9

Diseases of the Nerves

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Nerve Physiology

1.Action potential conduction (Fig. 9–1)

2.Peripheral nerve organization (Fig. 9–2)

Nernst equation for an ion’s reversal potential

Nerve Physiology

Figure 9–1 Action potential conduction. (From Koolman J, Rohm KH. Color Atlas of Biochemistry.

Stuttgart, Germany: Georg Thieme; 1996:219. 203 Reprinted by permission.)

9 Diseases of the Nerves

Figure 9–2 Peripheral nerve organization. (From Midha R, MacKay M. Principles of nerve regeneration and surgical repair. Semin Neurosurg 2001, 12:82, Fig. 1. Reprinted by permission.)

3.Peripheral motor axon classification (see p. 231)

4.Sensory receptors and peripheral sensory axon classification (Table 9–1)

II. Diagnostic Testing

1.Electromyography (EMG): see p. 232

2.Nerve conduction studies

a. motor nerve conduction studies (Fig. 9–3)

i.measures the muscle response to stimulation of a motor nerve (i.e., the compound muscle action potential [CMAP]); CMAP amplitude, distal latency, and conduction velocity can be used to assess the motor nerve integrity after stimulation of both distal and proximal nerve sites, and these measures should be compared against a reference range developed within the testing laboratory

204

Table 9–1 Sensory Neurons and Fibers

Types of sensory neurons

Classification	Classification	Size and
in motor	in cutaneous	conduction
nerves	nerves	velocity	Myelin	Function
I	A	20 m, 100 m/s
Ia				Ia: Muscle spindles
Ib				Ib: Golgi tendon organs
II	A	10 m, 60 m/s		Muscle spindles, cuta-
				neous receptors
III	A	5 m, 20 m/s		Fast localizable pain;
				temperature
IV	C/wide-dynamic	1 m, 1 m/s		Slow poorly localized
				(“burning”) pain

Cutaneous sensory terminals

Receptor type	Location depth	Adaptation rate	Sensation quality
Meissner’s corpuscle	Superficial	Rapid	Touch
Merkel’s cell	Superficial	Slow	Steady indentation
Pacchionian corpuscle	Deep	Rapid	Flutter
Ruffinian corpuscle	Deep	Slow	Vibration

Numerals represent increasing activation threshold

ii.usually done with the common peroneal and posterior tibial nerves in the lower extremity, and with the medial and ulnar nerves in the upper extremity

b.sensory nerve conduction studies

i.performed by stimulating a pure sensory nerve and measuring the amplitude and distal latency of the nerve potential (sensory nerve action potential [SNAP]); usually done with the sural nerve behind the lateral malleolus for the lower extremity, and with the median and ulnar nerves for the upper extremity

(1)tests only the integrity of the sensory nerve distal to the ganglion; evaluation of the nerve segment proximal to the ganglion requires somatosensory evoked potentials (SSEPs; see p. 108)

(2)detects only dysfunction of large sensory fibers, not small fibers

Diagnostic Testing

Figure 9–3 Motor nerve conduction study demonstrating partial motor conduction block. The median nerve was stimulated supramaximally at the wrist and elbow and the motor response was recorded from the abductor pollicis brevis muscle. There is a 67% reduction in CMAD comparing distal to proximal stimulation sites. The

antidronic median sensory nerve action potential recorded from the index fingers with ring electrodes was normal note differences in voltage. (From Nagale SV, Bosch EP. Multifocal motor neuropathy with conduction block. Semin Neurol 2003, 23:327, Fig. 1. Reprinted by permission.)

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9 Diseases of the Nerves

206

ii.measurements of SNAPs usually requires averaging because of their small amplitude

c. nerve conduction tests involving the spinal cord

i.F waves: an internally-generated anterograde potential from the mo-

toneuron soma caused by retrograde conduction of an action potential that is generated by distal, supramaximal axonal stimulation; the F waves are usually observed as a small response with a 20–50-ms delay after the CMAP that was directly activated by the stimulation {M response}

(1)useful for testing the integrity of proximal motor nerve segments

(2)can be performed on any motor nerve

ii.H reflex: specific stimulation of a sensory nerve that causes reflex activation of motoneurons in spinal cord (equivalent to the reflex arc), which can then be measured as a myographic response with a longlatency (30-ms delay) following the M response

(1)technically best performed by stimulating the tibial nerve while measuring gastrocnemius and soleus muscles (S1 innervation)

(2)sensitive to sensory fiber dysfunction more so than motor fiber dysfunction

(3)useful for testing integrity of proximal S1 nerve segments, therefore is good for distinguishing sciatic nerve injury from S1 radiculopathy

d.technical considerations

i.limb temperature variations: cold extremities slows the conduction velocities, and increases amplitudes and distal latencies

ii.patient age: slower conduction velocities and reduced amplitudes are normal in young children and in the elderly

iii.limb position should be kept constant and compared against a reference standard that was developed for that limb position

3.Nerve biopsy

a.diagnostic in some conditions with abnormalities of

i.axons (e.g., giant axon neuropathy)

ii.myelin (e.g., hereditary neuropathy with liability to pressure palsies, anti-myelin-associated glycoprotein [MAG] antibody neuropathies, leukodystrophies)

iii.connective tissue and supportive elements (e.g., vasculitis, amyloid, sarcoid, leprosy, tumor infiltration)

b.can be supportive, but not diagnostic, of Charcot-Marie-Tooth neuropathies and inflammatory demyelinating polyradiculopathies (Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy [CIDP])

c.procedure: generally involves both nerve and muscle biopsy simultaneously

i.sites for nerve biopsy

(1)sural nerve, 15 cm above the heel: complicated by sensory loss with paresthesias and allodynia around the lateral malleolus that generally resolves over a period of years; avoid nerve biopsy at the ankle because repeated trauma from shoes causes nonspecific changes in the nerve

(2)superficial peroneal nerve, at the lower third of the anterior calf

(3)superficial radial nerve: used only when the neuropathy is limited to the upper extremities or when severe, chronic neuropathy exists in the lower extremities that would prevent useful histological analysis of the nerve

(4)intermediate cutaneous nerve of the thigh, at the lower third of the anterior thigh: used mostly to confirm proximal diabetic plexopathy (i.e., diabetic amyotrophy/Bruns-Garland syndrome)

A	B
Figure 9–4 Wallerian degeneration in situ. (A) Light microscopy demon-	Microsurg 2003, 19:338, Fig. 14. From Oliveira EF et al. Correlation
strating ovoid myelin debris. (B) Electron microscopy demonstrating	between functional index and morphometry to evaluate recovery of the
degeneration axons in cross-section (arrows). (From Tseng CY et al.	rat sciatic nerve following crush injury. J Reconstruct Microsurg 2001,
Histologic analysis of schwann cell migration and peripheral nerve	17:73, Fig. 5B. Reprinted by permission.)
regeneration in the autogenous venous nerve conduit. J Reconstruct

ii.tissue preparation: sections of the nerve should be evaluated by

(1)formalin fixation followed by paraffin embedding, which demonstrates the connective tissue and blood vessels

(2)frozen section for immunostaining, which demonstrates leukocytes, complement components, and autoantibodies

(3)plastic embedding for high-resolution microscopy

(4)teased single nerve fibers, which demonstrates demyelination and remyelination, myelin wrinkling, myelin overlap {tomaculae}, and Wallerian degeneration (Fig. 9–4)

Plexopathies

III. Plexopathies

A. Cervical Plexus

1.Anatomy: involves only the motor roots of C1–4; the sensory roots from those levels are distributed through lesser occipital, greater auricular, transverse cervical, and supraclavicular nerves

a.innervates the diaphragm (via the phrenic nerves), scalenes, lower trapezius, infrahyoid/ strap muscles, and high cervical paravertebral muscles

2.Pathophysiology: relatively resistant to injury caused by distortion of the neck; injury is more commonly caused by local tumor growth

3.Symptoms

a.diaphragm weakness: diaphragm hemiparalysis may present only as orthopnea and exertional dyspnea; complete diaphragm paralysis produces severe dyspnea with inability to cough

b.infrahyoid/strap muscle paralysis generally does not produce symptoms

B. Brachial Plexus (Fig. 9–5)

1.Anatomy: composed of motor and sensory roots from C5–T1; variants may involve contributions from C4 or T2

2.General symptoms: pain in the neck and shoulders with radiation into the distribution of the affected nerves

Figure 9–5 Brachial plexus anatomy. (From Duus P, Topical Diagnosis in
Neurology. Stuttgart, Germany: Georg Thieme; 1998:24, Fig. 1.24. Reprinted by	207
permission.)

9 Diseases of the Nerves

3.Subtypes of lesions

a.supraclavicular lesions: more commonly injured than infraclavicular sites (severe trauma commonly involves all three trunks)

i.upper trunk/C5–6 root injury

(1)pathophysiology: caused by

(a)traumatic depression of the shoulder (e.g., neck–shoulder distraction, weight-bearing compression)

(i)traction trauma more commonly affects nerve trunks than roots, in comparison with lower trunk/C8–T1 injury

(b)birth trauma: maternal obesity, multiparity, and large baby size are greater risk factors than obstetrical intervention; can occur even with normal vertex head positioning

(2)symptoms

(a)weakness in shoulder abduction (supraspinatus and deltoid) and external rotation (infraspinatus), elbow flexion (biceps and brachioradialis), and forearm supination; produces an internally rotated and adducted shoulder with extended elbow and pronated hand {waiter’s tip/Duchenne-Erb palsy}

(i)winging of the scapula (weakness of the serratus) suggests involvement of the C5–7 nerve roots, from which the long thoracic nerve originates

(ii)weakness of scapula elevation (rhomboid) suggests involvement of the dorsal scapular nerve, which originates from the C5 nerve root

(b)sensory loss in lateral brachium and antebrachium

ii.middle trunk/C7 root injury

(1)pathophysiology: usually occurs in conjunction with upper or lower trunk injuries

(2)symptoms (specific for the middle trunk/C7 root)

(a)weakness in elbow extension, wrist extension, finger extension, and forearm pronation (pronator teres and quadratus); produces a decorticate-like posture

(b)sensory loss in the dorsal brachium, antebrachium, and hand

iii.lower trunk/C8-T1 root injury (Box 9.1)

(1)pathophysiology: commonly caused by traumatic extension of the shoulder (e.g., catching oneself while falling), breech delivery, and apical lung tumors {Pancoast’s tumor}

(a)traction trauma more commonly affects nerve roots than trunks, unlike upper trunk/C5–6 injury

(2)symptoms

(a)weakness in wrist flexion and all hand intrinsic muscles, resulting in a claw-like posture of the hand {Klumpke’s palsy}

(b)sensory loss in medial brachium, antebrachium, and hand

(c)ipsilateral mild ptosis, miosis, abnormal accommodation, and reduced face and neck sweating {Horner’s syndrome}, when the T1 motor root is injured prior to its fusion into the lower trunk, i.e., before the white ramus

(i)Horner’s syndrome may even involve loss of iris pigmentation and a decrease in intraocular pressure

(ii)Horner’s syndrome does not involve a real endophthalmos; it just appears to be so because of the upper and lower lid ptosis

b.infraclavicular lesions: less commonly injured than supraclavicular sites; generally are injured by penetrating trauma, shoulder dislocations, clavicular fractures, or irradiation (e.g., for breast cancer treatment)

Box 9.1

Neurological thoracic outlet syndrome—

Caused by a fibrous band from the C7 vertebra transverse process to 1st thoracic rib, which compresses C8 and T1 roots; not related to a cervical rib; symptoms include pain in the ulnar forearm, hand weakness, atrophy of the thenar eminence or that involves the whole hand and medial forearm

Arterial thoracic outlet syndrome—Caused by compression of the subclavian artery by a cervical rib; symptoms include pain and weakness from ischemia of the hand and forearm

Venous thoracic outlet syndrome—Caused by thrombosis of the subclavian vein; symptoms include cyanosis and swelling of the arm

208

i.lateral cord injury—symptoms include weakness in elbow flexion, forearm supination and pronation (pronator teres quadratus), and wrist flexion toward radial side (flexor carpi radialis), as well as sensory loss in the lateral antebrachium and thumb

ii.medial cord injury—symptoms include weakness in wrist flexion toward the ulnar side, finger flexion and extension, and hand intrinsic muscles including thumb flexion and opposition (similar to that of Klumpke’s palsy), as well as sensory loss along the whole medial side of the upper extremity

iii.posterior cord injury—symptoms include

(1)weakness in shoulder abduction (deltoid) and adduction (latissimus dorsi and teres major), elbow extension, forearm supination, wrist extension, and finger extension

(2)sensory loss that is usually limited to the thumb and deltoid, but it may extend over the entire radial

nerve sensory territory (i.e., dorsal webspace between the first and second digits, the dorsal brachium, and dorsal antebrachium)

4.Diagnostic testing

a.neuroimaging: not reliable for lesion localization in the brachial plexus

i.plain radiographs can demonstrate vertebral and clavicular fractures

ii.CT myelography and MRI can demonstrate nerve root avulsions and traumatic injury to the meninges and spinal cord; CT myelography is superior to conventional myelography, particularly for C5–6 lesions

b.nerve conduction study: results must be interpreted carefully because the presence of injury to the plexus will hide root injuries

c.EMG: the absence of fibrillation potentials in paraspinal muscles does not rule-out nerve root injury, but their presence does confirm it

5.Treatment

a.anastomosis of transected neural elements, although this is generally ineffective for nerve roots or for injuries to lower trunk

b.destruction of the dorsal root entry zone for elimination of chronic pain of nerve root injury

Figure 9–6 Lumbosacral plexus anatomy. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:24, Fig. 1.25.

Reprinted by permission.)

C. Lumbosacral Plexus (L1–S2) (Fig. 9–6)

1.Pathophysiology: Lesions are caused by

	a.	tumor compression or invasion (Box 9.2)	Box 9.2
			Malignant psoas syndrome—lumbar plex-
	b.	retroperitoneal mass (hematoma abscess)
			opathy caused by tumor infiltration of
	c.	pregnancy and delivery
			the psoas muscle
	d.	pelvic irradiation	Warm dry foot syndrome—pain and anhidro-
	e.	trauma (rare), which has to be immensely violent due to soft tissue and	sis of the entire lower extremity, caused
			by tumor invasion of the sympathetic
		bony protection	plexus

2.Symptoms

a.pain that is worsened with hip extension and often with straight-leg raises (as with radiculopathies); pain is most likely to be absent in radiation-induced plexopathies

Plexopathies

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9 Diseases of the Nerves

210

i.lumbar plexus lesions: pain is located in the back, pelvis, or anterior thigh

ii.sacral plexus lesions: pain is located in the posterior thigh, calf, or foot b. weakness

i.lumbar plexus lesions: weakness mostly in hip flexion and knee extension

ii.sacral plexus lesions: weakness mostly in ankle movements and hip extension; involvement of the pudendal nerve function or S2–4 nerve roots causes bowel and bladder dysfunction (rare)

3.Diagnostic testing

a.neuroimaging: MRI and radionucleotide scanning are useful for localization of tumors; CT is useful for imaging of hematomas

b.EMG: evidence of denervation in the gluteus muscles and the muscles innervated by the sciatic nerve indicates a sacral plexopathy rather than a sciatic neuropathy

IV. Traumatic and Compression Neuropathies

(“Entrapment Neuropathies”)

1.Pathophysiology: Patients with a preexisting neuropathy are at greater risk for compression neuropathies, but there is no evidence that one focal injury to a nerve increases the susceptibility of that nerve to a second focal injury

a. histology

i.focal compression causes longitudinal sliding of the myelin layers that collect on either side of the site of compression {tomaculae}; accumulations of excess myelin layers may impair axoplasmic transport

ii.Wallerian degeneration order of progression of historical changes

Figure 9–7 Median nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

(1)Schwann cell retraction and myelin breakdown begin proximal to the injury site; accumulation of mitochondria and transport vesicles occur at the nodes of Ranvier along the length of the axon

(2)disintegration of the smooth endoplasmic reticulum in the neuronal soma

(3)breakdown of microtubule and intermediate filament structures

(4)macrophage invasion of the nerve: a late response, therefore Wallerian degeneration is not a primary inflammatory reaction

(5)persistence of Schwann cell tubes and their basal lamina {bands of Bungner}

2.Specific compression neuropathies of the upper extremity

a.median nerve compression syndromes (Fig. 9–7)

i.carpal tunnel syndrome

(1)pathophysiology: compression occurs in the carpal tunnel of the wrist (Fig. 9–8), which is formed by the transverse carpal ligament superiorly and carpal bones inferiorly

(a)risk factors include repetitive uses of the hands (50%), obesity, pregnancy, endocrinopathy ( i . e . , h y p o t h y r o i d i s m , acromegaly), rheumatoid arthritis, osteoarthritis, and previous wrist fractures

(2)symptoms

Flexor digitorum superficialis and profundus tendons
Ulnar nerve	Flexor	Palmaris
	retinaculum	longus tendons
and artery		Median nerve	Flexor carpi
			radialis tendons
Pisiform
Medial			Lateral

Hamate	Scaphoid
	Capitate

Figure 9–8 The carpal tunnel. (From Platzere W. Atlas of Topographical Anatomy. Stuttgart, Germany: Georg Thieme; 1985:145, Fig. 153. Reprinted by permission.)

(a)pain in the wrist at the site of nerve injury; the pain may radiate into the forearm as well as into the fingers

(b)paresthesias of hand and fingers, particularly while sleeping or with sustained hand positions (Box 9.3)

(i)only 50% of patients will localize the paresthesias within the distribution of the distal median nerve; often the paresthesias will involve all fingers

(ii)may be elicited by tapping on carpal tunnel {Tinel’s sign} or by prolonged wrist flexion {Phalen’s sign}, which are insensitive and nonspecific means of inducing paresthesias for any focal nerve injury

(c)sensory loss, usually limited to part of the distal median nerve sensory territory; sensory loss should not involve the thenar eminence, which is supplied by a branch of the median nerve that leaves above the carpal tunnel

(d)weakness of thumb abduction (abductor pollicis brevis) and opposition (opponens pollicis) causing grip weakness; weakness of flexor pollicis brevis (partly ulnar nerve innervated) and 1st–2nd lumbricals are generally asymptomatic (Fig. 9–9)

(i)thenar atrophy may develop rapidly in the elderly

(3)diagnostic testing

(a)nerve conduction study: useful in prognostication because it identifies demyelination (mild injury) or axonal injury (severe injury)

(i)often detects abnormalities in asymptomatic individuals, therefore is overly sensitive

(b)EMG: may demonstrate the presence of denervation potentials in cases of severe injury

(c)serology for comorbid conditions: routinely evaluate for hypothyroidism, diabetes, and pregnancy

(4)treatment

(a)medical treatment: attempt for 4–6 weeks in patients with mild symptoms; high likelihood of failure in patients who have continuous symptoms or with duration of symptoms10 months

(i)avoidance of repetitive wrist motions; immobilization with neutral wrist splint

(ii)NSAIDS; diuretics if swelling is involved; local glucocorticoid injection

(b)surgical treatment: transverse carpal ligament release, either by open procedure or endoscopic approach, in patients with refractory symptoms or in cases with atrophy

ii.anterior interosseous syndrome

(1)pathophysiology: compression of the anterior interosseous branch of the median nerve as it passes over the two heads of the pronator teres muscle, usually related to abnormal tendon or muscle insertions, repetitive elbow flexion, or local trauma

(2)symptoms

(a)pain in the forearm at the site of nerve injury, but no sensory loss

(b)weakness of distal thumb flexion (flexor pollicis longus),

flexion of the second and third digits (radial side of the flexor digitorum profundus), and pronation (pronator quadratus)

(i)a variant innervation of the whole flexor digitorum profundus may cause weakness of flexion in all digits

Box 9.3

Unlike carpal tunnel syndrome, C6 radiculopathy has radiating neck pain, loss of sensation in thenar eminence, and weakness in the forearm, wrist flexion, and pronation

Figure 9–9 The “preacher’s hand” posture of median nerve lesions above the wrist, i.e., involving the median-nerve supplied finger flexor muscles of the forearm. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:414, Fig. 10.8. Reprinted by permission.)

Traumatic and Compression Neuropathies

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9 Diseases of the Nerves

Figure 9–10 The Martin-Gruber anastomosis, in which the median nerve carries part of the ulnar nerve. In such cases, stimulation (S) of the median nerve along the Martin-Gruber anastomosis causes an augmented motor response in the hand intrinsic muscles by involving ulnar-innervated muscles (B) in comparison with distal stimulation that involves only muscles typical for the median nerve (A). This activation of the ulnarinnervated muscles by median nerve stimulation (S1) can be blocked by retrograde action potentials from distal ulnar nerve stimulation (S2) (C).

(ii)weakness in the intrinsic muscles of the hand (normally ulnar nerve-innervated) as part of an anterior interosseous syndrome indicates the presence of a Martin-Gruber anastomosis between the median and ulnar

nerves (Fig. 9–10), which occurs in 15% of people

(3)diagnostic testing

(a)EMG: can distinguish between anterior interosseous nerve injury and a more proximal median nerve injury (which should additionally have radial wrist flexion weakness from flexor carpi radialis involvement)

(b)nerve conduction study: impractical because of the difficulty in isolating the anterior interosseous nerve

(4)treatment

(a)medical treatment: avoid provocative movements; NSAIDs; local glucocorticoid injection

(b)surgical treatment: exploration for an anatomical abnormality in cases without obvious cause or in cases refractory to medical treatment for 6 months

b.ulnar nerve compression syndromes (Fig. 9–11)

212	i. ulnar nerve entrapment at the elbow

Figure 9–11 Ulnar nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

(1)pathophysiology: compression of the ulnar nerve as it enters forearm through the cubital tunnel/humero-ulnar aponeurotic arcade, which lacks soft tissue protection

(a)anatomical variations (i.e., an accessory anconeus muscle, or olecranon hypertrophy causing nerve displacement) also can cause injury or predispose to trauma

(2)symptoms (Fig. 9–12): pain and paresthesias are exacerbated by elbow flexion

(a)pain at the elbow, or rarely in the hypothenar eminence

(b)paresthesias of fourth and fifth digits

(i)patients may describe a splitting of the fourth digit with paresthesias

(ii)20% will also have paresthesias in the third digit, whereas 20% will have paresthesias only of the fifth digit

(c)weakness of the hand intrinsic muscles manifesting as grip weakness and repeatedly catching the fifth digit against objects due to adduction weakness

(i)weakness of the adductor pollicis (ulnar nerve-innervated) can be demonstrated by having the patient pinch a piece of paper between the tips of the thumb and the second digit, which normally requires the flexor pollicis longus (median nerve-innervated); weakness of this pinching position is associated with an inability to form a circle with the thumb and the second digit {Froment’s sign} (Fig. 9–13)

(3)diagnostic testing

(a)nerve conduction study: 70% of cases with weakness demonstrate conduction block with stimulation above the elbow; the study should be performed with the elbow in a partially flexed position

(i)in some patients, anastomosis between the ulnar nerve and the anterior interosseous branch of the median nerve {Martin-Gruber anastomosis} allows the median nerve to supply some of the hand intrinsic muscles; therefore it is better to examine CMAPs in the ulnarinnervated muscles of the forearm

(b)EMG: presence of abnormalities in the flexor digitorum profundus diagnoses injury at the elbow better than abnormalities in the flexor carpi ulnaris

(4)treatment

(a)medical treatment: 2–3-month trial of splints, NSAIDs; no benefit of local glucocorticoid injection

(b)surgical treatment: the type of procedure is best determined by an intraoperative nerve conduction study, such that

(i)decompression is indicated with nerve injuries in the cubital tunnel

(ii)nerve transposition is indicated if injury occurs along medical epicondyle of the humerus

ii.ulnar nerve entrapment at the wrist

(1)pathophysiology: caused by repetitive wrist trauma or occasionally a ganglion cyst of the ulnar nerve as it enters the hand through Guyon’s tunnel (Fig. 9–14), which is formed by the deep forearm fascia and the carpal bones and ligaments; once through Guyon’s tunnel, the ulnar nerve then travels across the palm from the hypothenar eminence to the thenar eminence; along this course it is also susceptible to injury

(2)symptoms: may exhibit pure sensory or motor variants

(a)pain in the wrist and hand

Traumatic and Compression Neuropathies

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9 Diseases of the Nerves

A B C

Figure 9–12 Differentiation between a C8 root lesion (A), lower brachial plexus lesion (B), and an ulnar nerve palsy (C). (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:38, Fig. 16. Reprinted by permission.)

(b)paresthesias and sensory loss in the palm side of the fourth and fifth digits

(c)weakness in hand intrinsic muscles: distal lesions of the ulnar nerve in the hand may occur past the innervation of the hypothenar muscles, producing weakness only in the thumb and clawing of the second digit

(3)diagnostic testing

(a)nerve conduction study

Figure 9–13 Froment’s sign: Paralysis of the adductor pollicis requires that the thumb be held in flexion for an effective pinching motion. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:419, Fig. 10.12. Reprinted by permission.)

(i)for lesions in Guyon’s canal, identifies prolongation of distal CMAP latencies and reduced CMAP amplitudes in the abductor digiti minimi and 1st dorsal interosseous muscle

(ii)for lesions distal to Guyon’s canal, identify the lesion location by step-wise evaluation of distal motor latencies and CMAPs of interossei muscles

opponens digiti minimi

flexor retinaculum

ulnar artery

Figure 9–14 Guyon’s tunnel.

palmar arterial arches superficial

deep flexor digitorum superficial tendons

palmor digital nerves

	abductor
	pollicis
		entrance to
	opponens	Guyon’s tunnel
	pollicis	medial nerve
		Hexor carpi radialis &
	radial artery	flexor pollicis longus tendon
	palmaris longus	flexor digitorum superficialis tendon
	tendon

Traumatic and Compression Neuropathies

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9 Diseases of the Nerves

216

(b)treatment: wrist splinting, NSAIDs; surgical transection of Guyon’s canal, for cases caused by trauma or those refractory to medical care

c.radial nerve compression syndromes (Fig. 9–15)

i.radial nerve injury in the brachium

(1)pathophysiology: caused by fractures of the proximal humerus where the radial nerve crosses posteriorly in the spiral groove, or prolonged compression at that site {Saturday night palsy}

(2)symptoms

(a)weakness in wrist extension, and thumb and finger extension; weakness in elbow extension occurs only with radial nerve injury in the axilla

(i)apparent weakness in grip strength is caused by an inability to extend the wrist; intrinsic hand strength must be checked with the palm of the hand placed on a flat surface

(b)sensory loss on the radial side of dorsal hand and thumb, and the dorsal brachium and antebrachium

(c)pain over the dorsal brachium, which is generally mild

(3)diagnostic testing

(a)nerve conduction study: demonstrates focal CMAP conduction block and relative preservation of SNAPs

(b)EMG: evidence of denervation in the radial nerve-innervated muscles of the forearm

(4)treatment

(a)medical treatment: wrist splints to prevent contractures and to provide wrist extension to assist with use of hand

(b)surgical treatment: exploration of suspect injury site after failure of medical management for 4 months or in cases of severe trauma; in chronic cases with loss of wrist extension, tendon transfer from anterior forearm compartment to wrist and thumb extensors allows for wrist extension

ii.posterior interosseous nerve syndrome

(1)pathophysiology: commonly caused by trauma or repetitive pronation-supination movements; nerve injury occurs in the arcade of Frohse (Fig. 9–16) formed by the fascia of the supinator muscle

(2)symptoms

(a)weakness in forearm supination, wrist extension, and thumb abduction (extensor pollicis longus and brevis)

(i)extensor carpi radialis is usually unaffected because it is innervated by branches arising from the radial nerve above the arcade of Frohse

(b)may have pain in elbow, but does not have sensory deficits (similar to the anterior interosseous syndrome)

(3)diagnostic testing

(a)nerve conduction study: demonstrates focal motor conduction block; the diagnosis requires preserved SNAPs in the superficial radial nerve

(b)EMG: thorough testing of posterior forearm muscles can localize lesion site along the course of the nerve because the relative locations of the various branches of the posterior interosseous nerve are reliable

(4)treatment: wrist extension splint, which allows for better use of hand; local glucocorticoid injection; surgical exploration for cases caused by trauma or after failed medical management

Figure 9–15 Radial nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

	median nerve
	brachialis
	radial
biceps tendon	nerve

deep branch (posterior interoseus)

superficial branch

pronator teres

brachioradicialis

flexor carpi radialis

Figure 9–16 The arcade of Frohse.

brachial artery

radial recurrent artery

arcade of Frohse

bicipital aponeurosis

palmaris longus

flexor carpi ulnaris

Traumatic and Compression Neuropathies

3.Specific compression neuropathies of the lower extremity a. femoral nerve syndromes (Fig. 9–17)

i.pathophysiology: caused by

(1)entrapment in the psoas muscle: from trauma or mass lesions, or as a complication of retroperitoneal surgery

(2)entrapment under the inguinal ligament: from prolonged hip flexion or hip abduction and external rotation, or by compression from a fetus

ii.symptoms

(1)weakness in knee extension; weakness in hip flexion may occur with nerve entrapment in psoas muscle (i.e., a very proximal lesion), but this is not a reliable finding

Figure 9–17 Femoral nerve anatomy. (From
Rohkamm R. Color Atlas of Neurology.
Stuttgart, Germany: Georg Thieme; 2004:37.	217
Reprinted by permission.)

9 Diseases of the Nerves

218

(2)paresthesias and sensory loss in the anterior thigh and medial calf (from the saphenous nerve branch)

(3)pain in the groin, anterior thigh, and medial calf

iii.diagnostic testing: neuroimaging is necessary because much of the femoral nerve is not accessible to electrophysiological testing

(1)nerve conduction study: can demonstrate motor conduction block across the inguinal ligament

(2)EMG: can identify a pattern of muscle denervation that is consistent with root lesions (i.e., involving paraspinal and gluteus muscles), but the root lesions may be hiding a lesion of the femoral nerve

iv.treatment: knee bracing; surgical removal of any causative mass lesions

b.lateral femoral cutaneous nerve syndrome/meralgia paresthetica (Fig. 9–18)

i.pathophysiology: caused by compression of the nerve as it emerges from underneath the inguinal ligament on the anterolateral thigh (e.g., by tight pants or belts, or by an abdominal pannus in the obese)

ii.symptoms: paresthesias and sensory loss over lateral thigh, exacerbated by prolonged standing; no weakness

iii.treatment: weight loss; avoidance of compressive clothing

c.syndromes of the common peroneal nerve and its superficial and deep branches (Fig. 9–19)

i.pathophysiology: generally caused by external compression (e.g., prolonged bed rest, surgical positioning, weight loss, prolonged crossing of the legs)

ii.symptoms (Box 9.4)

(1)weakness in ankle eversion and dorsiflexion (Box 9.5), causing foot drop

(2)paresthesias and sensory loss in the lateral calf and lateral foot

(a)superficial peroneal nerve sensory symptoms are limited to the distal calf and dorsum of the foot, and may not involve the proximal calf as does common peroneal injury

(b)deep peroneal nerve sensory symptoms are limited to the webspace between the first and second digits

(3)may have pain in popliteal fossa

d.diagnostic testing

i.nerve conduction studies: evaluation of superficial peroneal nerve SNAPs is necessary to differentiate between the common and deep peroneal nerves as the cause of foot drop

ii.EMG: test the peroneus longus and brevis muscles to confirm involvement of the superficial peroneal nerve; should also test the short head of the biceps femoris, which is innervated by the common peroneal nerve above the popliteal fossa, to test for very proximal common peroneal nerve lesions

e.treatment: avoid posterior knee compression and pad the affected knee; use splints or casting only for superficial peroneal nerve compression

V.Hereditary Neuropathies

A.Charcot-Marie-Tooth (CMT) Neuropathies/Hereditary Motor-Sensory Neuropathies

1.General symptoms: distal weakness with atrophy; hypoor areflexia; mild sensory loss; acquired or congenital lower extremity deformity (Fig. 9–20); kyphoscoliosis

2.Subtypes (Table 9–2)

3.Diagnostic testing: generally relies upon genetic testing

Figure 9–18 Lateral femoral cutaneous nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:37. Reprinted by permission.)

Box 9.4

Unlike peroneal nerve injury, an L5 radiculopathy also has weakness in hip extension and abduction, and foot inversion, and sensory symptoms in the sole of the foot that extend above the knee into the lateral thigh.

Box 9.5

The tibial nerve mediates ankle inversion and plantar flexion.

Figure 9–19 Peroneal nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:37. Reprinted by permission.)

A B

Figure 9–20 Lower extremity deformities in CMT, including toe walking, foot eversion, and hammertoes (A), and distal atrophy (B). (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:306, Fig. 7.1a, 7.1b. Reprinted by permission.)

Table 9–2 Subtypes of Charcot-Marie-Tooth Neuropathies

		Distinguishing
Group & subtype	Pathophysiology and gene mutations	features
CMT-1	All AD; exhibit demyelination	Relatively normal NCS
A	Duplication or mutation of PMP-22, which	Nerve enlargement
	has an unknown function
B	Mutation of P0 protein, which opposes	Essential tremor
	the external faces of myelin sheets
	{compaction}
D	Mutation of early growth regulator
	(EGR)-2, a transcription factor
CMT-2	Have AD and AR subtypes; exhibit axonal	Relatively normal NCS
	loss
AD-A	Mutation of Kif-1b, which transports	? anticipation across
	mitochondria along microtubules	generations
AD-B	Unknown	ulcers → amputations
AD-C	Unknown	Vocal cord paralysis;
		respiratory failure
AR-A	Mutation in lamin A/C intermediate	Facial weakness
	filament that forms inner skeleton of the
	nucleus (Box 9.6)
CMT-3/	All are AD; exhibit demyelination	Severely abnormal NCS
Dejerine-Sottas
A	Mutation of PMP-22 (as with CMT-1A)
B	Mutation of P0 (as with CMT-1B)
CMT-4	All are AR; exhibit demyelination	Moderately abnormal
		NCS
A	Mutation in ganglioside-induced differen-	Facial synkinesis
	tiation-associated protein (GDA-P1)
B	Mutation in myotubularin-related	Thick lips
	protein-2 (MTMR-2), a protein
	phosphatase (Box 9.7)
F	Mutation in periaxin, which may regulate
	axon-Schwann cell interaction
CMT-X	X-linked mutations in connexin-32, which	Mildly abnormal NCS
	forms gap junctions; exhibits axonal loss

Box 9.6

Lamin A/C is also mutated in Emery-Dreifuss muscular dystrophy type II.

Box 9.7

Myotubularin mutations also occur in myotubular myoypathy.

Hereditary Neuropathies

Abbreviations: AD, autosomal dominant; AR; autosomal recessive; NCS, nerve conduction study.

219

9 Diseases of the Nerves

a.nerve biopsy: demonstrates radial layers of proliferative Schwann cells {myelin onion bulbs}, which is a nonspecific finding (Fig. 9–21)

4.Treatment: none specific

B. Hereditary Neuropathy with a

Predilection to Pressure Palsies (HNPP)

1.Subtypes

a.HNPP-A: caused by monosomy of the PMP-22 gene due to chromosomal deletion

b.HNPP-B: not linked to any genetic deficit

2.Histology (Fig. 9–22): telescoping of adjacent Schwann cells {tomaculae} with paranodal demyelination on teased sin-

gle nerve fibers; invagination of myelin Figure 9–21 Myelin onion bulbs. (From Hirano A. Color Atlas of Pathology of the Nervous

sheath into the axon demonstrated on	System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:138, Fig. 339. Reprinted by
transverse sections of the axons	permission.)

3.Symptoms: onset 30–40 years of age

a.recurrent focal neuropathies that are caused by minor trauma

b.mild sensorimotor neuropathy, often with hyporeflexia (40%)

c.may have pes cavus or scoliosis

d.rarely has pain

4.Diagnostic testing

a.nerve conduction study: demonstrates focal conduction block at sites of injury, but also generalized mild slowing consistent with diffuse demyelinating disease

b.genetic testing for the PMP-22 monosomy

5.Treatment: avoidance of trauma

	A	B
	Figure 9–22 (A) Thickening of the myelin sheaths with onion
	bulb formation on nerve cross-section (arrows). (B) Thickened
	myelin sheaths folding into the axon. (C) Tomacula on teased
	fiber preparation (arrow). (From Adlkofer K et al. Heterozygous
	peripheral myelin protein 22-deficient mice are affected by
	progressive demyelinating tomaculous neuropathy. J Neurosci
	1997, 17(12): 4662–71, Fig, 9.22A; 4664, Fig. 1F; 4668, Fig. 6D.
220	Copyright 1997 by the Society of Neuroscience. Reprinted by	C
	permission.)

6.Prognosis: 50% exhibit complete recovery after focal neuropathy; 10% exhibit long-term neurological dysfunction

C. Giant Axonal Neuropathy

1.Pathophysiology: caused by mutations in the gene for gigaxonin, the protein of which likely acts in microtubule organization and stabilization; mutations may lead to the breakdown of cytoskeletal organization

a.the majority of cases are sporadic mutations, although some familial cases with an autosomal recessive inheritance have been reported

b.histology: focal regions of axonal swelling that exhibit decreased myelination occurring in both the peripheral and central nervous systems, which are pronounced in the long tracts of spinal cord (particularly in the cervical region) (Fig. 9–23)

i.swollen astrocyte processes {Rosenthal fibers} are present in the subependymal region

Figure 9–23 Giant axonal neuropathy, peripheral nerve biopsy. Courtesy of Dr. C. Yamada.

ii.neurons and other cell types (e.g., fibroblasts, melanocytes, endothelial cells) exhibit accumulations of neuronal intermediate filaments, likely because they cannot be transplanted around the cell due to microtubule disruption

2.Symptoms: onset 7 years of age

a.General symptoms: Tightly curled hair; skeletal abnormalities (short stature, pes cavus, kyphoscoliosis)

b.peripheral nervous system symptoms

i.distal weakness, particularly in the lower extremities

ii.distal large-fiber sensory loss causing gait ataxia

iii.cranial neuropathies (CN VII III, XII)

c.central nervous system symptoms

i.cerebellar dysfunction: nystagmus, ataxia, dysarthria

ii.mental retardation; seizures (rare)

3.Diagnostic testing

a.nerve conduction study: SNAPs are reduced to much greater extent than are CMAPs

b.evoked potential studies are generally abnormal

c.EEG demonstrates areas of focal slowing

d.neuroimaging: diffusely increased T2 signal in the subcortical white matter with atrophy that is particularly pronounced in parietal and occipital lobes and in the cerebellum

4.Treatment: none specific

5.Prognosis: progressive loss of motor function invariably leads to use of wheelchair; death by 30 years of age

VI. Acquired Neuropathies

A. Guillain-Barre Syndrome (GBS)

1.General pathophysiology

a.caused by IgG and complement deposits in various parts of the nerve that recruit local macrophage infiltration; these deposits can be located on

i.the Schwann cells leading to demyelination, as in the acute inflammatory demyelinating polyneuropathy (AIDP) subtype

ii.the nodes of Ranvier so that macrophages directly attack the axon causing Wallerian degeneration, as in the acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN) subtypes

Acquired Neuropathies

221

9 Diseases of the Nerves

222

b.GBS is often preceded by . . .

i.infection: 65% of cases have history of recent infection, particularly an upper respiratory tract infection or gastroenteritis

(1)viral causes include Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus (HIV), influenza, Coxsackie, and hepatitis viruses

(2)bacterial causes include Campylobacter jejuni (30% of all cases),

Mycoplasma pneumoniae, and Escherichia coli

(a)preceding gastroenteritis is a risk factor for poor outcome from GBS

(3)parasitic causes include malaria and toxoplasma

ii.a systemic disorder: hyperthyroidism, cancer (Hodgkin’s lymphoma, chronic lymphocytic leukemia)

iii.pregnancy, immunizations, or recent surgery

c.epidemiology: sporadic occurrence except for AMAN, which can occur in epidemics in China

2.Subtypes of GBS with pronounced weakness

a.acute inflammatory demyelinating polyneuropathy (AIDP): accounts for 90% of all GBS cases

i.symptoms: develop over a period of a few hours to days

(1)pain in the back (often between the shoulders), buttocks, or lower extremities (in 50% at the onset, and 90% ultimately) with paresthesias and dysesthesias; the pain is exacerbated by the straight-leg raise

(2)weakness beginning in lower extremities that advances into the upper extremities; the weakness is usually symmetric and may occasionally be mild

(a)weakness involves the face in 60% of cases

(b)weakness may rarely begins in oropharynx, neck, and upper extremities {cervico-pharyngeo-brachial variant of AIDP}

(3)hypoor areflexia

(4)mild distal panmodal sensory loss

(5)ophthalmoplegia (20%)

(6)autonomic dysfunction (65%): arrhythmia, fluctuant blood pressure, gastroparesis, urinary retention

ii.diagnostic testing

(1)early cerebrospinal fluid analysis ( 1 week) may exhibit a pleo-

cytosis that is typically 10 cells/cc; protein increases after 1 week, which can be used to confirm the diagnosis

(2)nerve conduction study: abnormalities develop within 2–3 weeks, and include

(a)reduced conduction velocities and temporal dispersion

(b)conduction block (35%)

(c)prolonged or lost F waves in the presence of preserved distal CMAPs, which is fairly specific for inflammatory demyelinating neuropathies

(3)EMG: no evidence of denervation (i.e., fibrillation potentials)

(4)serology: poorly associated with increased titers of anti-ganglioside antibodies

iii.prognosis: worsening of symptoms over 4 weeks, during which 30% require mechanical ventilation; 5% mortality with treatment, and 80% exhibit complete recovery in 6 months

b.acute motor axonal neuropathy (AMAN)

i.symptoms: indistinguishable from AIDP, except for a shorter symptomatic course ( 1 week) because some of the weakness may be due to reversible axonal block

ii.diagnostic testing

(1)cerebrospinal fluid studies as per AIDP

(2)nerve conduction study: in comparison with AIDP, AMAN exhibits reduced CMAP amplitudes with preserved velocities and normal sensory nerve conduction velocities

(3)EMG: fibrillation potentials develop by 2–3 weeks

iii.prognosis: 5% mortality

c.acute motor-sensory axonal neuropathy (AMSAN)

i.symptoms: same as AIDP and AMAN, but more rapid onset and progression of weakness

ii.diagnostic testing

(1)cerebrospinal fluid: increased protein after 1 week, but not a pleocytosis

(2)nerve conduction study: in comparison with AIDP and AMAN, AMSAN exhibits reduced CMAP amplitudes and reduced sensory nerve conduction velocities

(3)EMG: fibrillation potentials develop within 2–3 weeks

iii.prognosis: slower recovery, more residual deficits; 10% mortality rate

d.subtypes of GBS without pronounced weakness

i.Miller-Fisher syndrome—accounts for 5% of GBS

(1)symptoms

(a)ophthalmoplegia: usually begins as a partial ophthalmoplegia (not necessarily in a cranial nerve distribution), but progresses to complete ophthalmoplegia within a few days that always spares the pupillary light reflex

(b)hypoor areflexia

(c)limb and gait ataxia, likely due to large fiber neuropathy rather than cerebellar dysfunction (i.e., no nystagmus or dysarthria)

(d)mild large fiber sensory loss in the distal extremities

(2)diagnostic testing

(a)cerebrospinal fluid: similar to other types of GBS

(b)nerve conduction study: reduced SNAP velocities; motor studies and EMG are normal

(c)serology: anti-GQ1b and anti-GT1a ganglioside antibodies are present in 95% of cases, but are nonspecific for other subtypes of GBS

(3)prognosis: self-limited course

ii.acute panautonomic neuropathy (rare)

(1)symptoms: orthostatic hypotension and syncope; gastroparesis or diarrhea, abdominal pain; abnormal diaphoresis; blurred vision and pupil dysfunction; cold or heat intolerance; sexual dysfunction

(a)minimal somatic motor and sensory dysfunction

(2)diagnostic testing

(a)cerebrospinal fluid: increased protein without pleocytosis occurs in 60% of cases and then only after 4 weeks

(b)normal nerve conduction study and EMG

iii.pure sensory neuropathy (rare)

(1)symptoms: tremor; limb and gait ataxia; hypoor areflexia

(2)diagnostic testing: reduced SNAP velocities on nerve conduction study

e.general treatment: intravenous immunoglobulin (IVIg; 0.4 g/kg/d for 5 days) or plasmapheresis (250 mL/kg total exchange volume divided over 5–6 q.o.d. sessions) administered within first 2 weeks increases the rate of recovery but does not ultimately improve functional recovery

Acquired Neuropathies

223

i.IVIg is preferred for acute panautonomic neuropathy subtype

ii.no benefit of combining both IVIg and plasmapheresis

iii.glucocorticoids are proven ineffective

B. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

	1.	Pathophysiology: unknown, but may be related to hyperactivity of CD8 T
		lymphocytes
		a.	often occurs in conjunction with monoclonal gammopathy of unknown
			significance (MGUS), cancer, connective tissue diseases, HIV infection, or
			hyperthyroidism
	Nerves		i. some MGUS and cancer (lymphoma, leukemia) patients have anti-
			bodies against myelin associate glycoprotein (MAG), and 25% develop
			a hematological malignancy shortly after they develop neuropathy
	the	b.	associated with human leukocyte antigen (HLA)-B8 and –DR2, and
			-antitrypsin polymorphisms; no association with anti-ganglioside
	of		antibodies like some subtypes of GBS
		c.	histology: evidence of demyelination and remyelination that is often exces-
	Diseases
			sive, resulting in myelin onion bulb formation (like the Charcot-Marie-Tooth
			neuropathies)
	9	d.	epidemiology: most common in patients 40–60 years of age, but can occur
			at any age
	2. Symptoms: course may be progressive or relapsing–remitting, but must have
		lasted at least a 2-month symptomatic period (Box 9.8)
		a.	weakness in multiple limbs that usually begins in the lower extremities
			but that involves both proximal and distal muscles simultaneously (which
			may best distinguish CIDP from other neuropathies); weakness is generally
			symmetric, but it may start focally before progressing to other limbs
			{Lewis-Sumner syndrome}
			i. neck flexor weakness is common and occasionally may spare upper
			extremities; rarely involves respiratory muscles
			ii. mild facial weakness occurs in 10%
		b.	large fiber sensory loss with paresthesias, generally in the distal lower
			extremities, that may cause a gait ataxia
		c.	hyporeflexia
		d.	Adie’s tonic pupil, from injury to the ciliary ganglion and short ciliary nerves
		e.	central nervous system dysfunction (5%): usually is mild and most commonly
			limited to spasticity, but it may have a multiple sclerosis-like course
	3.	Diagnostic testing
		a.	nerve conduction study: must demonstrate at least three demyelinating
			abnormalities (see p. 205)
			i. prolonged or lost F waves in presence of preserved distal CMAPs is
			fairly specific for inflammatory demyelinating neuropathies
		b.	cerebrospinal fluid demonstrates mild pleocytosis (usually 10 white
			blood cells (WBCs) in immunocompetent patients, or 50 WBCs in HIV
			patients) and increased protein
		c.	peripheral nerve biopsy may demonstrate demyelination and remyelination,
			but this is only observed in 60% of cases due to the multifocal nature of
			the disease
		d.	neuroimaging: 20% of cases demonstrate focal subcortical white matter
			lesions that are similar to multiple sclerosis plaques
	4.	Treatment: may use multiple treatments simultaneously in severe cases
		a.	glucocorticoids: high-dose prednisone PO or methylprednisolone IV to
			achieve a clinical response, followed by maintenance dosing that should
	224		continue until no further clinical improvement is obtained (generally 6
			months) and then tapered

Box 9.8

Diagnostic Requirements for Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Probable CIDP—2-month duration; weakness in multiple limbs; large fiber sensory loss; hyporeflexia; NCS with three demyelinating-type abnormalities (see p. 205); cerebrospinal fluid with minimal pleocytosis

Definite CIDP—Also requires consistent nerve biopsy abnormalities

b.IVIg and plasmapheresis are equally efficacious, and either is probably superior to glucocorticoids; generally require periodic treatments that are scheduled according to the patient’s clinical responsiveness

c.cyclophosphamide, azathioprine, interferon

5.Prognosis: 50% achieve maximal improvement within 6 months, 95% by 12 months

a.50% relapse rate, more commonly in patients with long-standing and treat- ment-resistant symptoms

C. Multifocal Motor Neuropathy

1.Pathophysiology: thought to be an autoimmune neuropathy because 50% of cases are associated with anti-GM1 antibodies, but there is no histological evidence of inflammation in nerve biopsies; antibody deposits develop at the nodes of Ranvier, as in the AMAN subtype of GBS

a.epidemiology: 3:1 male preference; no age preference

2.Symptoms: may be progressive or relapsing

a.asymmetric distal weakness developing over a period of years that often has a focal appearance (e.g., foot or wrist drop) suggestive of a mononeuropathy; rarely has facial weakness or respiratory muscle involvement

b.fasciculations are common, but there is disproportionately little atrophy

c.myokymia

d.hyporeflexia

e.minimal sensory abnormalities, if any

3.Diagnostic testing

a.nerve conduction study: demonstrates demyelinating abnormalities specifically affecting select motor nerves; no abnormalities in sensory nerve function are demonstrable

b.EMG: no evidence of denervation

c.serology: high anti-GM1 ganglioside IgM titers in 50% of cases

4.Treatment: IVIg, cyclophosphamide; glucocorticoids are rarely effective, and often worsens symptoms after initiation of treatment

5.Prognosis: Often requires chronic treatment, and has frequent relapses

Acquired Neuropathies

D. Paraproteinemic Neuropathies

1.Monoclonal gammopathies: caused by an overproduction of a single monoclonal antibody {M protein} from a clone of B lymphocytes/plasma cells

a.the antibody is IgG IgM or IgA a partial immunoglobulin protein (e.g., light chain)

i.5% have multiple monoclonal immunoglobulins, that is, they are biclonal or oligoclonal gammopathies

b.causes include

i.monoclonal gammopathy of undetermined significance (MGUS): accounts for 60% of monoclonal gammopathies; 20% will develop a hematologic malignancy

(1)in 40% of cases, the monoclonal antibody is an IgM specific for the myelin-associated glycoprotein (MAG) that acts to space the layers of myelin (Box 9.9)

(2)symptoms: often just neuropathy; does not even have nonspecific constitutional symptoms

(a)neuropathy is typically distal symmetric sensorimotor in patients with anti-MAG antibodies, or CIDP-like in patients without anti-MAG antibodies

Box 9.9

Anti-MAG antibodies also bind P0 protein

225

		(3)	specific diagnostic testing: increased IgM or IgG levels, but still
			3 g/dL total globulins
	ii.	multiple myeloma: accounts for 10% of monoclonal gammopathies
		(1)	symptoms: bone pain, weight loss, fatigue, neuropathy (only 5%)
		(2)	specific diagnostic testing: 10% plasmacytes on bone marrow
			aspirates; lytic bone lesions on skeletal survey
	iii.	amyloidosis: accounts for 10% of monoclonal gammopathies
	iv.	leukemia or lymphoma: account for 10% of monoclonal gammopathies;
		may exhibit anti-MAG antibodies, like MGUS and Waldenstrom’s
		macroglobulinemia
	v.	plasmacytomas: accounts for 5% of monoclonal gammopathies
Nerves		(1)	symptoms: bone pain from lytic bone lesions; neuropathy (50%)
			(a) POEMS syndrome—only common with osteosclerotic myeloma
			(a type of plasmacytoma); specific symptoms include
the			(i)	polyneuropathy
			(ii)	organomegaly
of
			(iii)	endocrinopathy: diabetes mellitus, hypothyroidism,
Diseases
				gonadal dysfunction
			(iv) M protein (only 90%)
9			(v) skin changes: hyperpigmentation, digit clubbing
	vi.	Waldenstrom’s macroglobulinemia: accounts for 5% of monoclonal
		gammopathies
		(1) exhibits		anti-MAG antibodies, like MGUS, lymphoma, and
			leukemia
		(2)	symptoms: fatigue, anemia, bleeding tendency, organomegaly;
			neuropathy (5%); no bone lesions
		(3)	specific diagnostic testing: 3 g/dL total globulin; malignant
			lymphoplasmacytoid cells on bone marrow biopsy
c.	general diagnostic testing
	i.	serum protein electrophoresis (SPEP): may detect only 70% of mono-
		clonal gammopathies by itself, therefore SPEP must be done with im-
		munofixation (IPEP)
	ii.	urine protein electrophoresis (UPEP) with urine concentrated from a
		24-hour sample, which is particularly useful in detecting and light
		chains or heavy chains
	iii.	blood cell differential
	iv.	radiological skeletal survey for malignancy
	v.	bone marrow biopsy for hematological malignancies
	vi.	soft tissue biopsy (e.g., fat, cutaneous nerves, kidney) for amyloidosis
2. Cryoglobulinemias
a.	subtypes
	i.	type I cryoglobulinemia: caused by monoclonal immunoglobulins that
		precipitate at reduced temperatures; often occurs with other monoclonal
		gammopathies
	ii.	types II and III cryoglobulinemias: caused by mixed immunoglobulins
		that precipitate at reduced temperatures, often occurs in autoimmune
		diseases or infection
		(1)	type II: monoclonal rheumatoid factor (anti-IgG IgM) and poly-
			clonal IgG
		(2) type III cryoglobulinemia: polyclonal IgG and IgM; strongly asso-
			ciated with hepatitis C infection
b. symptoms: organomegaly, renal failure, purpura, arthralgia; neuropathy is
226	usually a painful distal sensorimotor polyneuropathy, rarely mononeuritis
	multiplex (Box 9.10)

Box 9.10

Mononeuritis multiplex is much more commonly caused by polyarteritis nodosa.

Supraclavicular N.

Axillary N.

Radial N.

Medial Cutaneous N. of Arm

Medial Cutaneous N. of Forearm

Musculocutaneous N.

Genitofemoral N.

Dorsal Digital N.

(Radial N.

Median N.

Ulnar N.

llionguinal N. Pudendal N.

Lat. Cutaneous N. of Thigh

Obturator N.

Lateral Cutaneous N.

of the Calf

Saphenous N.
	N.
Superficial Peroneal N.	Calcaneal
Sural N.
Deep Peroneal N.
Plantar Digital N.
Lat. and Med. Plantar Nn.
Sural N.

Figure 9–24 Peripheral sensory dermatomes (right side of body) and radicular sensory dermatomes (left side of body). Shading indicates the important branches. (From Mumenthaler M, Neurological Differential

Iliohypogastric N.

Femoral N.

Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:141, Fig. 53a, Fig. 53b. Reprinted by permission.)

Acquired Neuropathies

227

9 Diseases of the Nerves

228

Superior Gluteal N.

Medial Gluteal N.

Figure 9–24 (Continued)

c.diagnostic testing

Supraclavicular N.

Axillary N.

Radial N.

Medial Cutaneous N.

of Arm

Musculocutaneous N.

Medial Cutaneous N.

of Forearm

Iliohypogastric N.

Dorsal Branch of

Ulnar N.

Inferior Gluteal N.

Superficial

Branch of

Radial N.

Lateral Cutaneous

N. of Thigh

Posterior Cutaneous N.

Lateral Cutaneous N.

of the Calf

Saphenous N.

Sural N.

Medial Plantar N.

i.serology: demonstration of immunoglobulin precipitates in the blood

ii.nerve conduction study demonstrates axonal loss; EMG demonstrates denervation

iii.nerve biopsy: often shows a necrotizing vasculitis from ischemia, even in cases of type I cryoglobulinemia that involve monoclonal immunoglobulins against myelin components

(1)leukocyte infiltration and precipitates of immunoglobulin in vasa nervorum can be demonstrated

(2)hepatitis C virus particles may be demonstrable in vascular endothelial cells

d.treatment

i.glucocorticoids, plasmapheresis, immunosuppressants

ii.interferon therapy for cryoglobulinemia patients with hepatitis C infection

Appendix 9–1 Key Movements, Muscles, Nerves, and Roots (Figure 9–24)

Upper Extremity

Movement	Muscle	Nerve	Root
Proximal thumb flexion	Flexor pollicis brevis	Ulnar nerve	T1 C8
		Median nerve
Distal thumb flexion	Flexor pollicis longus	Anterior interosseous branch, median nerve	C8 T1
Thumb adduction	Adductor pollicis	Ulnar nerve	T1
Thumb abduction	Abductor pollicis brevis	Median nerve	T1
	Abductor pollicis longus	Radial nerve
Thumb opposition	Opponens pollicis	Median nerve	T1
Distal finger flexion	Flexor digitorum profundus	Anterior interosseous branch, median nerve	C8
		(digits 2–3)
		Ulnar nerve (digits 3–4)
Supination	Supinator	Radial nerve	C6,7
Pronation	Pronator teres	Median nerve	C6,7
	Pronator quadratus	Anterior interosseous branch, median nerve	C8
Radial wrist flexion	Flexor carpi radialis	Median nerve	C6,7
Ulnar wrist flexion	Flexor carpi ulnaris	Ulnar nerve	C8
Shoulder abduction	Medial deltoid ( 15°)	Axillary nerve	C5
	Supraspinatus	Suprascapular nerve
Shoulder adduction	Teres major	Subscapular nerve	C5,6
	Latissimus dorsi	Thoracodorsal nerve	C7
Elbow flexion	Biceps brachialis	Musculocutaneous nerve	C5,6
	Brachioradialis	Radial nerve	C6
Elbow extension	Triceps	Radial nerve	C7
Lower Extremity
Movement	Muscle	Nerve	Root
Foot dorsiflexion	Tibialis anterior	Deep branch of the common peroneal nerve	L4
Foot plantar flexion	Gastrocnemius	Tibial nerve	S1,2
	Soleus
Foot inversion	Tibialis posterior	Tibial nerve	L4,5
Foot eversion	Peroneus longus and brevis	Superficial branch of the common peroneal	L5
		nerve
Knee extension	Quadriceps	Femoral nerve	L3,4
Knee flexion	Hamstrings	Sciatic nerve	L5, S1
Hip flexion	Iliopsoas	Femoral nerve and direct radicular branches	L1,2
Hip extension	Gluteus maximus	Inferior gluteal nerve	L5,S1
Hip abduction	Gluteus medius and minimus	Superior gluteal nerve	L4,5
Hip adduction	Adductor muscles	Obturator nerve	L2,3

Acquired Neuropathies

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