditary Motor and Sensory Neuropathy (HMSN) 1. Overview
a. Genetically and phenotypically heterogeneous group of disorders
Inherited Neuropathy Spot Diagnoses History
Abdominal pain: porphyria, MNGIE, MEN2B
Clinical Orange tonsils: Tangier disease Angiokeratoma: Fabry’s disease Retinitis pigmentosa: HMSN VII, SCA 7,
Refsum’s disease, mitochondrial disease Hypertrophic nerves: HMSN I, Refsum’s
disease, Dejerine-Sottas disease (HMSN III) Hypotelorism, short stature: hereditary
brachial plexopathy Absence of fungiform tongue papillae:
HSAN IV Tongue nodules: MEN2B Tightly curled hair: giant axonal neuropathy Gynacomastia: Kennedy’s disease Extensor plantars and absent ankle reflex:
Friedreich’s ataxia, but also vitamin B12 deficiency
Cardiomyopathy: amyloidosis, Friedreich’s ataxia, Fabry’s disease
Laboratory Very low level of HDL cholesterol: Tangier disease Elevated serum phytanic acid: Refsum’s disease
Electrodiagnostic Disproportionate prolongation of distal motor
latencies: HNPP, but also anti-MAG-related neuropathy
Pathology Onion bulbs: HMSN I, Refsum’s disease,
Dejerine-Sottas disease, CIDP Tomaculae: HNPP, less prominently in
HMSN I, CIDP Giant axons with dense cytoplasm: giant
axonal neuropathy Brown granules in Schwann cell cytoplasm:
metachromatic leukodystrophy Apple-green birefringence: TTR, gelsolin or
Apo A-I familial amyloidosis
b. Characterized by symmetric, length-dependent, motorpredominant, sensory and motor peripheral neuropathy
c. Pathology may be predominantly axonal loss or demyelinating
d. Except for rare types V, VI, and VII, these disorders are usually restricted to PNS
2. HMSN I (CMT 1) a. Autosomal dominant b. Demyelinating neuropathy (predominantly, with late
axonal changes) c. Pathology (Fig. 21-12)
1) Onion bulbs: repeated cycles of demyelination and remyelination result in nerve fibers surrounded by concentric layers of Schwann cell cytoplasmic processes resembling layers of an onion
2) Axonal loss a) Affects both myelinated and unmyelinated fibers b) Extent of axonal loss determines clinical severity:
earlier axonal loss often causes slower conduction velocities on electrophysiologic testing
d. Genetics 1) HMSN Ia
a) Duplication of segment of chromosome 17 (17p11.2-12) containing the peripheral myelin protein 22 gene (PMP22): the most commonly identified genetic abnormality in HMSN I group (approximately 75% of cases)
b) De novo duplication of PMP22: approximately 10% of HMSN Ia cases
c) Less common cause of HMSN Ia: point mutations of PMP22, often associated with a more severe neuropathy than patients with duplication
d) PMP 22 is produced in Schwann cells, where it is a membrane protein in compact myelin and has a role in maintaining myelin integrity
2) HMSN Ib a) Due to point mutations of gene encoding myelin
protein zero (MPZ or P0) b) Accounts for approximately 5% of cases of HMSN I c) New mutations not uncommon, so there may be
no family history d) MPZ is expressed by Schwann cells and is major
protein of peripheral nerve myelin e) MPZ: a transmembrane protein; probably serves
as adhesion molecule holding together adjacent myelin lamellae
f) Almost 100 different MPZ mutations have been described
g) Some of these mutations present in infancy with profound conduction slowing and a severe phenotype, others present in mid-adulthood with
HMSN I Usually inherited in autosomal dominant fashion
Distinguished from HMSN II by slowed conduction velocities (normal in HMSN II)
Distinguished from CIDP by lack of temporal dispersion or conduction block
variable degrees of slowing and severity h) Late-onset HMSN Ib cases can be confused with
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) due to sporadic onset and intermediate conduction velocities
3) HMSN Id a) Due to mutations of early growth response 2 gene
(EGR2) b) Unlike PMP 22, MPZ, and connexin 32 protein
(Cx32) (all transmembrane myelin proteins), EGR 2 is a transcription factor and is likely responsible for activating expression of these other myelin proteins
4) Other rare subtypes include HMSN Ic and HMSN If e. Clinical features: typical phenotype
1) Age at onset varies, most typically in second decade 2) Some patients may remain asymptomatic throughout
life or present in late adulthood 3) Insidious onset and slow progression 4) Length-dependent symmetric pattern: feet then hands
a) Pes cavus, hammer toes b) Weakness of intrinsic hand and feet muscles and
peroneal-innervated muscles c) Distal hyporeflexia or areflexia d) Reduced large-fiber (vibration and touch) sensory
modalities in feet and later in hands e) Distal atrophy with inverted “champagne bottle”
legs: characteristic but relatively uncommon, late finding (Fig. 21-13)
5) Some patients have upper limb action tremor: this group has been termed the “Roussy-Levy syndrome,” but probably not a distinct genetic entity
6) Palpable nerve hypertrophy in approximately 25% of patients
7) Rare respiratory, cranial, and autonomic involvement 8) HMSN Ib tends to be more severe disorder than
HMSN Ia, but otherwise they are clinically and electrophysiologically indistinguishable
f. Laboratory: normal CSF cell count and protein g. Electrodiagnosis
1) NCS (primarily demyelinating pattern) a) Upper limb motor conduction velocity: less than
38 m/s, usually about 20 m/s b) Generally, conduction velocities are less than 75%
of lower limit of normal c) In contrast to acquired demyelinating neuropathy,
conduction slowing is uniform (e.g., similar conduction velocity in median and ulnar forearm segments) and not associated with conduction block or temporal dispersion
d) Distal latencies are prolonged early in the disease e) Distal lower limb axonal changes: common in
more advanced or long-standing cases f) Reduced CMAP amplitudes with advanced disease
(correlates with degree of axonal loss) 2) EMG evidence of distal reinnervation with little
denervation h. HMSN I vs. CIDP
1) Younger onset vs. late adulthood (exceptions-rare, early-onset CIDP and occasional late-onset sporadic cases of HMSN Ib [MPZ])
2) Slow, steady progression over years vs. subacute or chronic relapsing
3) Uniform conduction slowing without conduction block or temporal dispersion more common in HMSN I
i. Treatment 1) No specific therapy 2) Appropriate footwear if foot deformity 3) Ankle foot orthoses if severe footdrop
j. Prognosis 1) Early childhood onset often associated with severe
neuropathy 2) Later onset cases associated with normal life expectancy,
many patients maintain independent ambulation because of relatively preserved proximal strength
3. HMSN II (CMT 2) a. Autosomal dominant
b. Axonal neuropathy c. Genetics
1) Heterogeneous and less well defined than HMSN I 2) At least 6 subtypes (a-f) by linkage analysis 3) Some specific genes identified
a) HMSN IIa: MFN2 and KIF1B b) HMSN IIb: RAB7, may also present similar to
HSAN I c) HMSN IId: GARS, may also present as motor
neuronopathy d) HMSN IIe: NFL
4) Most of patients in this group do not have an identifiable or known genetic abnormality; exception is MFN2 gene a) May account for up to 20% of patients with CMT
2, particularly in those presenting in childhood b) MFN2 is a nuclear gene that encodes the mito-
chondrial protein mitofusin 2 c) Deficient mitofusin 2 results in inability of mito-
chondria to fuse or move along microtubules during fast anterograde axonal transport, thus depriving the distal axon of an energy source
d. Clinical features 1) Generally indistinguishable from HMSN I without
NCSs 2) Tendency to present later in life and develop less
upper limb weakness than HMSN I 3) Patients with this condition may be mistaken for
idiopathic sensorimotor peripheral neuropathy, if careful family history and evaluation are not obtained
4) HMSN IIb: severe sensory loss 5) HMSN IIc: diaphragm and/or vocal cord paresis 6) HMSN IId: upper limb involvement early in disease
course e. Electrodiagnosis
1) NCSs (features predominantly axonal): reduced SNAPs and CMAPs, with EMG evidence of reinnervation and mild denervation
4. HMSN III (Dejerine-Sottas disease) a. Overview
1) Infantile onset of severe demyelinating neuropathy with profound slowing of conduction velocities
2) Genetically heterogeneous; has been described with mutations of PMP22, MPZ, and EGR2
3) HMSN III classification has been removed from modified HMSN classification, which emphasizes molecular genetic identification
b. Rare c. Autosomal dominant or sporadic (de novo mutation) d. NCSs (demyelinating neuropathy): markedly reduced
motor conduction velocities, usually less than 10 m/s e. Clinical features
1) Severe neuropathy manifesting in infancy as delayed motor milestones
2) Progressive weakness of arms and legs 3) Often wheelchair bound by early adulthood 4) Generalized areflexia 5) Palpable nerve hypertrophy
f. Laboratory 1) Prominent onion bulbs on nerve biopsy 2) Unlike most of the inherited neuropathies, marked CSF
protein elevation is common in Dejerine-Sottas disease 5. HMSN IV
a. Autosomal recessive b. Rare c. No longer refers to Refsum’s disease (see below) d. Usually severe, early-onset neuropathy e. Demyelinating pattern (discussed above) observed on
NCSs f. HMSN IVa (mutations of GDAP1 gene of unknown
function) causes basal-lamina onion bulbs, without intervening layers of Schwann cell cytoplasm
6. HMSN X (CMT X) a. Genetics
1) X-linked recessive: typical family history is apparently unaffected parents and/or affected brothers
2) Gap junction beta 1 (GJB1) gene (encoding Cx32): Cx32 is a Schwann cell transmembrane gap junction protein located in uncompacted myelin (in contrast to MPZ and PMP 22) at paranodal region
b. Clinical features 1) Resembles CMT 1, with onset in adolescence, early
proprioceptive loss, and sensory ataxia 2) Some with central hearing loss 3) A subset of patients may have transient encephalopa-
thy with exercise at altitude (usually >8,000 ft), with symmetric nonenhancing white matter abnormalities
c. Electrophysiology 1) Mixed axonal and demyelinating features with
conduction velocities intermediate between CMT 1 and CMT 2 (on electrodiagnostic evaluation)
2) Upper limb nerve conduction velocities: typically 30 to 38 m/s
7. Other rarer forms of HMSN a. HMSN V
1) Autosomal dominant 2) Associated with spastic paraplegia
b. HMSN VI 1) Autosomal recessive 2) Associated with optic atrophy
c. HMSN VII: associated with retinitis pigmentosa d. Giant axonal neuropathy
1) Rare 2) Autosomal recessive 3) Mutation of GAN gene on chromosome 16q24,
encoding gigaxonin: responsible for the underlying defect of nerve axons of both PNS and CNS
4) Onset in infancy of progressive severe sensory and motor axonal neuropathy
5) Patients tend to walk on the inner edges of their feet 6) Patients subsequently develop spinocerebellar
degeneration 7) Characteristic finding in some patients: tightly curled
hair 8) Death by the end of third decade 9) MRI: abnormal signal in cerebellum and subcortical
white matter 10) Nerve biopsy: giant axonal swellings up to 50 μm
(roughly 10 times average diameter of sural nerve myelinated axons) (Fig. 21-14) a) Swellings contain densely packed neurofilaments b) Often undergo secondary demyelination and may
have small onion bulbs 8. Genetic testing in HMSN
a. Commercially available “CMT panels”: very expensive, includes very broad range of genetic tests
b. Some genes that are tested are very rare or have been described only in single kindreds
c. Insufficient testing of normal controls to establish benign polymorphisms producing indeterminant results
d. Individual genetic tests can be selected based on clinical phenotype and nerve conduction characteristics 1) CMT 1-like phenotype
a) Fluorescent in situ hybridization testing for PMP22 duplication, if negative proceed to
b) PMP22, Cx32, MPZ sequencing 2) CMT 2-like phenotype
a) Cx32 (unless documented male to male transmission)
b) MPZ: although both Cx32 and MPZ are expressed in Schwann cells, they can produce intermediate range conduction velocities, thus mimicking CMT 2
c) MFN2, particularly if childhood onset d) Consider testing NFL e) PMP22 is very unlikely to produce this phenotype
3) Severe/early-onset CMT 1/Dejerine-Sottas-like phenotype a) PMP22 sequencing (usually not duplications) b) MPZ c) Consider EGR2, GDAP1 (both rare)
D. Hereditary Neuropathy With Liability to Pressure Palsies (HNPP)
1. Outside the HMSN classification 2. Genetics
a. Autosomal dominant b. Most common genetic abnormality: deletion of portion
of chromosome 17 (17p11.2-p12) containing PMP22 (this is same region duplicated in CMT 1A)
c. Approximately 20% of cases do not have a macrodeletion: sequencing of PMP22 in these patients may show point mutations
3. Clinical features
a. Onset: recurrent painless focal mononeuropathies at common sites of compression, often in second or third decade when patient develops 1) Ulnar neuropathy at the elbow 2) Peroneal neuropathy at the fibular head 3) Radial neuropathy at the spiral groove
b. Unlike sporadic compression palsies, these patients develop palsies after relatively minor compression or trauma
c. The preceding compression may not even be apparent to patient
d. Mononeuropathy typically improves, but over days or weeks rather than minutes or hours
e. With time, some patients develop distal sensory motor neuropathy with distal sensory loss and absent ankle reflexes
4. Electrophysiology a. Multifocal demyelinating peripheral neuropathy b. Focal conduction slowing or conduction block at
common sites of compression
c. Generalized prolongation of motor and sensory distal latencies out of proportion to conduction slowing
5. Pathologic hallmark: tomaculae (Fig. 21-15) a. Focal areas of myelin thickening due to myelin redupli-
cation or uncompacting of myelin lamellae b. Appear as focal sausage-shaped areas of teased fibers and
as fibers with abnormally thick myelin for fiber diameter on methylene blue semithin sections
6. Treatment: avoid nerve trauma or compression a. Advise against leaning on elbows b. Advise against crossing legs
E. Hereditary Brachial Plexopathy 1. Genetics
a. Autosomal dominant inheritance: a characteristic feature of the family history may be attacks in family members occurring post partum
b. Some (not all) families show linkage to chromosome 17q24-25, the gene has not been identified
c. Minor dysmorphic features reported in some families 1) Ocular hypotelorism (close-set eyes) 2) Prominent epicanthal folds 3) Short stature
2. Clinical features a. Recurrent attacks of painful brachial plexopathy, with
onset in first to third decade b. Individual attacks are usually indistinguishable from
idiopathic brachial plexus neuritis (Parsonage-Turner syndrome) but are recurrent 1) Pain is severe, acute onset, precedes onset of weakness 2) Unlike compressive radiculopathy, pain is not worse
with neck movements or Valsalva maneuver but often exacerbated by arm or shoulder movement
3) Tendency to affect muscles innervated by C5 and C6 segments, particularly shoulder girdle muscles
4) Pattern of weakness and atrophy often suggests patchy involvement of plexus and nerve trunks (i.e., not a pure plexopathy)
c. Pregnancy, parturition, trauma, infection, or immunization can precipitate attacks
d. Time course is variable, but typically pain lasts for days to weeks and weakness plateaus before 1 month
3. Differential diagnosis a. HNPP
1) HNPP can present with plexopathy but is usually painless
2) Attacks are associated with minor trauma or compression rather than immune system stimulating events
3) Patients with HNPP often have signs of generalized background neuropathy (high arches, generalized prolongation of distal motor latencies)
b. Idiopathic brachial neuritis (Parsonage-Turner syndrome) 1) Absence of family history 2) Attacks are not recurrent
4. Treatment a. Upper limb nerve biopsy samples from small number of
patients during an attack have shown prominent epineurial perivascular inflammation, providing rationale for treating acute attacks with immunotherapy
b. Corticosteroids started at onset of an attack shorten duration of pain (anecdotal evidence)
5. Prognosis a. Most patients, treated or not, make good functional
recovery from individual attacks: recovery may take up to 12 to 18 months
b. Patients with frequent attacks may with time accrue some degree of permanent deficit
c. Frequency of attacks varies greatly but tends to decrease with age
F. Hereditary Sensory and Autonomic Neuropathy (HSAN)
1. Overview a. Characterized by involvement of small-diameter nerve
fibers (temperature and pain sensation, autonomic nerves)
b. Genetics: less well defined than for HMSN c. Classification system: still based on clinical manifesta-
tions and pattern of inheritance d. One of the most devastating complications of HSAN:
painless neuropathic ulcers, may progress to osteomyelitis and distal mutilation
e. No specific treatment for HSAN 1) Patient education about care of the feet is critical 2) Advice includes following:
a) Always wear shoes b) Wear comfortable shoes that are not too tight c) Inspect shoes for foreign bodies d) Inspect feet daily e) Avoid heavy weight bearing on feet f) Keep feet well moisturized to prevent cracking of
the skin as a portal for infection g) Aggressively treat foot infections: include strict
avoidance of weight bearing 2. HSAN I
a. Most common form of HSAN: likely an underrecognized cause of adult-onset sensory neuropathy
b. Important differences compared with other HSANs 1) Only autosomal dominant HSAN 2) Only adult-onset HSAN (all others are congenital) 3) Slowly progressive (others are nonprogressive) 4) Tendency to be restricted to lower limbs
c. Genetics 1) Autosomal dominant 2) Mutation of SPTLC1 and RAB7 have been described
in some patients 3) Mutation of SPTLC1 on chromosome 9q22, encod-
ing a long-chain base 1 (LCB1) subunit of enzyme palmitoyltransferase, responsible for synthesis of sphingomyelin (found in neurilemma) a) Exact pathogenesis: not defined with certainty,
apoptotic role of the ceramide (sphingomyelin degradation product) may contribute
b) Phenotype of certain kindreds has included hearing loss and hyperhidrosis
4) Full clinical and genetic spectrum of disease is probably still to be defined
d. Clinical features of “typical” distal lower limb sensory and autonomic neuropathy and acral mutilation 1) Onset in adult life (wide variation)
2) Slow progression but remains restricted predominantly to lower limbs
3) Distal lower limb neuropathic pain (burning, aching, lancinating) or local pain at pressure points, mostly due to plantar ulcers and other foot orthopedic complications
4) Patients gradually develop loss of small-fiber sensory modalities in length-dependent pattern
5) Loss of pain sensation predisposes to development of foot orthopedic complications such as neuropathic plantar ulcers and stress fractures: in severe cases can lead to distal mutilation from infection and osteomyelitis
6) Autonomic involvement: usually restricted to asymptomatic distal sweating loss
e. Pathology 1) Both myelinated and unmyelinated fibers of all sizes
affected: small myelinated fibers may be affected more than large myelinated fibers
2) Axonal atrophy and degeneration, myelin remodeling f. Electrophysiology
1) Features consistent with length-dependent sensory predominant sensorimotor axonal neuropathy
2) Sensory potentials may be relatively preserved early in course because of selective small-fiber involvement
3) Mild motor involvement: common finding on EMG 3. HSAN II
a. Similar clinical features: similar to HSAN I but 1) Onset in early life 2) Severe panmodality sensory loss affecting upper and
lower limbs, trunk and face 3) Mutilating acropathy: distal pain insensitivity predis-
poses to neuropathic ulcers and mutilation of fingers and toes from early age, unrecognized fractures, and Charcot joints (Fig. 21-16)
4) Common autonomic features: distal anhidrosis, urinary sphincter disturbance, and impotence in men
b. Genetics 1) Autosomal recessive 2) Mutation of one gene at chromosome 12p13.33 may
possibly be causative; no other known genetic mutations or chromosomal linkage
c. Pathology 1) Loss of myelinated fibers of all sizes (more than
unmyelinated fibers) 2) Segmental demyelination and remyelination, axonal
degeneration and atrophy d. Electrophysiology: generalized loss of sensory potentials
4. HSAN III a. Also called familial dysautonomia or Riley-Day syndrome
b. Genetics 1) Autosomal recessive 2) Mainly reported in Ashkenazi Jews 3) Caused by mutation of IKBKAP located at chromo-
some 9q31, encoding IKAP (kinase complexassociated protein) a) A single mutation site appears responsible for
approximately 99.5% of all cases of HSAN III: this allows for reliable carrier and intrauterine detection
b) Mechanism by which this mutation causes disease is unknown
c. Clinical features 1) Presentation at birth with severe and widespread auto-
nomic failure a) Alacrima (absence of overflow tears) b) Frequent respiratory infections because of dry
respiratory secretions c) Gastrointestinal tract dysmotility: esophageal
dysmotility and megaesophagus, gastroparesis, megacolon (vomiting, poor feeding, abnormal sucking in first few years of life)
2) Symptoms of autonomic dysregulation and overactivity, often precipitated by emotional upset a) Profuse sweating b) Skin blotching c) Tachycardia d) Hypertension
3) Characteristic feature: absence of tongue fungiform papillae
4) Hypotonia, hyporeflexia 5) Kyphoscoliosis 6) Stunted growth 7) Decreased pain sensation at older age: distal pain
sensation is relatively preserved early in disease and may become impaired later in life (in contrast to HSAN I and HSAN II)—the exception is corneal insensitivity (an early feature)
d. Pathology 1) Marked decrease in unmyelinated and small
myelinated fibers 2) Degeneration of neuronal cell bodies of spinal and
sympathetic ganglia e. Prognosis: death in infancy or childhood
5. Rare HSAN subtypes a. HSAN IV
1) Inheritance: autosomal recessive 2) Mutations of TRKA, encoding protein tyrosine
receptor kinase A (TrkA) 3) Congenital insensitivity to pain with anhidrosis 4) Hyperthermia due to anhidrosis 5) Mild mental retardation in some patients (IQ in 70s) 6) Absence of unmyelinated fibers in sural nerve biopsies 7) Normal SNAPs
b. HSAN V 1) Phenotypically similar to HSAN IV, but different
pathology 2) Severe loss of small myelinated fibers, mild decrease in
unmyelinated fibers 3) Associated with mutations of TRKA and NGFB 4) Normal SNAPs
G. Multiple Endocrine Neoplasia 2B (MEN 2B) 1. Genetics: autosomal dominant or sporadic mutation of
RET proto-oncogene 2. Clinical features
a. Dysmorphic features
1) Diffuse irregular thickening of lips 2) Apparent eversion of eyelids 3) Broad nasal root 4) Marfanoid body habitus without ectopic lens or
aortic defects 5) Tongue nodules
b. Neoplasms 1) Medullary thyroid carcinoma 2) Pheochromocytoma
c. Visceral autonomic neuropathy (ganglioneuromatosis): poor colonic motility with severe constipation and megacolon
d. Variable degree of axonal peripheral sensorimotor neuropathy
A. Overview 1. Diverse group of disorders 2. Shared features
a. Inheritance: autosomal recessive or X-linked recessive (e.g. Fabry’s disease, adrenomyeloneuropathy)
b. Involvement of PNS plus CNS or other organs 3. Two broad categories of presentations
a. Demyelinating neuropathy with CNS disease 1) Metachromatic leukodystrophy 2) Krabbe’s disease 3) Adrenomyeloneuropathy 4) Refsum’s disease
b. Small-fiber sensory neuropathy 1) Fabry’s disease 2) Tangier disease
B. Metabolic Classification (most common conditions listed here, see Chapter 25)
1. Lysosomal enzymes a. Metachromatic leukodystrophy b. Krabbe’s disease
2. Peroxisomal enzymes a. Adrenoleukodystrophy and adrenomyeloneuropathy b. Fabry’s disease c. Refsum’s disease
3. Lipoprotein deficiency: Tangier disease
C. Metachromatic Leukodystrophy 1. Inheritance: autosomal recessive 2. Metabolic abnormality: arylsulfatase A deficiency
a. Lysosomal enzyme
b. Activity can be measured in leukocytes or skin fibroblasts 3. Clinical features
a. Childhood or adult onset: early-onset disease is associated with more rapid progression
b. PNS: distal sensorimotor peripheral neuropathy c. CNS
1) Mental retardation, optic atrophy, spasticity 2) MRI: confluent white matter plaques and atrophy
4. Electrophysiology: demyelinating features 5. Pathology: metachromatic granules
a. Schwann cell cytoplasmic inclusions that stain differently from rest of cytoplasm (hence, metachromatic)
b. Methylene blue preparations: normal Schwann cell cytoplasm is light blue and granules are red or black
6. Treatment: bone marrow transplantation may stabilize cognition in patients with early disease but motor dysfunction may continue to progress
D. Globoid Cell Leukodystrophy (Krabbe’s disease) 1. Inheritance: autosomal recessive 2. Metabolic abnormality: galactosylceramidase
(lysosomal enzyme) 3. Clinical features
a. Infantile, late infantile, juvenile, and adult-onset forms b. PNS and CNS features similar to metachromatic
leukodystrophy 4. Electrophysiology: demyelinating features 5. Pathology: globoid cells
a. Giant multinucleated epitheloid cells in brain white matter
b. Globoid cells are not found in peripheral nerve biopsies, which instead may show tubular clear Schwann cell cytoplasmic inclusions on electron microscopy
6. Treatment is similar to metachromatic leukodystrophy: bone marrow transplantation early in disease course may stabilize progression
E. Adrenomyeloneuropathy (see also Chapter 20) 1. Genetics and pathogenesis
a. X-linked recessive b. Allelic with adrenoleukodystrophy c. Mutation of the ABCD1 on chromosome Xq28
encoding adrenoleukodystrophy protein (ADLP), a member of the ATP-binding cassette (ABC) transporter protein family
d. ADLP is a transmembrane protein located in the peroxisomal membrane, functions to transport very-long-chain fatty acids (VLCFAs) into peroxisome
e. Deficiency causes accumulation of VLCFAs 2. Clinical features
a. Most common phenotype of the mutation is that of adrenoleukodystrophy (see Chapter 25)
b. Adrenomyeloneuropathy is a milder phenotype of slowly progressive spastic paraplegia in third and fourth decades, usually in adult men, sometimes with mild adrenal insufficiency
c. Female carriers may be mildly affected and present with slowly progressive spastic paraparesis
d. Mild peripheral neuropathy e. Loss of both myelinated and unmyelinated fibers
3. Electrophysiology a. Mixed axonal-demyelinating peripheral neuropathy b. Abnormal somatosensory evoked potentials
4. Treatment: supportive
F. Refsum’s Disease 1. Previously classified as HMSN IV 2. Inheritance: autosomal recessive 3. Metabolic deficiency: deficiency of phytanoyl-CoA
hydroxylase (peroxisomal enzyme involved in oxidation of phytanic acid)
4. Clinical features a. Onset in second decade b. Initial symptom: often night blindness due to retinitis
pigmentosa c. Distal sensory motor neuropathy d. Palpable nerve hypertrophy e. CNS and cranial nerve disease: ataxia, anosmia, deafness f. Skeletal abnormalities: short fourth metatarsal g. Diabetes mellitus and cardiac disease
5. Electrophysiology: demyelinating features 6. Pathology
a. Variable hypertrophic change involving mostly brachial and lumbosacral plexi
b. Segmental demyelination and variable loss of myelinated fibers
7. Other laboratory findings a. CSF protein is often very high b. Elevated serum phytanic acid levels
8. Treatment: dietary restriction of phytanic acid
G. Fabry’s Disease 1. Genetics
a. X-linked recessive b. Female hemizygotes can also manifest disease but typi-
cally milder severity and later onset 2. Metabolic deficiency: deficiency of α-galactosidase
(a peroxisomal enzyme) resulting in accumulation of ceramide trihexoside in PNS, kidney, heart
3. Clinical features
a. Onset: usually in second decade b. Primary manifestation of peripheral neuropathy: distal
burning pain worsened by heat or physical exertion, which may occur in attacks lasting minutes to hours
c. Small-fiber sensory loss (predominantly affecting temperature sensation)
d. Autonomic neuropathy 1) Hypohidrosis 2) Impotence
e. Systemic manifestations 1) Cerebrovascular disease, cardiac failure 2) Renal failure 3) Angiokeratomas: small raised venous skin lesions
around groin 4) Corneal opacities
4. Pathology (see Fig. 25-13): electron microscopy show accumulation of ceramide trihexoside appearing as concentric laminated cytoplasmic inclusions (likely in lysosomes)
5. Electrophysiology: may be normal (predominantly small-fiber process)
6. Treatment a. Symptomatic treatment of painful neuropathy: pheny-
toin, carbamazepine b. Enzyme replacement therapy is available: early work
suggesting beneficial effect on neuropathy
H. Tangier Disease 1. Genetics
a. Autosomal recessive b. Mutation of ABCA1 encoding ABCA1 protein, member
of ABC transporter family 2. Normal state: high-density lipoprotein (HDL) is
responsible for a. Cholesterol efflux from peripheral tissues via ABCA1
transporter b. Esterification of free cholesterol extracted from peripheral
tissue c. Transfer of cholesteryl esters to very-low-density lipopro-
tein (VLDL) and low-density lipoproteins (LDL) in exchange for triglycerol
d. Carrying cholesteryl esters to liver to be degraded 3. Pathogenesis
a. Defective transporter activity yields lipid-depleted HDLs, which are degraded quickly
b. Deficient HDL results in absence of cholesteryl ester degradation, which overloads macrophages of reticuloendothelial system with deposition of cholesteryl esters
c. Intracellular deposition of cholesteryl esters does not downregulate macrophage cholesterol scavenger recep-
tors, and cholesterol accumulation in macrophages continues unchecked
d. Deficient HDL also results in poor extraction of triglycerol from VLDL, resulting in elevated triglycerides and triglyceride-rich VLDLs
e. Poor extraction of triglycerol from VLDL prevents it from becoming more dense, preventing formation of LDL
4. Clinical features a. Age at onset: wide range b. Mononeuritis multiplex-like phenotype: relapsing,
asymmetric sensorimotor multiple mononeuropathies often involving individual cranial or limb nerves
c. Distal symmetric small-fiber sensory neuropathy (slowly progressive)
d. Pseudosyrinx phenotype: slowly progressive weakness and atrophy of face and bilateral upper limbs (and later the trunk), relative preservation of reflexes, and preferential loss of pain and temperature early in disease (other sensory modalities affected later in disease course)
e. Enlarged orange tonsils due to lipid accumulation in reticuloendothelial system
f. Premature coronary artery disease 5. Laboratory features (serum)
a. Very low or absent HDL levels b. Low LDL levels c. Low or normal serum cholesterol levels d. Elevated VLDL levels (contain abundant triglycerides,
more than cholesteryl esters) e. Elevated triglycerides
6. Electrophysiology: predominantly axonal but may have some demyelinating features
7. Pathology a. Lipid-laden vacuoles in endothelial cells of the vasa
vasorum and Schwann cells (best observed with teased fiber analysis and electron microscopy)
b. Segmental demyelination and remyelination in patients with relapsing multiple mononeuropathy presentation
c. Axonal degeneration with loss of small myelinated and unmyelinated axons in patients with symmetric, slowly progressive peripheral neuropathy
d. Cholesteryl ester deposits in macrophages of tonsils, spleen, lymphatic system, and other components of reticuloendothelial system
8. Treatment: supportive
I. Porphyric Neuropathy 1. Inheritance: usually autosomal dominant 2. Porphyrins: intermediate metabolites in synthesis of
heme
3. Porphyrias: due to defects in synthesis of porphyrins 4. Neurologic manifestations probably due to accumula-
tion of toxic precursors rather than deficiency of end product
5. Porphyric neuropathy is seen in following hepatic porphyrias: a. Acute intermittent porphyria: deficiency of porpho-
bilinogen deaminase causing accumulation of mitochondrial δ-aminolevulinic acid and cytoplasmic porphobilinogen
b. Hereditary coproporphyria: deficiency of coproporphyrinogen oxidase causing increased levels of coproporphyrinogen (including in between attacks)
c. Variegate porphyria: deficiency of the mitochondrial protoporphyrinogen oxidase causing accumulation of protoporphyrinogen IX (cannot be measured); often normal urine porphyrin levels in between attacks (elevated fecal coproporphyrin levels)
d. Neuropathy or other neurologic dysfunction: not a feature of erythroid porphyrias
6. Clinical features-acute intermittent porphyria, hereditary coproporphyria, variegate porphyria all share following characteristic features: a. Usually more severe in patients with acute intermittent
porphyria b. Typical presentation pattern: acute abdominal pain,
then psychiatric disturbance, then acute neurologic dysfunction
c. Acute colicky abdominal pain 1) Associated with nausea, vomiting, severe constipation 2) May be due to acute gastrointestinal autonomic neu-
ropathy or effect of deficiency of heme or its precursors on autonomic innervation and smooth muscle components of gastrointestinal tract
d. Other autonomic features (usually sympathetic overactivity) 1) Labile blood pressure 2) Tachycardia 3) Urinary retention 4) Pupillary dilatation
e. Psychiatric disturbance and CNS involvement: acute encephalopathy 1) Agitation, restlessness, delirium, anxiety 2) Hallucinations 3) Psychosis 4) Seizures 5) May progress to coma
f. Acute attacks of neurologic dysfunction: PNS involvement 1) Resembles Guillain-Barré syndrome
2) Early back or limb pain 3) Subacute onset and progression of axonal, asymmetric
generalized predominantly motor neuropathy, usually within 2 or 3 days after abdominal and psychiatric symptoms
4) Preferential involvement of upper limbs and proximal muscle groups
5) Distribution of weakness: may be patchy 6) Hyporeflexia in proportion to degree of muscle weak-
ness: reflexes are preserved early in disease course (unlike Guillain-Barré syndrome)
7) Severe cases: flaccid quadriplegia; respiratory muscle paralysis and respiratory failure
8) Rapidly progressive muscle atrophy: early feature, may be severe
9) Variable sensory involvement (usually much less prominent than motor involvement): may be distal glove-stocking distribution or proximal and patchy
10) Cranial nerve involvement is common: especially facial weakness and difficulty swallowing, other cranial nerves may be affected if more severe (causing extraocular muscle or tongue weakness)
g. Dark urine (on exposure to light and air) h. Attacks precipitated by
1) Drugs 2) Hormonal changes 3) Stress
i. Cutaneous photosensitivity with variegate porphyria and hereditary coproporphyria (with hyperpigmentation and hypertrichosis of the skin)
j. Acute intermittent porphyria clinically differs from hereditary coproporphyria and variegate porphyria by 1) No photosensitivity 2) Attacks are usually more severe
7. Differential diagnosis a. Guillain-Barré syndrome: absence of encephalopathy
and reflexes b. Arsenic or thallium poisoning
1) Closely mimics triad of gastrointestinal symptoms, neuropathy, encephalopathy
2) Urinary heavy metals should be tested in all patients not known to have porphyria presenting with this triad
8. Diagnosis a. Electrophysiology
1) NCS and needle EMG may be normal during first few days of acute attack
2) Often the first abnormality is fibrillation potentials on needle EMG seen after 5 to 10 days
3) NCS shows predominantly axonal pattern but is not otherwise specific
b. Urinary porphyrins 1) δ-Aminolevulinic acid: severely elevated during acute
attacks of acute intermittent porphyria, hereditary coproporphyria, variegate porphyria; normal or mildly elevated in between attacks
2) Porphobilinogen a) Increased more than δ-aminolevulinic acid in
hereditary coproporphyria and variegate porphyria b) Increased less than δ-aminolevulinic acid in acute
intermittent porphyria c) Usually increased in between attacks in acute inter-
mittent porphyria 3) Coproporphyrin: greatly increased in both hereditary
coproporphyria and variegate porphyria (even in between attacks) a) Increased urine excretion can be a reversible drug
or heavy metal effect unrelated to disease b) Urine heavy metal screen may be done to rule out
metal intoxication c) Normal fecal excretion of porphyrins if due to drug
effect (urine coproporphyrins normalize 2 weeks after cessation of offending agent)
9. Treatment a. Patients with acute intermittent porphyria are asympto-
matic in between attacks unless they have residual neuropathy from previous severe attacks
b. Avoidance of excessive sun exposure in patients with hereditary coproporphyria and variegate porphyria
c. Prevention of acute attacks 1) Avoidance of known porphyrogenic drugs (many are
inducers of cytochrome P-450, such as barbiturates, phenytoin, alcohol, estrogens, sulfonamides)
2) Avoidance of prolonged starvation or excessive physical exertion without carbohydrate loading
d. Treatment of acute attacks 1) Careful review of current medications, cessation of
any potentially exacerbating medications 2) Acceptable acute symptomatic treatments
a) Abdominal pain: morphine b) Agitation: chlorpromazine c) Seizures: clonazepam in small doses
3) Identify and treat hyponatremia due to commonly associated syndrome of inappropriate antidiuretic hormone
4) Maintain adequate carbohydrate intake: intravenous glucose if patient is vomiting
5) Daily intravenous heme infusion until attack has abated, usually 3 to 14 days a) Suppresses induction of δ-aminolevulinic acid
synthase
b) If used early in attack, heme treatment can result in rapid resolution of psychiatric and autonomic symptoms
e. Prognosis 1) Recovery from acute neuropathy is related to severity 2) Severe attacks associated with marked axonal degener-
ation: often prolonged, usually incomplete recovery
J. Familial Amyloid Polyneuropathy (FAP) 1. Overview
a. Inheritance: autosomal dominant b. Extracellular deposition of mutant fibrillar protein that
forms β-pleated structures leading to tissue infiltration and organ dysfunction
c. Exact mechanism by which this deposition causes neuropathy is uncertain
d. Proposed mechanisms: ischemia due to vessel occlusion by amyloid deposits in vasa nervorum, compression, or direct toxic effect
e. Three different constituent proteins known to cause FAP f. Mutations of the protein’s gene results in structural
change of the protein that favors formation of a β-pleated structure
g. Most cases of acquired amyloid neuropathy are AL type (immunoglobulin light chains)
2. Classification a. Old phenotypic classification
1) FAP type I (transthyretin mutation): lower limb onset
2) FAP type II (transthyretin mutation): upper limb onset (often CTS)
3) FAP type III (apolipoprotein A-I mutation): lower limb onset, nephropathy, gastric ulcers
4) FAP type IV (gelsolin mutation): cranial nerve involvement
b. New genotypic classification 1) Transthyretin (TTR) FAP 2) Apolipoprotein A-I FAP 3) Gelsolin FAP
3. Genetics a. TTR amyloidosis
1) Autosomal dominant 2) Most common cause of FAP 3) Found worldwide but increased prevalence in people
of Portuguese, Swedish, or Japanese descent 4) TTR is produced in liver 5) More than 80 known point mutations but methio-
nine 30 (Met30) is most common b. Apolipoprotein A-I amyloidosis
1) Autosomal dominant
2) Neuropathic form described in a kindred from Iowa with Gly26Arg mutation
3) Other mutations of this gene reported to cause nonneuropathic systemic amyloidosis
c. Gelsolin 1) Autosomal dominant 2) First described in a Finnish kindred but also reported
with other genetic backgrounds 3) Protein is expressed mainly in muscle
4. Clinical Features a. Common features
1) Variable age at onset, most commonly in fourth decade
2) Painful axonal sensory more than motor neuropathy a) Small-fiber function affected early b) Motor involvement late
3) Prominent autonomic involvement 4) Cardiac and renal failure
b. TTR amyloidosis Met30 (formerly classified as FAP I) 1) Most common point mutation (Val30Met) 2) Onset of neuropathy usually in third to fifth decades 3) Prominent autonomic symptoms (may be early and
severe) a) Orthostatic hypotension b) Impotence c) Urinary retention d) Gastrointestinal dysmotility, alternating constipa-
tion, diarrhea 4) Length-dependent sensory and motor neuropathy
that usually starts in lower limbs and affects predominantly sensory small fibers
5) With progression: eventual involvement of all sensory modalities and motor fibers later in disease course (with progressive weakness and atrophy starting in distal lower limbs and progressing to involve upper limbs)
6) Cardiac failure more than renal failure 7) Vitreous opacities (amyloid deposits) 8) Rare CNS symptoms: stroke, seizures, dementia,
spasticity, episodes of confusion 9) Average survival: about 10 years
10) Specific pathologic features of TTR amyloidosis (Fig. 21-17) a) Amyloid deposits in epineurium, endoneurium,
perineurium b) Deposits often found around blood vessels c) Axonal loss, wallerian degeneration (initially affect-
ing unmyelinated and small myelinated fibers, then larger myelinated fibers)
c. TTR amyloidosis Tyr 77
1) Second most common TTR point mutation 2) CTS very common, is often initial manifestation 3) Absence of vitreous opacities 4) Otherwise, clinical features identical to Met30
phenotype d. TTR amyloidosis Ser 84 and His 58 (formerly classified
as FAP II) 1) Onset of neuropathy: usually in fourth or fifth
decades with CTS 2) Slowly progressive generalized sensory and motor
peripheral neuropathy starting in upper limbs 3) Autonomic symptoms and failure 4) Sometimes cardiomyopathy 5) Not associated with renal or ocular manifestations
e. Apolipoprotein A-I amyloidosis (formerly classified as FAP III) 1) Pattern of neuropathy similar to TTR amyloidosis,
but less prominent autonomic involvement 2) High incidence of gastric ulcers and renal failure
(early) 3) Pathology: amyloid deposits throughout PNS includ-
ing the dorsal root ganglia and roots, immunohistochemical characteristics of apolipoprotein A-I
f. Gelsolin amyloidosis (formerly classified as FAP IV) 1) Presentation often in 30s with corneal lattice dystro-
phy due to amyloid deposition in corneal branches of trigeminal nerve
2) Progressive cranial neuropathy ensues (often facial nerve involved, with facial weakness, beginning in upper facial branches supplying forehead)
3) Other cranial nerves involved: V, VIII, XII 4) Bulbar symptoms in older patients 5) Mild axonal peripheral sensory and autonomic
neuropathy 6) Cardiac involvement clinically rare 7) Benign course with normal life span 8) Specific pathologic features: deposition of gelsolin
amyloid in vessel walls and perineurial sheaths, nerve roots may be more severely affected than distal nerves
5. Diagnosis a. Electrophysiology
1) Features of axonal sensorimotor length-dependent polyneuropathy and/or CTS
2) May be limited to small-fiber neuropathy (early in disease course) with normal NCS
b. Pathology: common features 1) Amyloid best demonstrated with alkaline Congo red
preparations observed with polarizing filters to demonstrate the apple-green birefringence
2) Immunohistochemistry preparations (using anti-TTR, -λ, -κ, -Apo A-I monoclonal antibodies) can help determine constituent protein but are not always reliable
3) Negative anti-TTR preparation does not exclude TTR amyloid and consideration should be given to sequencing the TTR gene if patient does not have a monoclonal protein
4) Rectal or abdominal fat biopsy may provide pathologic confirmation of amyloid without need for nerve biopsy
c. Molecular genetic testing: commercially available for TTR amyloid
d. Clinical features important for staging 1) To assess severity of systemic disease 2) Electrocardiography to detect conduction block and
echocardiography should be performed in all patients
3) Renal involvement (often begins as proteinuria) 6. Treatment
a. Liver transplantation for patients with TTR amyloidosis, by removing production site of mutant TTR protein, may improve cardiac and renal function but affect on neuropathy is less clear
b. Apolipoprotein A-I is produced by liver and other organs; role of liver transplantation in this condition is not defined
c. Gelsolin is produced in muscle, so liver transplantation would not be beneficial
K. Spinal Muscular Atrophy (see Chapter 20)
L. Spinocerebellar Ataxias (see Chapter 9)
M. Friedreich’s Ataxia (see Chapter 9)
N. Peripheral Nerve Manifestations of Mitochondrial Disorders (see also Chapter 24)
1. Overview a. Heterogeneous group of disorders due to mutations of
mitochondrial DNA causing impaired respiratory chain function
b. Marked phenotype/genotype variability but common features include ophthalmoplegia, retinitis pigmentosa, deafness, seizures, dementia, ataxia, myopathy
c. Some respiratory chain proteins are encoded by nuclear DNA; these mutations produce phenotype similar to some mitochondrial DNA mutations and do not demonstrate mitochondrial inheritance
d. Neuropathy (usually axonal) may be found in up to 25% of patients with mitochondrial disease but is frequently overshadowed by other clinical features
e. Limited number of mitochondrial phenotypes in which neuropathy may be most prominent and/or presenting feature
2. MNGIE a. Genetics: autosomal recessive (nuclear-encoded mito-
chondrial proteins) 1) Mutation of thymidine phosphorylase gene on chro-
mosome 22 2) Abnormal cellular nucleotide pool causes multiple
deletions of mitochondrial DNA with tendency to occur at certain sites
b. Clinical features 1) Onset before age 20, with death in fourth decade 2) Usually presents with gastrointestinal symptoms
(abdominal pain, nausea, early satiety, diarrhea) due to visceral neuropathy
3) Demyelinating length-dependent sensorimotor neuropathy occurs in almost all patients
4) Leukoencephalopathy 3. Leigh disease
a. Genetics: heterogeneous but usually autosomal recessive with mutations of one of several nuclear genes involved in assembly of complex IV of respiratory chain
b. Clinical features 1) Devastating encephalomyopathy, with onset in infancy 2) Demyelinating neuropathy, with sometimes pro-
found slowing of conduction velocity reported in multiple families
4. Neuropathy, ataxia, retinitis pigmentosa (NARP) a. Genetics: true mitochondrial DNA disease b. Clinical features: axonal sensory neuropathy c. Muscle biopsies do not show ragged red fibers
A. Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP), Guillain-Barré Syndrome
1. History a. Although recognized in the nineteenth century, the disease
was characterized by and named eponymously for Guillain, Barré, and Strohl, who recognized the key cytoalbuminologic dissociation in the CSF of affected patients
2. Clinical presentation a. Often preceded by illnesses ranging from nonspecific
upper respiratory infections to Campylobacter jejuni infections, triggering autoimmune response toward root and nerve antigens
b. Typical presentation 1) Acute or subacute, with ascending paresthesias,
sensory loss, and weakness, which may initially be distal or proximal
2) Hyporeflexia or areflexia in early phase of disease (usually out of proportion to any weakness): Achilles tendon reflexes usually lost; biceps reflexes often spared
3) Back pain, distal leg pain and paresthesias 4) Cranial nerve involvement: cranial nerve VII,
extraocular movements 5) Autonomic involvement: sympathetic overactivity
(transient or sustained hypertension, cardiac arrhythmias, diaphoresis), reduced sympathetic activity (orthostatism, hypotension, anhidrosis), reduced parasympathetic activity (urinary retention, ilieus)
c. Rate and extent of progression can vary widely: most patients reach the worst stage of disease within 2 to 4 weeks, and approximately one-third require ventilatory assistance at some point
d. Most cases in North America: patchy proximal and distal demyelination with later, secondary axonal damage in many cases
3. Laboratory features a. CSF analysis
1) Elevated protein (often >100 mg/dL) with normal or modest CSF leukocyte count
2) CSF is useful in excluding clinical entities, mainly viral infections (e.g., HIV, CMV), which may mimic AIDP, but often have increased cell counts
b. Serum studies may include assays for antibodies known to be associated with AIDP and its variants 1) GQ1b antibodies are commonly associated with
Miller Fisher syndrome (also, perhaps not coincidentally, with Bickerstaff ’s brainstem encephalitis)
2) GM1 antibodies and other ganglioside antibodies associated with axonal variants
4. Electrophysiologic features a. Role of needle EMG and NCS: confirm diagnosis,
exclude alternatives, and determine axonal damage (which may correlate roughly with prognosis)
b. NCSs 1) Slowing of conduction velocities and prolongation of
distal latencies 2) Temporal dispersion of CMAPs 3) Conduction block may be present 4) F waves may be absent or prolonged in latency 5) Early in disease course: sensory responses often normal 6) About 1 to 2 weeks after onset: may be relative spar-
ing of sural response (called sural sparing, referring to normal sural response, in face of reduced or absent median and ulnar SNAPs); may be due to relative resistance of larger diameter myelinated fibers in sural nerve to early inflammatory attack
7) Smaller diameter of end sensory branches of ulnar and median nerves (site of the recorded potentials from antidromic studies) are probably more predisposed to inflammatory attack
8) Later in disease course: all sensory responses may be absent or show demyelinating changes in conduction velocity and latency
c. Needle EMG 1) Acute phase: may reveal only reduced recruitment of
motor unit potentials in affected muscles 2) Subacute or chronic phase: presence of fibrillation
potentials and increased motor unit potential complexity or size correlates roughly with extent of axonal damage (suggesting longer, more protracted course and worse prognosis)
5. Pathology a. Inflammation with endoneural lymphocytic infiltration b. Demyelination: degradation of myelin lamellae from
penetration and disruption of Schwann cell basal lamina by macrophages
c. Axonal degeneration 6. Management
a. Immediate management of patients with AIDP focuses on close monitoring and supportive care 1) Serial maximal respiratory pressures and forced vital
capacities (FVC)
2) Mechanical ventilation and intensive care for precipitous decrease in any measure or low respiratory values (FVC <20 mL/kg, maximal inspiratory pressure <30 mm Hg, or maximal expiratory pressure <40 mm Hg)
3) Management of autonomic instability: labile blood pressure, cardiac arrhythmias (cardiac monitoring required), urine retention, and ileus
4) Management of pain (very common symptom in acute and plateau phases of care): refractory pain may be treated with antiepileptic medications; short-term narcotics may be necessary
b. Management of disease course: immunomodulation 1) Corticosteroids have never been conclusively shown
to help shorten disease course or minimize morbidity 2) Intravenous immunoglobulin and plasmapheresis are
likely equally effective in mitigating disease severity and should be instituted early
B. AIDP Variants 1. Acute motor axonal neuropathy (AMAN): axonal
variant a. Most common in China; characterized by summer epi-
demics, closely tied to C. jejuni outbreaks b. Primarily affects children c. Has been associated with various ganglioside antibodies
(GM1, GM1b, and GD1a) d. Characterized by flaccid symmetric paralysis (limbs; cra-
nial, including facial and pharyngeal muscles; respiratory muscles) developing over several weeks, without clinical or electrophysiologic sensory involvement
e. Pathophysiology: widespread selective wallerian degeneration of motor axons
f. Pathology 1) Widespread wallerian-like axonal degeneration, pri-
marily involving motor fibers (in roots and peripheral nerves)
2) Little evidence of demyelination or lymphocytic inflammation
3) Little, if any, involvement of sensory nerves g. NCSs: reduced or absent CMAPs, normal motor distal
latencies and conduction velocities, normal SNAPs h. Needle EMG: widespread fibrillation potentials after
several days i. Most patients experience rapid recovery, comparable to
patients with prototypic demyelinating Guillain-Barré syndrome
2. Acute motor and sensory axonal neuropathy (AMSAN): axonal variant a. Presentation similar to AMAN but also involves sensory
axons
b. Also associated with C. jejuni infection c. Acute, severe ascending quadraparesis, atrophy, sensory
loss d. NCSs: reduced or absent CMAPs and SNAPs, with
normal conduction velocities and distal latencies, without conduction block
e. Needle EMG: widespread fibrillation potentials f. Immunoglobulin and complement-mediated attack on
axolemma, without much demyelination g. Pathology
1) Widespread wallerian-like axonal degeneration 2) Axonal degeneration of sensory fibers 3) Little evidence of demyelination or lymphocytic
inflammation h. Treatment
1) Same as for Guillain-Barré syndrome 2) Unlike Guillain-Barré syndrome and AMAN,
patients often have incomplete and prolonged recovery
3. Miller Fisher variant a. Acute or subacute ataxia, areflexia, ophthalmoplegia
(may also have difficulty swallowing due to craniobulbar weakness)
b. Diplopia is usually first symptom (often from unilateral or bilateral cranial nerve VI palsy), followed by gait and limb ataxia
c. Debatable whether Miller Fisher variant is brainstem encephalitis in clinical spectrum with Bickerstaff ’s brainstem encephalitis
d. Believed to be triggered by a C. jejuni or Haemophilus influenzae infection
e. Pathophysiology likely related to immune-mediated attack on antigens at neuromuscular junctions in somatic and extraocular muscles causing rapid, reversible defect of the acetylcholine release from presynaptic membrane, possibly due to nerve-terminal disease and conduction failure
f. Associated with antibodies to GQ1b ganglioside, probably through molecular mimicry (present in more than 85% of cases)
g. GQ1b antibodies also reported in Bickerstaff ’s brainstem encephalitis
h. Elevated CSF protein i. Treatment: same as for Guillain-Barré syndrome
C. Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
1. History a. “Relapsing polyneuropathies” and “recurrent Guillain-Barré
syndrome” were recognized in early twentieth century
b. CIDP was identified as a distinct entity by Dyck and colleagues in 1975
2. Clinical presentation a. Antecedent immune challenge such as a vaccination or
infection may be seen in patients with CIDP (less common than with AIDP)
b. Presentation in children: subacute, relatively rapid onset and progression with good response to treatment, followed by relapsing-remitting course
c. Presentation in adults (three forms) 1) Usually insidious onset and slow, gradual progression;
may be interrupted by sequential improvements and relapses
2) Stepwise progression 3) Relapses: often in face of slow progressive disease
course, relapsing-remitting course less common than in children
d. Subacute or chronic presentation of weakness and sensory symptoms of large-fiber dysfunction
e. Proximal and distal weakness: predominant feature f. Numbness, paresthesias, sensory ataxia g. Cranial nerves may be involved: most commonly, facial
(VII) or oculomotor (III) cranial nerves h. Reflexes are reduced or absent i. Diagnostic criteria include disease progression longer
than 8 weeks or relapses 3. Clinical variants
a. Motor predominant CIDP 1) Multifocal demyelinating motor neuropathy 2) Asymmetric, predominantly motor symptoms 3) May primarily affect upper limbs 4) Careful electrophysiologic examination needed to exclude
multifocal motor neuropathy with conduction block b. Sensory predominant CIDP
1) Subacute or chronic ascending paresthesias and pain in a stocking distribution
2) Sensory ataxia 3) Normal strength, although some patients later
develop weakness 4) Electrophysiologic testing often shows generalized
demyelinating peripheral neuropathy, including motor involvement
c. Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also called Lewis-Sumner syndrome or, more simply, multifocal CIDP 1) Usually slowly progressive (sometimes relapsing-
remitting) onset and progression 2) Distribution of symptoms: asymmetric, distal more
than proximal, onset in upper limbs much more frequent than lower limbs or cranial muscles
3) Sensory symptoms of paresthesias, numbness, pain localized to distribution of single nerves: usually first manifestation
4) Motor deficits may follow and usually involve upper limb asymmetrically
5) Absent deep tendon reflexes 6) Inflammatory demyelinating hypertrophy of nerves
in brachial plexus (may be palpable) 7) Pathology and electrophysiologic testing both show
multifocal demyelination on background of generalized neuropathy
8) NCSs: pattern of multiple mononeuropathies and focal (or multifocal) motor and sensory conduction block
9) Treatment of first choice is intravenous immunoglobulin; coticosteroids shown to be effective
4. Pathology (Fig. 21-18 and 21-19) a. Endoneurial lymphocytic infiltration b. Segemental, multifocal demyelination and remyelina-
tion, with onion-bulb formation c. Multifocal varying degrees of interstitial edema and
inflammatory cell infiltrates d. Axonal loss (primary or secondary) and axonal sprouting e. May be demyelination secondary to axonal atrophy f. Involvement of motor and other large fibers more than
small fibers g. One proposed mechanism of segmental demyelination:
invasion of Schwann cells and compact myelin by macrophages
5. Laboratory features a. CSF analysis: elevated protein, normal leukocyte count
(should be <10 cells/μL); rule out infectious causes b. Serum studies to exclude metabolic conditions such as
hypothyroidism c. Serum protein electrophoresis with immunofixation to
exclude paraproteinemia 6. Electrophysiologic features
a. NCSs 1) Slowed motor and sensory conduction velocities with
prolonged distal latencies 2) Temporal dispersion and sometimes block of
conduction 3) Prolonged or absent F-wave latencies 4) Sensory responses often absent
b. Needle EMG 1) May show only reduced recruitment of motor unit
potentials if predominantly demyelinating lesion 2) With secondary axonal damage (especially after years
of disease), there may be fibrillation potentials and increased motor unit size and complexity
disorders it may resemble clinically and electrophysiologically (e.g., motor neuron disease and CIDP)
c. Prevalence: men more than women (2.6:1) d. Mean age at onset: 40 years (80% of patients are
between 20 and 50 years old) 2. Clinical presentation
a. Typical presentation: insidiously progressive (occasionally stepwise) asymmetric painless weakness in individual nerve distributions (80% of cases occur in forearm or hand muscles)
b. Most often occurs in upper limbs initially c. Sensory symptoms of any type should cast doubt on this
diagnosis, but they are described in a marked percentage of patients (up to 10%-20%)
d. Presenting symptom in proximal distribution in 5% and
7. Treatment a. Unlike AIDP, parenteral and oral corticosteroids are
particularly helpful in treatment and maintenance b. If complications of corticosteroid therapy develop,
steroid-sparing agents may be used (but they may take months to become effective) 1) Azathioprine 2) Cyclophosphamide 3) Mycophenolate mofetil 4) Cyclosporine
c. For patients with refractory disease or relapse, intravenous immunoglobulin or plasmapheresis is often effective
d. Prognosis and response to treatment in adults: generally less favorable than in children
D. Multifocal Motor Neuropathy With Conduction Block (MMNCB)
1. Introduction a. MMNCB was recognized as distinct clinical entity by
several authors in 1980s b. Much less common (approximately 1-2/100,000) than
in leg(s) in 10% of patients e. Muscle atrophy of involved muscle groups: mild in early
stages f. Natural history: one of slow progression, which may be
slowed by treatment g. Infrequent cranial nerve involvement (often limited to
CN XII) h. Absent upper motor neuron signs i. Pathologic mechanism is poorly understood, and it is
unknown if focal demyelination, axonal damage, or a combination is responsible for conduction block
3. Laboratory features a. Ganglioside antibodies: about half of patients with
MMNCB have anti-GM1 antibodies, which are not specific and may be seen with other neuropathies
b. Serum and CSF tests generally serve to exclude other neuropathies
4. Electrophysiologic features (Taylor et al. 2000) a. One area, preferentially two areas, of persistent motor
conduction block not at common sites of compression: commonly partial conduction block (definition of conduction block, see Chapter 5B)
b. “Inching” technique is most useful for determining conduction block (definite conduction block by inching is accepted as ≥20% reduction in CMAP amplitude or area over a 10-cm segment by most authorities)
c. No evidence of diffuse demyelination outside of segments with conduction block
d. Normal sensory conductions in individual mixed sensory-motor nerves affected by motor conduction block
e. Needle EMG: chronic or ongoing denervation and reinnervation in distribution affected by partial motor conduction blocks
f. Evidence of denervation in myotomal pattern should raise specter of motor neuron disease
5. Pathology a. Focal areas of conduction block have not been definitely
shown to be associated with focal demyelination b. No hypertrophic changes c. Minimal inflammation d. Multifocal active axonal degeneration and regeneration
6. Treatment a. Intravenous immunoglobulin (initial “load” followed
by maintenance therapy): most patients have initial response to this treatment, but response is often transient and many relentlessly (but slowly) show progression despite maintenance therapy
b. Only chemotherapy agent reported to have been successful: intravenous cyclophosphamide (with or without intravenous immunoglobulin)
c. Case reports of stabilization with the use of azathioprine
E. Neuropathies Associated With Paraproteinemias 1. Introduction
a. The presence of monoclonal immunoglobin proteins (M proteins or M spikes) is risk factor for peripheral neuropathy (conversely, patients with “idiopathic” neuropathies are more likely than controls to have a serum monoclonal protein)
b. Direct, biologically causative links between the protein and neuropathy are often, but not always, demonstrable
c. Characteristics of the M protein and any associated condition often dictate type and severity of neuropathy
2. Waldenström’s macroglobulinemia a. Likely the first recognized neuropathic paraproteinemia b. Caused by rampant proliferation of plasma and lympho-
cytoid cells that produce the M protein c. The M protein in these patients consists of IgM, 75%
of cases are associated with a κ light chain d. Patients are often elderly men e. Presenting symptoms often nonspecific (fatigue,
dyspnea, weight loss) f. Hyperviscosity and bleeding complications may be
present g. Hepatomegaly, splenomegaly
h. Associated polyneuropathy 1) Usually length-dependent sensorimotor peripheral
neuropathy similar to that associated with monoclonal gammopathy of undetermined significance (MGUS) (may be predominantly demyelinating or axonal)
2) Less often, multiple mononeuropathies associated with cryoglobulinemia and/or hyperviscosity
3) Rarely, small-fiber neuropathy associated with amyloidosis
i. Laboratory and ancillary evaluation 1) IgM M protein: often elevated more than 3 g/dL 2) Monoclonal light chain is seen in urine in most cases 3) Anti-MAG reactivity in some patients: the neuropa-
thy tends to be predominantly demyelinating 4) High erythrocyte sedimentation rate 5) Moderate to severe normocytic, normochromic anemia 6) Hyperviscosity 7) Associated with cold agglutinins and
cryoglobulinemia 8) No lytic bone lesions
j. Treatment with plasma exchange or intravenous immunoglobulin may slow progression of neuropathy, but generally the response of IgM-associated neuropathies is less robust than with IgG-associated neuropathies 1) Primary disease management with chemotherapy
may also slow progression of the neuropathy 3. POEMS (polyneuropathy, organomegaly,
endocrinopathy, M protein, skin changes) syndrome (osteosclerotic myeloma) a. Peak incidence in fifth to sixth decades of life b. Osteosclerotic myeloma is much less common than
multiple myeloma (at a ratio of approximately 20:1) and are distinct entities 1) Neuropathy is rare in multiple myeloma 2) Neuropathy is a hallmark of osteosclerotic myeloma
(occurring in 85%-90% of patients) c. Clinical features
1) Polyneuropathy: often primary complaint 2) Organomegaly: spelnomegaly, hepatomegaly,
lymphadenopathy 3) Endocrinopathy: gynecomastia, testicular atrophy,
impotence in men, secondary amenorrhea in women, diabetes mellitus, hypothyroidism
4) M protein (most often IgG or less likely IgA): usually λ light chain and α or γ heavy chain class
5) Skin changes: hyperpigmentation, hypertrichosis, clubbing of fingers and toes, white nail beds, hemangiomas
6) Other findings: pitting edema of lower extremities, ascites, pleural effusions, thrombocytosis, polycythemia, weight loss
d. Most patients have radiographic evidence of sclerotic bone lesion: most commonly axial skeleton (spine, pelvis, ribs)
e. Polyneuropathy 1) Length-dependent 2) Slowly progressive course with severe deficits 3) Both sensory and motor symptoms begin in lower
extremities and ascend proximally: motor predominant
4) Often present with sensory symptoms of numbness and paresthesias, followed by symmetric weakness
5) Motor impairment often becomes severe enough to overshadow sensory symptoms
f. Electrodiagnosis of the neuropathy: features of demyelination (conduction block, temporal dispersion, slowing of conduction velocities, and prolongation of distal latencies) and frequently distal secondary axonal damage
g. CSF protein is almost universally elevated (to >100 mg/dL in 50% of patients), without cellular response
h. From 11% to 30% of patients have Castleman’s syndrome (angiofollicular lymph node hyperplasia)
i. Treatment of osteosclerotic myeloma with focused irradiation and chemotherapy may halt or slow progression of neuropathy
j. Neuropathy may continue to respond 1 or 2 years after completion of therapy
k. Efficacy of plasma exchange and intravenous immunoglobulin in the treatment of neuropathy: conflicting results
4. Multiple myeloma a. Peak incidence in seventh decade b. Usual presenting features: fatigue, anemia,
hypercalcemia c. Associated with lytic lesions, osteoporosis, or fractures d. Most common neurologic manifestation: compressive
radiculopathy (due to myelomatous infiltration and spread); in 5% of cases, myelopathy or cauda equina syndrome due to extradural spread of myeloma from vertebral body
e. Most multiple myeloma patients have serum and urine M protein
f. Multiple myeloma is associated with symptomatic neuropathy in less than 10% of patients (half of whom have pathologic evidence of amyloid deposition on nerve biopsy)
g. Neuropathic presentation varies and may be length-
dependent in pattern or, less likely, polyradicular (most often features of axonal loss on electrodiagnostic evaluation)
5. Primary acquired amyloidosis a. Amyloid: a deposited proteinaceous material that is
eosinophilic on light microscopy and appears the same regardless of origin of protein
b. Amyloidosis can be divided loosely into acquired (primary and secondary) and familial forms (discussed above)
c. Most cases are acquired; of these, primary amyloidosis is most commonly associated with neuropathic complications (focus of this discussion)
d. Primary acquired amyloidosis is uncommon, occurring in fewer than 1/100,000 persons per year
e. Presenting features: fatigue, weight loss, bruising, symptoms of associated neuropathy
f. Serum M protein is present in about 70% of patients, reflecting plasma cell proliferative disorder; this may be 1) Primary or 2) Related to coexistent multiple myeloma
g. Neuropathic manifestations of amyloidosis are protean 1) Autonomic neuropathy: orthostatism, syncope, and
impotence are common complaints 2) Length-dependent sensorimotor peripheral neuropa-
thy: common, manifests with predominantly painful sensory complaints and small-fiber involvement
3) Median neuropathies at wrists: very common; are predisposed with deposition of amyloid in flexor retinaculum at the wrist
4) Neuropathic presentation may be clouded by coexistent proximal myopathy also caused by amyloid deposition
h. Diagnosis relies on demonstrating amyloid in tissue in appropriate clinical context: demonstration of amyloid in any affected tissue (skin, nerve, muscle, bowel, abdominal fat pad) is sufficient for diagnosis 1) Screen for amyloid: Congo red staining (but not
highly sensitive, particularly for secondary amyloid) 2) Staining with labeled antisera to light chains may be
necessary if amyloid is strongly suspected 3) Nerve biopsies (most often performed on sural nerve)
demonstrate epineurial and endoneurial deposition of amyloid, often with concomitant deposition in nerve microvasculature
4) Amyloid appears pink with hematoxylin-eosin staining, but assumes apple-green birefringence when Congo red preparation is viewed under polarized light
i. Electrophysiologic abnormalities may be subtle, with mild neuropathies or exclusive small-fiber involvement,
but most patients with symptomatic neuropathies have abnormal EMG findings 1) NCSs: mild slowing, often absent compound sensory
nerve action potentials 2) Needle EMG: fibrillation potentials; large, complex
motor unit potentials (and possibly features of concurrent myopathy)
j. Survival after diagnosis of systemic amyloidosis averages approximately 1 year
k. Multiple chemotherapy agents (melphalan, high-dose corticosteroids, alkylating agents) have been used, generally with disappointing results
l. Possibly better success with autologous peripheral blood stem cell transplantation for patients who are candidates
m. Treatment of amyloid neuropathy: directed at type of neuropathy and associated symptoms 1) Symptomatic treatment of autonomic insufficiency
a) High support stockings b) Cautious volume expansion with fludrocortisone
or pressure support with midodrine c) Behavioral modification (e.g, sitting at the edge of
bed) and bed tilting 2) Symptomatic treatment of pain or dysesthesias
associated with sensorimotor peripheral neuropathy a) Antiepileptic medications (carbamazepine or
gabapentin) b) Tricyclic antidepressants (amitriptyline or
nortriptyline) c) In some cases, opioids may be necessary
3) Median neuropathies may respond to release of flexor retinaculum
6. Neuropathies associated with MGUS a. Hallmark: serum (or urine) M protein; serum M pro-
tein concentration less than 3 g/dL (urine M protein may be absent or present in very small amounts)
b. No clinical or laboratory evidence of another condition associated with M proteins, systemic amyloidosis, or other lymphoproliferative disorders: absence of lytic bone lesions, hypercalcemia, anemia, renal disease, or other systemic manifestations
c. By definition, M protein remains stable and patients do not develop other abnormalities
d. Substantial proportion of patients originally diagnosed with MGUS ultimately develop lymphoproliferative disorders or complications of paraproteinemia
e. Incidence: 3% of Europeans and European descendants older than 70 years
f. Rate of progression (prorated) of these patients to marked associated comorbidity (lymphoproliferative disorder or complication of paraproteinemia): approximately
1% per year g. Size of M spike is independently predictive of this risk h. Association of MGUS with sensorimotor peripheral neu-
ropathy is clear, but relative risk of neuropathy in these patients varies among studies according to patient selection and definition of neuropathy
i. Features of peripheral neuropathy associated with MGUS 1) Usually insidious onset and progression 2) Generally presents as symmetric sensorimotor length-
dependent neuropathy or polyradiculoneuropathy with axonal and demyelinating features
3) More common in men 4) Paresthesias and pain are often prominent features 5) CSF protein is typically elevated without an elevated
cellular response j. In MGUS patients with neuropathy, the associated M
protein may be any subtype, but the protein is more likely to be IgM than in patients with MGUS and no neuropathy 1) Two-thirds of patients have κ subtype light chain 2) IgM patients also more likely to have demyelinating
features on nerve biopsy and electrodiagnostic studies 3) IgM patients likely have more severe neuropathies 4) Approximately half of these patients have anti-MAG
antibodies 5) MAG: minor myelin protein (noncompacted
myelin), concentrated in periaxonal inner myelin membrane of Schwann cells and paranodal myelin loops
6) Antibodies to MAG likely target oligosaccharide residues of molecule and block adhesive interactions between Schwann cells and underlying axon
7) Antibodies to MAG also likely cross-react with other antigens (glycolipids and gangliosides)
k. Treatment of MGUS-associated neuropathies 1) Has included plasma exchange and chemotherapeutic
agents, each with mixed success 2) As with other paraproteinemic neuropathies, patients
with monoclonal IgG and IgA respond better to treatment than do those with IgM
7. Cryoglobulinemia a. Hallmark: cryoglobulins, which precipitate on cooling
and redissolve on warming (core body temperatures) b. Type I: monoclonal immunoglobulins
1) Associated with multiple myeloma, Waldenström’s macroglobulinemia, chronic leukemia, lymphoma
2) May be asymptomatic 3) Symptoms (when present): Reynaud’s phenomenon,
cyanosis, purpura
c. Type II: mixed polyclonal (usually IgG) and monoclonal (usually IgMκwith anti-rheumatoid factor activity) 1) Also possible: monoclonal IgG or IgA with polyclon-
al IgM 2) Associated with hepatitis C 3) Symptoms: purpura, cutaneous vasculitis, poly-
arthralgias, glomerulonephritis, Reynaud’s phenomenon, peripheral neuropathy
d. Type III: mixed polyclonal IgG e. Amount of protein present correlates poorly with severity
of neuropathy (the temperature of precipitation is more predictive of symptoms than quantity)
f. Peripheral neuropathy associated with cryoglobulinemia may be asymmetric and multifocal, affecting cooler parts of body, as multiple mononeuropathies (mononeuritis multiplex) or length-dependent sensorimotor peripheral neuropathy
A. Diabetic Polyneuropathy 1. Usually chronic and insidious onset; rapid onset of
small-fiber-type neuropathy with dysautonomia is possible but rare
2. Predisposing factors for development of diabetes polyneuropathy: poor hyperglycemic control, male sex, long-duration of diabetes, age, and cooccurrence of hypertension
3. Pathogenesis a. Elevated plasma glucose is directly toxic to nerve; chronic
hyperglycemia induces long-term, repetitive metabolic insults to nerve
b. Rheologic effects of hyperglycemia may reduce microvascular blood flow, inducing hypoperfusion and hypoxia
c. Poorly controlled, chronic hyperglycemia predisposes to microvascular disease of small vessels of endoneurium
d. Endoneural capillaries often thickened e. May be focal areas of axonal loss, which may be due to
microinfarcts of nerve 4. Predominantly length-dependent axonal degeneration 5. Prominent demyelinating features on EMG, such as
multifocal conduction block or slowing and nerve
conduction velocities less than 70% of low limit of normal are atypical
6. Presentation a. Slowly progressive distal sensory loss (predominantly sen-
sory neuropathy) with feet injuries that heal poorly b. Neuropathic pain, paresthesias, dysesthesias c. Small fibers usually affected first; large-fiber sensation is
affected later in course, and patients may experience sensory imbalance as a result
d. Clinical weakness and atrophy are late signs (fibrillation potentials and neurogenic motor unit potentials may be present on needle EMG)
e. Selective involvement of large fibers and weakness with no sensory loss are both clues that a cause other than diabetes needs to be considered
f. Despite this, there is a less common large-fiber variant in which patients are often asymptomatic but may present with painless paresthesias, loss of joint position and vibration sensation, and gait sensory ataxia
g. Autonomic neuropathy often complicates diabetic polyneuropathies (see below)
7. Testing a. Fasting blood glucose of 126 mg/dL on two or more
occasions is indicative of diabetes b. Fasting blood glucose of more than 110 mg/dL (<126
mg/dL) is indicative of glucose intolerance and needs to be followed
c. Hemoglobin A1C reflects plasma glucose control within last 5 to 8 weeks: a negative result does not exclude diabetes
d. Glucose tolerance test: 2-hour plasma glucose of 200 mg/dL is suggestive of diabetes
e. EMG and NCS are important in confirming pattern and characterization of neuropathy (length-dependent axonal) and diagnosis of a superimposed process such as compression neuropathy
8. Treatment a. Routine foot care and inspection of feet for early
abrasions or ulcers b. Aggressive control of blood glucose to prevent or slow
progression of neuropathy c. Treatment of neuropathic pain with tricyclic antide-
pressants (amitriptyline, nortriptyline), anticonvulsive agents (gabapentin, carbamazepine, lamotrigine, topiramate)
d. Treatment of orthostatic hypotension (usually mild)
B. Acute Diabetic Polyneuropathy 1. Also called diabetic cachexia 2. Monophasic illness lasting for more than 1 month 3. Usually precipitated by change (worsening or
improving) in glycemic control 4. Acute and rapid onset, which usually follows unwanted
weight loss (hence, “diabetic cachexia”), insomnia, depression, and impotence
5. Autonomic features other than impotence are rare and usually do not occur
6. Primarily involvement of small pain sensory fibers: relative sparing or mild involvement of nerve conductions, painful neuropathy (usually severe burning pain with allodynia and hypersensitivity in lower extremities), ankle jerks are present, reduced, or absent and distal weakness is very mild
7. No muscle weakness; sensory loss may be minimal
C. Insulin Neuritis 1. Acute onset of neuropathic pain and paresthesias in
distal lower extremities shortly after initiating insulin therapy and obtaining glycemic control
2. Pathogenesis unclear but may be due to active regeneration
D. Autonomic Neuropathy 1. Orthostatic hypotension 2. Gastroparesis and delayed gastric emptying, constipation
may be due to colonic atony, diarrhea due to involvement of small intestine autonomic innervation
3. Impotence in men: usually one of first autonomic symptoms
4. Bladder atony with urinary retention, followed by overflow incontinence
5. Sudomotor abnormalities: distal anhidrosis, hyperhidrosis of face and forehead with eating (gustatory sweating)
E. Diabetic Lumbosacral Radiculoplexus Neuropathy (DLRPN)
1. Also called proximal diabetic neuropathy or diabetic amyotrophy
2. Characteristics similar to the nondiabetic lumbosacral radiculoplexus neuropathy
3. Rare: occurs in 1% of patients 4. Usually occurs in adults with non-insulin-dependent
diabetes (men more often than women) 5. Glycemic dysregulation often not severe 6. Patients often do not have many long-term complica-
tions of diabetes mellitus (e.g., retinopathy or nephropathy)
7. May occur together with diabetic thoracic radiculoplexus neuropathy
8. Abrupt and rapidly progressive onset of asymmetric, focal, predominantly proximal leg pain and weakness
a. Usually no precipitating factor can be identified b. Pain is often severe and early, and followed by severe
weakness (which then becomes a more important problem than pain)
c. Pain is usually focal, unilateral (or bilateral and asymmetric): often occurs in proximal lower limb (anterolateral thigh, hip, buttock)
d. Symptoms often quickly spread to involve both proximal and distal segments and contralateral leg and become more symmetric with early progression
e. Muscle weakness may be only proximal (e.g., involving thigh and hip) and/or distal (e.g., peroneal-innervated muscles such as anterior tibialis): distribution is usually focal and unilateral
f. Symptoms of pain and weakness may appear bilateral and symmetric at onset
9. Large, concomitant weight loss is common 10. Usually monophasic illness 11. Patients also often have sensory and autonomic
symptoms 12. CSF: markedly elevated protein 13. NCSs
a. Findings indicative of axonal loss: reduced motor and sensory nerve action potential amplitudes
b. Femoral motor conduction studies may be helpful: relatively early in disease, femoral CMAP amplitude is lower on affected side than on opposite side (asymmetric), reflecting the degree of axonal loss
c. CMAP amplitudes improve with adequate reinnervation 14. Needle EMG
a. Fibrillation potentials in involved segments, including paraspinal muscles
b. With collateral sprouting and reinnervation, needle EMG shows polyphasic varying motor unit potentials of longer duration than normal
c. With adequate reinnervation, fibrillation potentials eventually disappear
15. Pathogenesis and pathology (Fig. 21-20 and 21-21) a. Likely axonal loss due to ischemic insult to nerves as a
result of microvasculitis b. Epineurial and perineurial vasculitis and resultant
ischemia and multiple foci of microinfarct, perineurial thickening, neovascularization
c. Usual clinical presentation of subacute onset of an asymmetric syndrome is typical for a vasculitic process
16. Prognosis a. Spontaneous recovery is the rule b. Pain may be the first manifestation to improve c. Role of treatment is questionable and resolution of the
syndrome may not be attributable to treatment, given
the natural history of spontaneous recovery d. Fewer long-term complications of diabetes mellitus (e.g.,
nephropathy) and better glycemic control than for other diabetic patients
e. Recovery usually delayed and incomplete (although usually little residua)
17. Treatment a. Corticosteroids can produce dramatic response b. Corticosteroids and intravenous immunogloblin may be
considered for severely affected patients or those with active progression
F. Diabetic Truncal Radiculoneuropathy 1. Thoracic radiculopathy of T4-T12 segments 2. Occurs in setting of weight loss or change in the
glycemic control 3. Gradual or abrupt onset 4. Thoracic dermatomal distribution sensory loss, dyses-
thesias, hypesthesias, focal anhidrosis (as noted on
thermoregulatory sweat test) 5. EMG: denervation and neurogenic changes in der-
matomes involved, including paraspinal muscles and abdominal muscles of same dermatomal distribution
6. Natural history of several weeks to months 7. Pain persists for up to 2 months, and sensory symp-
toms may be lifelong
G. Diabetes-Related Mononeuropathies 1. Result of nerve infarction or entrapment 2. Nerve infarction
a. Usually not at typical sites of compression b. Less common than entrapment neuropathies c. Marked by sudden onset of pain and weakness and
development of atrophy d. Pathogenesis predominantly axonal loss
3. Entrapment a. Patients with diabetic neuropathies are more prone to
compression neuropathies at usual sites of nerve compression
b. With early, mild to moderate entrapment neuropathies, there is often focal slowing or conduction block on NCS
c. Electrophysiologic features of axonal loss with more severe lesions that include wallerian degeneration: fibrillation potentials and reduced CMAP amplitudes
4. Cranial mononeuropathies (microvascular infarction) a. Most frequently affected nerves: CNs III, IV, VI; less
commonly CN VII (idiopathic Bell’s palsy is more common in diabetics than nondiabetics)
b. Presentation of acute onset (often painful and associated with headache) diplopia due to unilateral cranial motor neuropathy
c. CN III palsy is often pupil-sparing given the deep location of pupillary fibers in CN III
d. About 72% of patients are expected to recover completely in 1 to 3 months
A. General Characteristics 1. Systemic or nonsystemic vasculitis 2. Predominantly axonal neuropathies 3. Pathogenesis
a. Humoral-mediated autoimmunity: deposition of antigen-antibody complexes formed in circulation, targeting the vessel wall antigen and complement activation; antiendothelial antibody attack on endothelial antigenic determinants; ANCA-mediated humoral autoimmunity against cytoplasmic proteins on neutrophils and monocytes
b. Cellular autoimmunity: direct T-cell-mediated cytotoxic effect, primarily on endothelial cells
4. Histologic tissue is often necessary for diagnosis, given potentially toxic adverse effects of treatment options a. Sural nerve is usually adequate for biopsy b. Combined muscle and nerve biopsy may have higher
yield (such as superficial peroneal nerve and peroneus brevis muscle through a single incision)
5. Pathology (Fig. 21-22) a. Transmural or perivascular inflammation: inflammatory
infiltrates within vessel wall b. Vascular destruction and fibrinoid necrosis c. Necrotizing vasculitis: segmental inflammatory necrosis
and destruction of arterial wall
d. Microvasculitis: inflammatory cellular infiltration of the wall of microvessels (small arterioles and venules), causing disruption of vessel wall
e. Perivascular hemorrhage (hemosiderin deposits) f. Thickening of vessel wall with or without intraluminal
thrombus, causing narrowing or occlusion of the vessel, which can produce nerve infarcts and multifocal nervefiber loss
g. Vasculitis predilection for epineurial (more than endoneurial) vessels
h. Large myelinated fibers especially susceptible to ischemic injury
6. Two most common systemic vasculitic conditions: polyarteritis nodosa, rheumatoid arthritis
7. Clinical presentation a. Rapid (acute or subacute) onset of painful multifocal
sensory and motor deficits in distribution of one or more nerves: pattern of mononeuritis multiplex or asymmetric polyneuropathy
b. Relatively rapid onset of symptoms is consistent with pattern of ischemic injury
c. Most commonly affected lower extremity nerve: common peroneal nerve, followed by tibial and sural nerves
d. Most commonly affected upper extremity nerve: ulnar nerve, followed by median and radial nerves
e. Usually: asymmetric polyneuropathy due to extensive, overlapping multifocal involvement of peripheral nerves
8. Electrodiagnostic evaluation a. Role
1) To characterize pattern and localization of disease, severity and extent of axonal loss
2) To identify suitable nerves for nerve biopsy 3) May be used to follow clinical course of patient after
obtaining baseline results before treatment b. Features predominantly of axonal loss: low-amplitude
CMAP and SNAP responses, with fibrillation potentials, reduced recruitment, and chronic neurogenic changes (in chronic stage)
c. Features suggestive of mononeuritis multiplex or asymmetric polyneuropathy: predominant involvement of upper extremities and/or asymmetric findings on needle EMG between the two sides and/or between individual nerves of same dermatomal distribution in same limb
9. Generalizations about treatment options a. Corticosteroids
1) Usually first line of treatment 2) Typical starting dose: 1 mg/kg oral prednisone (if
severe, intravenous methylprednisolone) 3) Daily dose is continued for at least 2 months 4) Gradual taper and transition to alternate-day dosing
and discontinuation of drug in 12 months is usual goal
5) Treatment strategy is based on underlying disease, severity at presentation, age, other factors
6) Patients should be monitored for hypertension, glucose intolerance, weight gain, glaucoma, cataracts, osteoporosis, avascular necrosis of hip, other complications related to long-term corticosteroid use
b. Cytotoxic adjuvant therapy 1) Decision to add cytotoxic agent is based on many
factors: patient’s response to corticosteroids, possible complications of corticosteroids in relation to underlying comorbidities, and underlying disease (e.g., all cases of Wegener’s granulomatosis are treated with glucocorticoids and cyclophosphamide, as first-line agents)
2) After remission, cyclophosphamide is switched to less toxic agent such as methotrexate or azathioprine
3) Nonsystemic vasculitic neuropathy is often less aggressive and has a better prognosis than systemic vasculitic neuropathies
4) Less aggressive immunosuppressant therapy (e.g., azathioprine or methotrexte) is indicated for nonsystemic vasculitic neuropathies
5) Azathioprine is usually steroid-sparing agent of choice and is typically initiated within 6 months after initiating prednisone
B. Specific Vasculitic and Granulomatous Syndromes Associated With Peripheral Neuropathy
1. Classic polyarteritis nodosa a. Most common cause of systemic necrotizing vasculitis
and most frequent cause of vasculitic neuropathy b. Focal, segmental necrotizing inflammatory vasculitis of
small-and medium-size arteries c. Typically starts with subacute onset of constitutional
symptoms, such as fever and weight loss d. Some cases are associated with hepatitis B virus e. Laboratory findings: leukocytosis, normocytic anemia,
thrombocytosis, high erythrocyte sedimentation rate, antinuclear antibody (ANA), rheumatoid factor (RF), hypocomplementemia
2. Rheumatoid arthritis a. Systemic disease: rheumatoid arthritis, rheumatoid nodules
occurring in extremities, pericarditis, pleuritis, interstitial lung disease, and systemic vasculitis causing organ infarction, glomerulonephritis, cutaneous vasculitic involvement
b. Presentations of PNS disease 1) Entrapment compression neuropathies 2) Necrotizing small-vessel vasculitis causing mononeu-
ropathy or mononeuritis multiplex (cranial nerve mononeuropathy is rare)
3) Sensory or sensorimotor length-dependent polyneuropathy
4) Predominantly sensory distal polyneuropathy (some patients)
c. Laboratory findings 1) Increased RF in 90%-95% of cases and increased
erythrocyte sedimentation rate in 85% of cases 2) C4 complement level is often low
3. Churg-Strauss syndrome a. ANCA-associated vasculitic syndrome of asthma,
eosinophilia, systemic necrotizing vasculitis b. Clinical manifestations
1) Prodromal asthma, allergic rhinitis, polyposis 2) Intermediate stage of peripheral eosinophilia 3) Final phase: necrotizing systemic vasculitis, including
necrotizing glomerulonephritis and necrotizing neuropathy
c. Sural nerve biopsy: epineural necrotizing vasculitis, sometimes with eosinophilic infiltrates
4. Sjögren’s syndrome a. 90% female predominance b. PNS involvement in 10% to 30% of patients (also
strong predilection for women) c. May be termed secondary Sjögren’s syndrome if there are
systemic signs of another connective tissue disease such as rheumatoid arthritis or systemic lupus erythematosus
d. Sicca complex: reduced lacrimation and salivation (dry eyes, dry mouth) from lymphocytic and plasmacytic infiltration and destruction of exocrine glands (lacrimal and salivary glands)
e. Lymphocytic infiltration of dorsal root and gasserian ganglia result in ataxic sensory neuropathy and trigeminal neuropathy, respectively
f. Trigeminal sensory neuropathy (unilateral or bilateral) has also been associated with systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis
g. Presentations of PNS disease are as follows: 1) Ganglionopathy
a) Ataxic sensory neuropathy from involvement of dorsal root ganglia
b) Large-fiber sensory loss, sensory ataxia, pseudoathetosis, areflexia, autonomic dysfunction
c) Trigeminal neuropathy from involvement of the gasserian ganglion: facial numbness (bilateral in half of cases) and painful paresthesias primarily involving second and third divisions of CN V (sometimes all three divisions), sparing motor fibers
2) Mononeuritis multiplex 3) Sensory or sensorimotor distal symmetric
polyneuropathy a) Most common neuropathy in this setting b) Often presenting with slowly progressive numb-
ness and paresthesias c) May be primarily sensory or there may be mild
weakness d) Much less common: polyradiculoneuropathy,
sometimes resembling CIDP h. Investigations
1) Increased erythrocyte sedimentation rate, ANA (90% of cases), anti-Ro and anti-La (60%-70%), positive RF (60%-90%), hypergammaglobulinemia
2) EMG and NCS: features of axonal loss (low sensory and motor amplitudes, fibrillation potentials)
3) High T2 signal in dorsal columns of patients with sensory ganglionopathy
4) Rose Bengal staining of cornea 5) Schirmer’s test (<5 mm wetting of paper strip at 5
minutes) 6) Minor salivary gland biopsy of lower lip showing
lymphocytic infiltrates i. Prognosis: generally good, many patients stabilize with
or without treatment j. Treatment
1) Corticosteroids and cytotoxic immunosuppressants 2) Supportive treatment with artificial tears and periodic
ophthalmologic examinations are indicated for primary Sjögren’s syndrome involving exocrine glands
5. Systemic lupus erythematosus a. Predilection for women of child-bearing age and African-
American race b. Systemic manifestations: arthralgias, cutaneous manifes-
tations (malar “butterfly” rash, discoid rash), photosensitivity, anemia, leukopenia, thrombocytopenia, pleuritis, pericarditis, nephropathy (proteinuria and urinary casts), Libman-Sacks endocarditis (associated with antiphospholipid antibody syndrome)
c. CNS manifestations (see Chapter 14) d. Peripheral nerve manifestations
1) Mild, distal sensorimotor neuropathy, with slow progression, may be asymmetric in onset
2) Mononeuritis multiplex: necrotizing vasculitis of small-and medium-size arteries
3) Polyradiculoneuropathy: sometimes inflammatory demyelinating, with subacute progression, resembling AIDP or CIDP
4) Inflammatory brachial plexus neuropathy 5) Cranial neuropathies: predilection for CNs III, IV, V,
VII e. Evaluation
1) ANA positive in 95% to 100% of cases 2) Other markers: anti-dsDNA, Anti-Sm, anti-Ro
6. Systemic sclerosis (scleroderma) a. Excessive proliferation and deposition of collagen and
extracellular matrix proteins and fibrosis involving skin, lungs, heart, kidneys, gastrointestinal tract, muscle, nerve
b. Associated with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia)
c. Diffuse myopathy d. Peripheral nerve involvement: peripheral sensorimotor
neuropathy, mononeuropathy or multiple mononeuropathies (usually entrapment neuropathies due to fibrosis and calcinosis), isolated trigeminal sensory neuropathy
7. Mixed connective tissue disease a. Predilection for women in third and fourth decades b. Usual symptom at onset: Raynaud’s phenomenon c. Laboratory data: characterized by antibodies to ribonu-
clear proteins (anti-U1 RNP) d. CNS manifestations: seizures, psychosis, aseptic
meningitis e. Peripheral nerve involvement
1) Trigeminal sensory neuropathy 2) Symmetric distal sensory neuropathy 3) Chronic polyradiculoneuropathy resembling CIDP 4) Autonomic neuropathy
8. PNS manifestations of sarcoidosis (sarcoid neuropathy) a. CNS and systemic manifestations (see Chapter 14) b. PNS involvement: relatively rare but heterogeneous c. Cranial nerve involvement: CN VII is most commonly
involved peripheral nerve d. There may be multiple cranial neuropathies with fluctu-
ating course e. Multiple mononeuropathies and multifocal, asymmetric
sensorimotor neuropathy f. Chronic symmetric distal sensorimotor peripheral
neuropathy g. Polyradiculopathy and Guillain-Barré-like syndrome h. Pure motor neuropathy i. Pathology (Fig. 21-23)
1) Initially: mononuclear infiltration, followed by formation of noncaseating granulomas
2) Granuloma: collection of epithelioid cells derived from macrophages, which may form multinucleated giant cells, with fibrosis and hyalinization
3) Epineurial and perineurial granulomatous necrotizing vasculitis
4) CD4+ cellular proliferation in regions of active granulomatous inflammation
j. Almost all patients with neuropathy related to sarcoid also have sarcoid myopathy 1) A high percentage of patients with sarcoidosis have
muscle involvement, although most of the patients are asymptomatic
2) Symptomatic patients often present with proximal weakness, myalgias, tenderness of involved muscles
A. Ischemic Monomelic Neuropathy (IMN) 1. Rare disorder 2. Nerve damage secondary to ischemic insult resulting
from insufficient perfusion inducing axonal loss 3. IMN of upper extremities
a. Less common than IMN of lower extremities b. Almost always unilateral and iatrogenic c. Almost always secondary to arteriovenous shunt place-
ment in upper limb for dialysis treatment in patients with end-stage renal disease
d. Almost always in diabetics with end-stage renal disease due to diabetic nephropathy (underlying diabetic neuropathy may potentially be a predisposition)
4. IMN of lower extremities a. Often bilateral, noniatrogenic or iatrogenic (intra-aortic
balloon pump placement, cardiopulmonary bypass
cannulation) b. Less commonly, there may be compressive lesion such as
neoplasm, hematoma, or bony anomaly that may precipitously produce limb ischemia
5. Clinical presentation a. Abrupt onset of deep, burning pain and paresthesias in
hand or foot, with subsequent development of weakness and atrophy (after several weeks, if persistent)
b. Despite abrupt onset, symptoms reach maximal intensity after several days
c. Weakness is most prominent distally and there is a distalto-proximal gradient (deficits “fade out” proximally, both clinically and electrophysiologically)
d. This may be due to more severe nerve fiber ischemia distally; alternatively, there may be focal nerve infarctions proximally, with length-dependent axonal degeneration that accumulates along longest axons
e. Multiple (distal-predominant axonal loss) mononeuropathies
f. Other tissues are relatively preserved (i.e., relative absence of skin pallor, atrophic skin, or hair loss and normal pulses)
g. Duration of the ischemic events: varies but may last as long as few minutes to hours
6. Electrodiagnostic evaluation a. NCS (both sensory and motor): length-dependent pat-
tern of axonal loss (e.g., normal antebrachial conductions but motor and sensory conductions recorded at the hand tend to be abnormal)
b. Needle EMG: fibrillation potentials and reduced recruitment noted distally, with motor unit changes noted with reinnervation
7. Treatment a. Shunt ligation for upper extremity IMN b. Carbamazepine and gabapentin for neuropathic pain
8. Prognosis a. Variable b. Spontaneous recovery may occur after several weeks to
months c. Otherwise, symptoms may persist (including pain)
B. Acute Ischemic Mononeuropathy and Plexopathy 1. Causes
a. Typical: large-vessel atherosclerotic occlusion or stenosis (almost always occurs in lower limbs because proximal lower limb vessels prone to atherosclerosis)
b. Abdominal aortoiliac surgery often for treatment of ruptured aneurysms: may be due to combination of prolonged intraoperative hypotension, thromboembolism, insufficient anticoagulation, and cross-clamping of major vessels
c. Small-vessel disease (vasculitis) d. Acute compartment syndrome
2. Abrupt onset of sensory loss and weakness in distribution of affected nerves
3. Changes of vascular insufficiency are often present (in contrast to IMN) and often overshadow neurologic complaints
4. Most frequently affected nerves: femoral nerve and lumbosacral plexus
5. Some patients may present with exercise-induced ischemia of lumbosacral plexus or femoral nerve
6. Neurologic examination: often normal at rest 7. With exercise, patients often experience pain (e.g., but-
tock pain/distribution of femoral nerve) and motor and sensory deficits in distribution of lumbosacral plexus or femoral nerve
8. Treatment: supportive 9. Prognosis: adequate data lacking, but little improve-
ment in many cases
C. Acute Compartment Syndromes 1. Often due to trauma causing soft tissue damage, frac-
tures, arterial compromise, burns, prolonged compression, and others
2. Often, edema and accumulation of blood, and subsequent increased intracompartmental pressure compromising tissue perfusion and predisposing to ischemia
3. Usual presentation: acute onset of deep severe pain localized to involved compartment, associated with sensory loss, paresthesias, dysesthesias, weakness-all in distribution of nerves expected to be affected
4. NCSs: may demonstrate conduction block in early phase
5. Treatment often involves urgent surgical decompression and fasciotomy
6. Volkmann’s ischemic contracture (Volkmann’s contracture): muscle fibrosis and resultant contractures that form as residua of severe tissue necrosis from acute compartment syndrome
D. Chronic Compartment Syndromes 1. Almost always due to overuse and exercise 2. More than one compartment often involved 3. Lower extremity compartments involved most often 4. Most commonly experience pain provoked with activity
and exercise and alleviated by rest (less commonly, paresthesias and weakness)
5. Self-limited condition that responds to long periods of rest and inactivity
6. Occasionally may be acute exacerbation needing urgent treatment
A. Introduction 1. Infection involving PNS may be isolated manifestation
of a primarily neurologic process or a secondary manifestation of multisystemic disease
2. Generally present in subacute or insidious fashion 3. May derange the PNS in virtually any recognized pattern
B. Leprosy 1. For decades has been recognized as leading cause of
peripheral neuropathy worldwide 2. Is caused by Mycobacterium leprae 3. Neuropathy in leprosy classically presents in one of two
forms, both of which are predominately sensory and both of which involve direct infection of peripheral nerves a. Tuberculoid leprosy
1) Presents with multifocal, circumscribed areas of anesthesia
2) Generally represents robust cell-mediated response to infection
b. Lepromatous leprosy 1) Presents with more widespread anesthesia (due to
confluent multifocality) primarily affecting cooler areas of skin (pinnae, dorsum of forearms, etc.)
2) Generally represents disease dissemination due to inadequate cell-mediated response
3) Possible involvement of multiple organ systems c. Intermediate form (borderline leprosy) is recognized and
presents with combination of tuberculoid and lepromatous findings
4. Diagnosis: based on clinical findings and characteristic neuropathologic findings a. Tuberculoid leprosy: destruction of peripheral nerve
ultrastructure by reactive granulomas b. Lepromatous leprosy: diffuse infiltration of peripheral
nerves, with preservation of histologic structure until late in disease
5. Treatment with multidrug therapy has become the WHO standard a. Dapsone b. Rifampin c. Clofazimine d. Minocycline e. Fluoroquinolones f. More recently, thalidomide has been used for suppres-
sion of treatment reactions
C. Lyme Disease 1. One of most common tick-borne diseases in United States 2. Caused by spirochete Borrelia burgdorferi and
transmitted by Ixodes dammini and I. pacificus 3. Stage 1: infection is heralded at the tick site by the
erythema migrans rash
4. Stage 2: disseminated infection may follow days to weeks later; there is commonly an associated lymphocytic meningitis, in the context of which several common peripheral manifestations may occur a. Single or multiple cranial neuropathies, most commonly
CN VII (up to 10% of all patients with seropositive Lyme disease)
b. Monoradiculopathies, polyradiculopathies, or radiculoplexopathies generally present with pain, paresthesias, and subsequently weakness in distribution of affected roots or plexi: may be widespread and fulminant, resembling AIDP
c. Mononeuritis multiplex is a less common presentation 5. Stage 3: neurologic symptoms in late infection are
usually dominated by central manifestations (encephalomyelitis), but a length-dependent sensorimotor peripheral neuropathy may develop in a few a. Electrophysiologic abnormalities are more common than
clinical neuropathy 6. Diagnosis: made with combination of clinical (classic
dermatologic findings) and serologic data 7. CSF PCR may be instructive when polyradiculoneu-
ropathy is suspected 8. Treatment
a. Oral doxycycline for early, limited disease b. Parenteral ceftriaxone for central or peripheral neurologic
involvement
D. Viruses 1. HIV-related neuropathies
a. Peripheral neurologic manifestations may occur from primary infection, any of several opportunistic infections, or potentially neurotoxic antiviral medications
b. Peripheral nerve dysfunction varies with stage of infection 1) Clinical syndrome resembling AIDP or CIDP may
occur at seroconversion 2) Length-dependent axonal sensory predominant
peripheral neuropathy a) Most common peripheral manifestation of HIV
infection (up to 30% of patients) b) Usually occurs years into infection c) Must often be distinguished from neuropathy
associated with nucleic acid analogue antiviral medications
3) Accompanying autonomic neuropathy may develop with sensory neuropathy
4) Mononeuritis multiplex also occurs with chronic HIV infection, often after development of acquired immunodeficiency syndrome
c. Neuropathic diagnosis relies on clinical assessment of
systemic stage of infection and recognition of pattern of neuropathy 1) EMG: may help identify subclinical disease, quantify
axonal damage, or identify conduction block 2) CSF examination: may help corroborate suspected
polyradiculoneuropathy d. Management of neuropathic complications of HIV
depends largely on 1) Optimizing antiretroviral regimen to slow progression
of neuropathy 2) Exclusion of other causes of presenting symptoms:
opportunistic infections, antiviral medications (e.g., ddI)
3) Symptomatic management of pain associated with neuropathy
2. CMV-associated neuropathies a. CMV: human herpesvirus with DNA-based genome b. Symptomatic CMV infection of CNS or PNS: rare in
immunocompetent persons c. CMV may present with the two following typical neuro-
pathic patterns: 1) Painful, rapidly, or subacutely progressive polyradicu-
loneuropathy that may result in severe weakness a) Much more common in immunocompromised
patients, but CMV may also present in a fashion similar to AIDP in immunologically normal patients
2) Necrotizing microvasculitis caused by CMV may present with mononeuritis multiplex
d. PCR for CMV in CSF: quite sensitive for most peripheral manifestations of CMV and for CNS infections (myelopathy, encephalitis, optic neuritis/retinitis)
e. Treatment: intravenous antiviral antibiotics with activity against CMV 1) Ganciclovir 2) Foscarnet
f. Optimization of any underlying immune insult (e.g., HIV infection, immunosuppression for transplantation) helps prevention and may speed recovery
3. VZV-associated neuropathies a. VZV: nearly ubiquitous DNA-based human herpes-
virus with predilection for peripheral nerves, commonly remaining latent in sensory ganglia
b. Typically, VZV reactivation presents in immunocompetent adults as monoradiculitis 1) Lancinating pain in distribution of affected nerve is
common harbinger of classic vesicular rash 2) Thoracic dorsal root ganglia are most commonly
affected, although any spinal or cranial level may be involved
3) Reactivation of VZV in geniculate ganglion presents with ipsilateral facial neuropathy and intra-auricular vesicles (Ramsey Hunt syndrome)
4) Reactivation in ophthalmic division (V1) of CN V may result in delayed infectious granulomatous vasculitis of ipsilateral middle cerebral artery, producing cerebral ischemia or infarction
c. Reactivation is usually self-limited, but persistent pain (postherpetic neuralgia) is common sequela and often refractory 1) Treatment with antiviral antibiotics early in reactiva-
tion (most commonly with valacyclovir or acyclovir) may help reduce this burden
2) Symptomatic management with other medications is often necessary a) Gabapentin b) Carbamazepine c) Amitriptyline (and other tricyclic antidepressants) d) Topical lidocaine e) Topical ketamine
4. Herpes simplex virus (HSV)-associated neuropathies a. A recurrently activated neurotrophic infection b. Common presentation: painful eruptions around
mouth or genitals, having remained latent in trigeminal or lumbosacral ganglia, respectively
c. Typically, reactivation is not associated with peripheral nerve dysfunction
d. Persistent neuralgia is uncommon e. HSV-1 and HSV-2 have been implicated in Bell’s palsy
and Mollaret’s meningitis, prompting empiric antiviral treatment of these conditions
E. Mycobacteria 1. Mainly in immunocompromised patients, a polyradicu-
lopathy caused by leptomeningeal infection with Mycobacterium tuberculosis
2. Treatment with antimycobacterial antibiotics is helpful, but patients often do poorly unless underlying immunocompromise is corrected
F. Parasites 1. Mild sensorimotor peripheral neuropathy is relatively
common in patients infected with Trypanosoma cruzi (causative agent in Chagas’ disease) a. Chagas’ disease is also associated with severe
cardiomyopathy 2. Visceral neuropathies may also be caused by T. cruzi,
Schistosoma spp, and Strongyloides stercoralis 3. Syndrome closely resembling AIDP may develop after
infection with Plasmodium spp (causative of malaria)
G. Toxoplasmosis 1. Rarely, polyradiculoneuropathy may develop from initial
infection with Toxoplasma gondii or with its reactivation (most cases occur in the immunocompromised patients)
H. Syphilis 1. Historical ubiquity of syphilis has led to descriptions of
most types of neuropathies associated with it 2. In antibiotic era, patients who develop peripheral
nerve manifestations of syphilis often are immunosuppressed and commonly present with polyradiculoneuropathy
I. EBV 1. Polyradiculoneuropathy caused by EBV is uncommon
and generally seen in immunocompromised patients in setting of multisystemic viral manifestations
J. Corynebacterium diphtheriae 1. Diphtheritic neuropathy generally follows subacutely after
exudative pharyngitis, progressing over a period of weeks 2. Pharyngeal exudation is sometimes followed by local
palatal neuropathy 3. Bulbar weakness is followed by diffuse sensory dysfunc-
tion and limb weakness and is mediated by secreted toxin rather than direct infestation of nerves
4. Neuropathy has prominent features of demyelination both pathologically and electrophysiologically, but axonal damage is not infrequent
5. 10% of patients may develop diffuse sensorimotor polyneuropathy
6. Treatment a. Antibiotics (often penicillin unless resistant) for
infection b. Antitoxin for neuropathy
A. Epidemiology: occurs in 50% to 70% of patients with systemic inflammatory response syndrome (SIRS)
B. Possible Pathophysiologic Mechanisms 1. Increased microvascular permeability from circulating
cytokines and other mediators 2. Direct toxic effects of mediators of sepsis, including
cytokines 3. Lack of autoregulation of blood vessels supplying
peripheral nerves may predispose them to ischemic injury in septic shock
C. Clinical Features 1. SIRS often occurs in patients with severe infection and
septic shock or evidence of severe traumatic insult 2. Usually preceded by septic encephalopathy 3. Patients: typically critically ill; have sepsis, septic
shock, or evidence of multiple organ failure 4. Early indications: often difficulty in weaning patient
from ventilator (even after improvement of underlying septic encephalopathy), limb weakness apparent by poor leg movements with deep painful stimulation (mild weakness to severe quadriparesis)
5. Exclusion of pulmonary or cardiac causes for difficulty weaning from ventilator
6. Tendon reflexes are preserved in up to half of patients
D. Creatine Kinase: levels often normal or near normal
E. CSF: normal or mildly elevated protein level
F. Electrophysiologic Evaluation 1. NCSs
a. Reduced amplitude SNAPs and CMAPs, relatively preserved distal latencies and conduction velocities (in keeping with an electrophysiologic pattern of axonal
polyradiculoneuropathy) b. Prolongation of CMAP duration: indicative of accom-
panying critical illness myopathy c. Sensory nerve responses may be normal in early stage of
illness d. Repetitive stimulation studies may be abnormal if
patient is given neuromuscular junction-blocking agents 2. Needle EMG
a. Fibrillation potentials occur about 3 weeks after illness onset
b. Recruitment is often reduced c. Motor unit potentials may appear to be short duration,
low amplitude with reduced recruitment, which is likely due to dysfunction of terminal axons and not myopathy
d. May be evidence of concurrent myopathy (critical illness myopathy) with rapidly recruited short-duration motor unit potentials
G. Pathology 1. Acute axonal degeneration of both motor and sensory
fibers 2. No evidence of demyelination or inflammatory
infiltrates
A. Each step is presented in an order that progressively narrows the differential diagnosis and also serves to focus the evaluation of each subsequent step (Modified from Dyck PJ, Dyck PJB, Grant IA, Fealey RD. Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology. 1996;47:10-7. Used with permission.)
B. Step 1: characterize anatomic-pathologic pattern of involvement-“Where is the lesion?”
