topics

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3498 PART 13 Neurologic Disorders

wrist is flexed for 30–60 s (Phalen sign); and weakness of thumb opposition and abduction. EDx is extremely sensitive and shows slowing

of sensory and, to a lesser extent, motor median potentials across the

wrist. Ultrasound can show focal swelling of the median nerve at the

wrist. Treatment options consist of avoidance of precipitating activities; control of underlying systemic-associated conditions if present;

nonsteroidal anti-inflammatory medications; neutral (volar) position

wrist splints, especially for night use; glucocorticoid/anesthetic injection into the carpal tunnel; and surgical decompression by dividing the

transverse carpal ligament. The surgical option should be considered

if there is a poor response to nonsurgical treatments; if there is thenar

muscle atrophy and/or weakness; and if there are significant denervation potentials on EMG.

Other proximal median neuropathies are very uncommon and

include the pronator teres syndrome and anterior interosseous neuropathy. These often occur as a partial form of brachial plexitis.

■ ULNAR NEUROPATHY AT THE ELBOW— “CUBITAL

TUNNEL SYNDROME”

The ulnar nerve passes through the condylar groove between the medial

epicondyle and the olecranon. Symptoms consist of paresthesias, tingling, and numbness in the medial hand and half of the fourth and the

entire fifth fingers, pain at the elbow or forearm, and weakness. Signs

consist of decreased sensation in an ulnar distribution, Tinel’s sign at

the elbow, and weakness and atrophy of ulnar-innervated hand muscles.

The Froment sign indicates thumb adductor weakness and consists of

flexion of the thumb at the interphalangeal joint when attempting to

oppose the thumb against the lateral border of the second digit. EDx

may show slowing of ulnar motor NCV across the elbow with prolonged

ulnar sensory latencies. Ultrasound can show swelling of the ulnar nerve

around the elbow as well. Treatment consists of avoiding aggravating

factors, using elbow pads, and surgery to decompress the nerve in the

cubital tunnel. Ulnar neuropathies can also rarely occur at the wrist in

the ulnar (Guyon) canal or in the hand, usually after trauma.

■ RADIAL NEUROPATHY

The radial nerve winds around the proximal humerus in the spiral

groove and proceeds down the lateral arm and enters the forearm,

dividing into the posterior interosseous nerve and superficial nerve.

The symptoms and signs consist of wrist drop; finger extension

weakness; thumb abduction weakness; and sensory loss in the dorsal

web between the thumb and index finger. Triceps and brachioradialis

strength is often normal, and triceps reflex is often intact. Most cases

of radial neuropathy are transient compressive (neuropraxic) injuries

that recover spontaneously in 6–8 weeks. If there has been prolonged

compression and severe axonal damage, it may take several months

to recover. Treatment consists of cock-up wrist and finger splints,

avoiding further compression, and physical therapy to avoid flexion

contracture. If there is no improvement in 2–3 weeks, an EDx study

is recommended to confirm the clinical diagnosis and determine the

degree of severity.

■ LATERAL FEMORAL CUTANEOUS NEUROPATHY

(MERALGIA PARESTHETICA)

The lateral femoral cutaneous nerve arises from the upper lumbar

plexus (spinal levels L2/3), crosses through the inguinal ligament near

its attachment to the iliac bone, and supplies sensation to the anterior

lateral thigh. The neuropathy affecting this nerve is also known as

meralgia paresthetica. Symptoms and signs consist of paresthesias,

numbness, and occasionally pain in the lateral thigh. Symptoms are

increased by standing or walking and are relieved by sitting. There is

normal strength, and knee reflexes are intact. The diagnosis is clinical,

and further tests usually are not performed. EDx is only needed to

rule out lumbar plexopathy, radiculopathy, or femoral neuropathy. If

the symptoms and signs are classic, EMG is not necessary. Symptoms

often resolve spontaneously over weeks or months, but the patient may

be left with permanent numbness. Treatment consists of weight loss

and avoiding tight belts. Analgesics in the form of a lidocaine patch,

nonsteroidal agents, and occasionally medications for neuropathic pain

can be used (Table 446-6). Rarely, locally injecting the nerve with an

anesthetic can be tried. There is no role for surgery.

■ FEMORAL NEUROPATHY

Femoral neuropathies can arise as complications of retroperitoneal

hematoma, lithotomy positioning, hip arthroplasty or dislocation, iliac

artery occlusion, femoral arterial procedures, infiltration by hematogenous malignancy, penetrating groin trauma, pelvic surgery including

hysterectomy and renal transplantation, and diabetes (a partial form of

lumbosacral diabetic plexopathy); some cases are idiopathic. Patients

with femoral neuropathy have difficulty extending their knee and

flexing the hip. Sensory symptoms occurring either on the anterior

thigh and/or medial leg occur in only half of reported cases. A prominent painful component is the exception rather than the rule, may be

delayed, and is often self-limited in nature. The quadriceps (patellar)

reflex is diminished.

■ SCIATIC NEUROPATHY

Sciatic neuropathies commonly complicate hip arthroplasty, pelvic

procedures in which patients are placed in a prolonged lithotomy position, trauma, hematomas, tumor infiltration, and vasculitis. In addition, many sciatic neuropathies are idiopathic. Weakness may involve

all motions of the ankles and toes as well as flexion of the leg at the

knee; abduction and extension of the thigh at the hip are spared. Sensory loss occurs in the entire foot and the distal lateral leg. The ankle

jerk and, on occasion, the internal hamstring reflex are diminished or

more typically absent on the affected side. The peroneal subdivision

of the sciatic nerve is typically involved disproportionately to the tibial counterpart. Thus, patients may have only ankle dorsiflexion and

eversion weakness with sparing of knee flexion, ankle inversion, and

plantar flexion; these features can lead to misdiagnosis of a common

peroneal neuropathy.

PERONEAL NEUROPATHY

The sciatic nerve divides at the distal femur into the tibial and peroneal nerve. The common peroneal nerve passes posterior and laterally

around the fibular head, under the fibular tunnel. It then divides into

the superficial peroneal nerve, which supplies the ankle evertor muscles and sensation over the anterolateral distal leg and dorsum of the

foot, and the deep peroneal nerve, which supplies ankle dorsiflexors

and toe extensor muscles and a small area of sensation dorsally in the

area of the first and second toes.

Symptoms and signs consist of foot drop (ankle dorsiflexion, toe

extension, and ankle eversion weakness) and variable sensory loss,

which may involve the superficial and deep peroneal pattern. There

is usually no pain. Onset may be on awakening in the morning. Peroneal neuropathy needs to be distinguished from L5 radiculopathy. In

L5 radiculopathy, ankle invertors and evertors are weak and needle

EMG reveals denervation. EDx can help localize the lesion. Peroneal

motor conduction velocity shows slowing and amplitude drop across

the fibular head. Management consists of rapid weight loss and avoiding leg crossing. Foot drop is treated with an ankle brace. A knee pad

can be worn over the lateral knee to avoid further compression. Most

cases spontaneously resolve over weeks or months.

RADICULOPATHIES

Radiculopathies are most often due to compression from degenerative

joint disease and herniated disks, but there are a number of unusual etiologies (Table 446-9). Degenerative spine disease affects a number of

different structures, which narrow the diameter of the neural foramen

or canal of the spinal column and compromise nerve root integrity;

these are discussed in detail in Chap. 17.

PLEXOPATHIES (PATTERN 4; TABLE 446-2)

■ BRACHIAL PLEXUS

The brachial plexus is composed of three trunks (upper, middle,

and lower), with two divisions (anterior and posterior) per trunk

(Fig. 446-2). Subsequently, the trunks divide into three cords (medial,

lateral, and posterior), and from these, arise the multiple terminal

3499Peripheral Neuropathy CHAPTER 446

TABLE 446-9 Causes of Radiculopathy

• Herniated nucleus pulposus

• Degenerative joint disease

• Rheumatoid arthritis

• Trauma

• Vertebral body compression fracture

• Pott’s disease

• Compression by extradural mass (e.g., meningioma, metastatic tumor,

hematoma, abscess)

• Primary nerve tumor (e.g., neurofibroma, schwannoma, neurinoma)

• Carcinomatous meningitis

• Perineurial spread of tumor (e.g., prostate cancer)

• Acute inflammatory demyelinating polyradiculopathy

• Chronic inflammatory demyelinating polyradiculopathy

• Sarcoidosis

• Amyloidoma

• Diabetic radiculopathy

• Infection (Lyme disease, herpes zoster, HIV, cytomegalovirus, syphilis,

schistosomiasis, Strongyloides)

• Arachnoiditis (e.g., postsurgical)

• Radiation

nerves innervating the arm. The anterior primary rami of C5 and C6

fuse to form the upper trunk; the anterior primary ramus of C7 continues as the middle trunk, while the anterior rami of C8 and T1 join to

form the lower trunk. There are several disorders commonly associated

with brachial plexopathy.

Immune-Mediated Brachial Plexus Neuropathy Immunemediated brachial plexus neuropathy (IBPN) goes by various

terms, including acute brachial plexitis, neuralgic amyotrophy, and

Parsonage-Turner syndrome. IBPN usually presents with an acute onset

of severe pain in the shoulder region. The intense pain usually lasts

several days to a few weeks, but a dull ache can persist. Individuals

who are affected may not appreciate weakness of the arm early in the

course because the pain limits movement. However, as the pain dissipates, weakness and often sensory loss are appreciated. Attacks can

occasionally recur.

Clinical findings are dependent on the distribution of involvement

(e.g., specific trunk, divisions, cords, or terminal nerves). The most

common pattern of IBPN involves the upper trunk or a single or

multiple mononeuropathies primarily involving the suprascapular,

long thoracic, or axillary nerves. Additionally, the phrenic and anterior interosseous nerves may be concomitantly affected. Any of these

nerves may also be affected in isolation. EDx is useful to confirm and

localize the site(s) of involvement. Empirical treatment of severe pain

with glucocorticoids is often used in the acute period.

Brachial Plexopathies Associated with Neoplasms Neoplasms involving the brachial plexus may be primary nerve tumors,

local cancers expanding into the plexus (e.g., Pancoast lung tumor or

lymphoma), and metastatic tumors. Primary brachial plexus tumors

are less common than the secondary tumors and include schwannomas, neurinomas, and neurofibromas. Secondary tumors affecting the

brachial plexus are more common and are always malignant. These

may arise from local tumors, expanding into the plexus. For example, a

Pancoast tumor of the upper lobe of the lung may invade or compress

the lower trunk, whereas a primary lymphoma arising from the cervical or axillary lymph nodes may also infiltrate the plexus. Pancoast

tumors typically present as an insidious onset of pain in the upper arm,

sensory disturbance in the medial aspect of the forearm and hand, and

weakness and atrophy of the intrinsic hand muscles along with an ipsilateral Horner’s syndrome. Chest computed tomography (CT) scans or

magnetic resonance imaging (MRI) can demonstrate extension of the

tumor into the plexus. Metastatic involvement of the brachial plexus

may occur with spread of breast cancer into the axillary lymph nodes

and local spread into the nearby nerves.

Perioperative Plexopathies (Median Sternotomy) The most

common surgical procedures associated with brachial plexopathy as a

complication are those that involve median sternotomies (e.g., openheart surgeries and thoracotomies). Brachial plexopathies occur in as

many as 5% of patients following a median sternotomy and typically

affect the lower trunk. Thus, individuals manifest with sensory disturbance affecting the medial aspect of forearm and hand along with

weakness of the intrinsic hand muscles. The mechanism is related to

the stretch of the lower trunk, so most individuals who are affected

recover within a few months.

Lumbosacral Plexus The lumbar plexus arises from the ventral primary rami of the first to the fourth lumbar spinal nerves

(Fig. 446-3). These nerves pass downward and laterally from the

vertebral column within the psoas major muscle. The femoral nerve

derives from the dorsal branches of the second to the fourth lumbar

ventral rami. The obturator nerve arises from the ventral branches

Dorsal scapular

Long thoracic

Medial

thoracic

Anterior Posterior

PERIPHERAL NERVES CORDS DIVISIONS TRUNKS ROOTS

Upper

subscapular

Axillary

Musculocutaneous

Radial

Median

Ulnar

Medial

antibrachial

cutaneous

Medial

brachial

cutaneous

Lateral

thoracic

Thoracodorsal

Lower

subscapular

Suprascapular

Subclavius

FIGURE 446-2 Brachial plexus anatomy. L, lateral; M, medial; P, posterior. (Reproduced with permission J Goodgold: Anatomical Correlates of Clinical Electromyography.

Baltimore, Williams and Wilkins, 1974.)

3500 PART 13 Neurologic Disorders

of the same lumbar rami. The lumbar plexus communicates with the

sacral plexus by the lumbosacral trunk, which contains some fibers

from the fourth and all of the fibers from the fifth lumbar ventral

rami (Fig. 446-4).

The sacral plexus is the part of the lumbosacral plexus that is

formed by the union of the lumbosacral trunk with the ventral rami

of the first to fourth sacral nerves. The plexus lies on the posterior and

posterolateral wall of the pelvis with its components converging toward

the sciatic notch. The lateral trunk of the sciatic nerve (which forms the

common peroneal nerve) arises from the union of the dorsal branches

of the lumbosacral trunk (L4, L5) and the dorsal branches of the S1

and S2 spinal nerve ventral rami. The medial trunk of the sciatic nerve

(which forms the tibial nerve) derives from the ventral branches of the

same ventral rami (L4-S2).

■ LUMBOSACRAL PLEXOPATHIES

Plexopathies are typically recognized when motor, sensory, and if

applicable, reflex deficits occur in multiple nerve and segmental

distributions confined to one extremity. If localization within the

lumbosacral plexus can be accomplished, designation as a lumbar

plexopathy, a sacral plexopathy, a lumbosacral trunk lesion, or a panplexopathy is the best localization that can be expected. Although

lumbar plexopathies may be bilateral, usually occurring in a stepwise

and chronologically dissociated manner, sacral plexopathies are more

likely to behave in this manner due to their closer anatomic proximity. The differential diagnosis of plexopathy includes disorders of

the conus medullaris and cauda equina (polyradiculopathy). If there

is a paucity of pain and sensory involvement, motor neuron disease

should be considered as well.

The causes of lumbosacral plexopathies are listed in Table 446-

10. Diabetic radiculopathy (discussed above) is a fairly common

cause of painful leg weakness. Lumbosacral plexopathies are a wellrecognized complication of retroperitoneal hemorrhage. Various

primary and metastatic malignancies can affect the lumbosacral

plexus as well; these include carcinoma of the cervix, endometrium,

and ovary; osteosarcoma; testicular cancer; MM; lymphoma; acute

myelogenous leukemia; colon cancer; squamous cell carcinoma of the

rectum; adenocarcinoma of unknown origin; and intraneural spread

of prostate cancer.

■ RECURRENT NEOPLASTIC DISEASE OR

RADIATION-INDUCED PLEXOPATHY

The treatment for various malignancies is often radiation therapy, the

field of which may include parts of the brachial plexus. It can be difficult in such situations to determine if a new brachial or lumbosacral

plexopathy is related to tumor within the plexus or from radiationinduced nerve damage. Radiation can be associated with microvascular

abnormalities and fibrosis of surrounding tissues, which can damage

the axons and the Schwann cells. Radiation-induced plexopathy can

develop months or years following therapy and is dose dependent.

TERMINAL AND

COLLATERAL BRANCHES

BRANCHES FROM

POSTERIOR DIVISIONS

(From anterior

primary divisions)

(Posterior [black]

and anterior)

(To pudendal plexus)

Sciatic

nerve

Common peroneal

nerve

(To hamstring muscles)

Tibial nerve

Inferior medial clunial nerve (S2, 3)

BRANCHES FROM ANTERIOR DIVISIONS

L5, S1, 2 To obturator internus and

gemellus superior muscles

Posterior femoral

cutaneous nerve

(S1, 2, 3)

(To lumbar plexus)

(Lumbosacral

trunk)

BRANCH FROM BOTH

ANTERIOR AND

POSTERIOR DIVISIONS

Inferior gluteal

nerve (L5, S1, 2)

Nerves to piriformis (S1, 2)

Superior gluteal nerve (L4, 5, S1)

To quadratus femons and

gemellus inferior muscles L4, 5, S1

DIVISIONS

PLEXUS ROOTS

FIGURE 446-4 Lumbosacral trunk sacral plexus and sciatic nerve. (From AA Amato,

JA Russell (eds): Neuromuscular Disorders, 2nd ed. McGraw-Hill Education, 2016,

Figure 24-4, p. 542, with permission.)

TABLE 446-10 Lumbosacral Plexopathies: Etiologies

• Retroperitoneal hematoma

• Psoas abscess

• Malignant neoplasm

• Benign neoplasm

• Radiation

• Amyloid

• Diabetic radiculoplexus neuropathy

• Idiopathic radiculoplexus neuropathy

• Sarcoidosis

• Aortic occlusion/surgery

• Lithotomy positioning

• Hip arthroplasty

• Pelvic fracture

• Obstetric injury

Genitofemoral nerve

IIiohypogastric nerve

IIioinguinal nerve

Lateral cutaneous nerve of thigh

To lliacus and psoas muscles

Obturator nerve

Femoral nerve

Lumbo-sacral trunk

Gluteal nerves

Pudendal nerve

Sciatic nerve

Post. cutaneous nerve of thigh

FIGURE 446-3 Lumbosacral plexus. (From AA Amato, JA Russell (eds):

Neuromuscular Disorders, 2nd ed. McGraw-Hill Education, 2016, Figure 24-3, p. 542,

with permission.)

3501 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies CHAPTER 447

Tumor invasion is usually painful and more commonly affects the

lower trunk, whereas radiation injury is often painless and affects the

upper trunk. Imaging studies such as MRI and CT scans are useful but

can be misleading, especially when there is small microscopic invasion of the plexus. EMG can be informative if myokymic discharges

are appreciated, as this finding strongly suggests radiation-induced

damage.

■ EVALUATION AND TREATMENT OF

PLEXOPATHIES

Most patients with plexopathies will undergo both imaging with MRI

and EDx evaluations. Severe pain from acute idiopathic lumbosacral

plexopathy may respond to a short course of glucocorticoids.

■ FURTHER READING

Adams D et al: Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379:11, 2018.

Amato AA, Ropper AH: Sensory ganglionopathy. N Engl J Med

383:1657, 2020.

Amato AA, Russell J: Neuromuscular Disorders, 2nd ed. New York,

McGraw-Hill, 2016.

Barohn RJ, Amato AA: Pattern-recognition approach to neuropathy

and neuronopathy. Neurol Clin 31:343, 2013.

Barohn RJ et al: Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)

Bayesian adaptive comparative effectiveness randomized trial. JAMA

Neurol 78:68, 2021.

Benson M et al: Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 379:22, 2018.

Carroll AS et al: Inherited neuropathies. Semin Neurol 39:620, 2019.

England JD et al: Evaluation of distal symmetric polyneuropathy:

The role of autonomic testing, nerve biopsy, and skin biopsy

(an evidence-based review). Muscle Nerve 39:106, 2009.

England JD et al: Evaluation of distal symmetric polyneuropathy: The

role of laboratory and genetic testing (an evidence-based review).

Muscle Nerve 39:116, 2009.

Feldman EL et al: Diabetic neuropathy. Nat Rev Dis Primers 5:41,

2019.

Hobson-Webb LD, Juel VC: Common entrapment neuropathies.

Continuum (Minneap Minn) 23:487, 2017.

Jin PH, Shin SC: Neuropathy of connective tissue diseases and other

systemic diseases. Semin Neurol 39:651, 2019.

Waldfogel JM et al: Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology

87:978, 2016.

GUILLAIN-BARRÉ SYNDROME

Guillain-Barré syndrome (GBS) is an acute, frequently severe, and

fulminant polyradiculoneuropathy that is autoimmune in nature. It

occurs year-round at a rate of between 10 to 20 cases per million annually; in the United States, ~5000–6000 cases occur per year. Males are

at slightly higher risk for GBS than females, and in Western countries,

adults are more frequently affected than children.

Clinical Manifestations GBS manifests as a rapidly evolving

areflexic motor paralysis with or without sensory disturbance. The

usual pattern is an ascending paralysis that may be first noticed as

447 Guillain-Barré Syndrome

and Other Immune-Mediated

Neuropathies

Stephen L. Hauser, Anthony A. Amato

rubbery legs. Weakness typically evolves over hours to a few days and

is frequently accompanied by tingling dysesthesias in the extremities.

The legs are usually more affected than the arms, and facial diparesis is

present in 50% of affected individuals. The lower cranial nerves are also

frequently involved, causing bulbar weakness with difficulty handling

secretions and maintaining an airway; the diagnosis in these patients

may initially be mistaken for brainstem ischemia. Pain in the neck,

shoulder, back, or diffusely over the spine is also common in the early

stages of GBS, occurring in ~50% of patients. Most patients require

hospitalization, and in different series, up to 30% require ventilatory

assistance at some time during the illness. The need for mechanical

ventilation is associated with more severe weakness on admission, a

rapid tempo of progression, and the presence of facial and/or bulbar

weakness during the first week of symptoms. Fever and constitutional

symptoms are absent at the onset and, if present, cast doubt on the

diagnosis. Deep tendon reflexes attenuate or disappear within the

first few days of onset. Cutaneous sensory deficits (e.g., loss of pain

and temperature sensation) are usually relatively mild, but functions

subserved by large sensory fibers, such as deep tendon reflexes and

proprioception, are more severely affected. Bladder dysfunction may

occur in severe cases but is usually transient. If bladder dysfunction is

a prominent feature and comes early in the course or there is a sensory

level on examination, diagnostic possibilities other than GBS should

be considered, particularly spinal cord disease (Chap. 442). Once clinical worsening stops and the patient reaches a plateau (almost always

within 4 weeks of onset), further progression is unlikely.

Autonomic involvement is common and may occur even in patients

whose GBS is otherwise mild. The usual manifestations are loss of

vasomotor control with wide fluctuations in blood pressure, postural

hypotension, and cardiac dysrhythmias. These features require close

monitoring and management and can be fatal. Pain is another common

feature of GBS; in addition to the acute pain described above, a deep

aching pain may be present in weakened muscles that patients liken

to having overexercised the previous day. Other pains in GBS include

dysesthetic pain in the extremities as a manifestation of sensory nerve

fiber involvement. These pains are self-limited and often respond to

standard analgesics (Chap. 13).

Several subtypes of GBS are recognized, as determined primarily by

electrodiagnostic (EDx) and pathologic distinctions (Table 447-1). The

most common variant is acute inflammatory demyelinating polyneuropathy (AIDP). Additionally, there are two “axonal” or “nodal/paranodal” variants, which are often clinically severe: the acute motor axonal

neuropathy (AMAN) and acute motor sensory axonal neuropathy

(AMSAN) subtypes. In addition, a range of limited or regional GBS

syndromes are also encountered. Notable among these is the Miller

Fisher syndrome (MFS), which presents as rapidly evolving ataxia and

areflexia of limbs without weakness, and ophthalmoplegia, often with

pupillary paralysis. The MFS variant accounts for ~5% of all cases

and is strongly associated with antibodies to the ganglioside GQ1b

(see “Immunopathogenesis,” below). Other regional variants of GBS

include (1) pure sensory forms; (2) ophthalmoplegia with anti-GQ1b

antibodies as part of severe motor-sensory GBS; (3) GBS with severe

bulbar and facial paralysis, sometimes associated with antecedent

cytomegalovirus (CMV) infection and anti-GM2 antibodies; and (4)

acute pandysautonomia (Chap. 440).

Antecedent Events Approximately 70% of cases of GBS occur

1–3 weeks after an acute infectious process, usually respiratory or

gastrointestinal. Culture and seroepidemiologic techniques show that

20–30% of all cases occurring in North America, Europe, and Australia are preceded by infection or reinfection with Campylobacter jejuni.

A similar proportion is preceded by a human herpes virus infection,

often CMV or Epstein-Barr virus. Other viruses (e.g., HIV, hepatitis E,

Zika) and also Mycoplasma pneumoniae have been identified as agents

involved in antecedent infections, as have recent immunizations. The

swine influenza vaccine, administered widely in the United States in

1976, is the most notable example. Influenza vaccines in use from

1992 to 1994, however, resulted in only one additional case of GBS per

million persons vaccinated, and the more recent seasonal influenza

3502 PART 13 Neurologic Disorders

of cases), particularly in AMAN and AMSAN, and in those cases,

they are preceded by C. jejuni infection. Some AIDP autoantibodies

may recognize glycolipid heterocomplexes, rather than single species,

present on cell membranes. Furthermore, isolates of C. jejuni from

stool cultures of patients with GBS have surface glycolipid structures

that antigenically cross react with gangliosides, including GM1, concentrated in human nerves. Sialic acid residues from pathogenic C.

jejuni strains can also trigger activation of dendritic cells via signaling

through Toll-like receptor 4 (TLR4), promoting B-cell differentiation

and further amplifying humoral autoimmunity. Another line of evidence implicating humoral autoimmunity is derived from cases of GBS

that followed intravenous administration of bovine brain gangliosides

for treatment of various neuropathies; 5–15 days after injection, some

recipients developed AMAN with high titers of anti-GM1 antibodies

that recognized epitopes at nodes of Ranvier and motor endplates.

Experimentally, anti-GM1 antibodies can trigger complementmediated injury at paranodal axon-glial junctions, disrupting the clustering of sodium channels and likely contributing to conduction block

(see “Pathophysiology,” below).

Anti-GQ1b IgG antibodies are found in >90% of patients with

MFS (Table 447-2; Fig. 447-2), and titers of IgG are highest early in

the course. Anti-GQ1b antibodies are not found in other forms of

GBS unless there is extraocular motor nerve involvement. A possible explanation for this association is that extraocular motor nerves

are enriched in GQ1b gangliosides in comparison to limb nerves. In

addition, a monoclonal anti-GQ1b antibody raised against C. jejuni

isolated from a patient with MFS blocked neuromuscular transmission

experimentally.

Taken together, these observations provide strong but still inconclusive evidence that autoantibodies play an important pathogenic

role in GBS. Although antiganglioside antibodies have been studied

most intensively, other antigenic targets may also be important. Proof

that these antibodies are pathogenic requires that they be capable of

mediating disease following direct passive transfer to naïve hosts; this

has not yet been demonstrated, although one case of possible maternalfetal transplacental transfer of GBS has been described.

In AIDP, an early step in the induction of tissue damage appears

to be complement deposition along the outer surface of the Schwann

cell. Activation of complement initiates a characteristic vesicular

disintegration of the myelin sheath and also leads to recruitment

of activated macrophages, which participate in damage to myelin

and axons. In AMAN, the pattern is different in that complement is

deposited along with IgG at the nodes of Ranvier along large motor

axons. Interestingly, in cases of AMAN, antibodies against GD1a

appear to have a fine specificity that favors binding to motor rather

than sensory nerve roots, even though this ganglioside is expressed

on both fiber types.

Pathophysiology In the demyelinating forms of GBS, the basis

for flaccid paralysis and sensory disturbance is conduction block. This

finding, demonstrable electrophysiologically, implies that the axonal

connections remain intact. Hence, recovery can take place rapidly as

remyelination occurs. In severe cases of demyelinating GBS, secondary

TABLE 447-1 Subtypes of Guillain-Barré Syndrome (GBS)

SUBTYPE FEATURES ELECTRODIAGNOSIS PATHOLOGY

Acute inflammatory demyelinating

polyneuropathy (AIDP)

Adults affected more than children; 90%

of cases in Western world; recovery

rapid; anti-GM1 antibodies (<50%)

Demyelinating First attack on Schwann cell surface; widespread myelin

damage, macrophage activation, and lymphocytic

infiltration; variable secondary axonal damage

Acute motor axonal neuropathy (AMAN) Children and young adults; prevalent

in China and Mexico; may be seasonal;

recovery rapid; anti-GD1a antibodies

Axonal First attack at motor nodes of Ranvier; macrophage

activation, few lymphocytes, frequent periaxonal

macrophages; extent of axonal damage highly variable

Acute motor sensory axonal neuropathy

(AMSAN)

Mostly adults; uncommon; recovery

slow, often incomplete; closely related

to AMAN

Axonal Same as AMAN, but also affects sensory nerves and

roots; axonal damage usually severe

Miller Fisher syndrome (MFS) Adults and children; ophthalmoplegia,

ataxia, and areflexia; anti-GQ1b

antibodies (90%)

Axonal or

demyelinating

Few cases examined; resembles AIDP

vaccines appear to confer a GBS risk of <1 per million. Epidemiologic

studies looking at H1N1 vaccination demonstrated at most only a

slight increased risk of GBS. Meningococcal vaccinations (Menactra)

do not appear to carry an increased risk. Older-type rabies vaccine,

prepared in nervous system tissue, is implicated as a trigger of GBS

in developing countries where it is still used; the mechanism is presumably immunization against neural antigens. GBS also occurs more

frequently than can be attributed to chance alone in patients with lymphoma (including Hodgkin’s disease), in HIV-seropositive individuals,

and in patients with systemic lupus erythematosus (SLE). GBS, other

inflammatory neuropathies, and myositis can also occur as a complication of immune checkpoint inhibitors used to treat various cancers.

C. jejuni has also been implicated in summer outbreaks of AMAN

among children and young adults exposed to chickens in rural China.

Infection by Zika virus recently has been implicated in the increased

incidence of GBS in Brazil and other endemic regions. Recently, GBS

has been reported with SARS-CoV-2 infection during the COVID-19

pandemic, but a causal relationship has not been established. There

appears to be an increased risk of GBS with SARS-CoV-2 vaccines

using adenovirus vectors, but not the messenger RNA vaccines.

Immunopathogenesis Several lines of evidence support an autoimmune basis for acute inflammatory demyelinating polyneuropathy

(AIDP), the most common and best-studied type of GBS; the concept

extends to all of the subtypes of GBS (Table 447-1).

It is likely that both cellular and humoral immune mechanisms

contribute to tissue damage in AIDP. T-cell activation is suggested by

the finding that elevated levels of cytokines and cytokine receptors

are present in serum (interleukin [IL] 2, soluble IL-2 receptor) and in

cerebrospinal fluid (CSF) (IL-6, tumor necrosis factor α, interferon γ).

AIDP is also closely analogous to an experimental T cell–mediated

immunopathy designated experimental allergic neuritis (EAN). EAN is

induced in laboratory animals by immune sensitization against protein

fragments derived from peripheral nerve proteins and, in particular,

against the P2 protein. Based on analogy to EAN, it was initially

thought that AIDP was likely to be primarily a T cell–mediated disorder; however, abundant data now suggest that autoantibodies directed

against T cell–independent nonprotein determinants may be central

to many cases.

Circumstantial evidence suggests that all GBS results from

immune responses to nonself antigens (infectious agents, vaccines)

that misdirect to host nerve tissue through a resemblance-of-epitope

(molecular mimicry) mechanism (Fig. 447-1). The neural targets are

likely to be glycoconjugates, specifically gangliosides (Table 447-2;

Fig. 447-2). Gangliosides are complex glycosphingolipids that

contain one or more sialic acid residues; various gangliosides participate in cell-cell interactions (including those between axons

and glia), modulation of receptors, and regulation of growth. They

are typically exposed on the plasma membrane of cells, rendering

them susceptible to an antibody-mediated attack. Gangliosides and

other glycoconjugates are present in large quantity in human nervous

tissues and in key sites, such as nodes of Ranvier. Antiganglioside

antibodies, most frequently to GM1, are common in GBS (20–50%

3503 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies CHAPTER 447

axonal degeneration usually occurs; its extent can be estimated electrophysiologically. More secondary axonal degeneration correlates with a

slower rate of recovery and a greater degree of residual disability. With

AMAN and AMSAN, a primary axonal pattern is encountered electrophysiologically (low-amplitude compound muscle action potentials).

The implication has been that axons have degenerated and become disconnected from their targets, specifically the neuromuscular junctions,

and must therefore regenerate for recovery to take place. However, the

rapid recover in many cases suggests the low amplitudes are often from

reversible conduction block due to binding of antibodies to ion channel

proteins in the nodes and paranodes. In severe cases, axonal degeneration can occur, and it is in these cases that recovery is much slower.

Laboratory Features CSF findings are distinctive, consisting of

an elevated CSF protein level (1–10 g/L [100–1000 mg/dL]) without

accompanying pleocytosis. The CSF is often normal when symptoms

have been present for ≤48 h; by the end of the first week, the level

of protein is usually elevated. A transient increase in the CSF white

cell count (10–100/μL) occurs on occasion in otherwise typical GBS;

however, a sustained CSF pleocytosis suggests an alternative diagnosis (viral myelitis) or a concurrent diagnosis such as unrecognized

HIV infection, leukemia or lymphoma with infiltration of nerves, or

neurosarcoidosis. EDx features are mild or absent in the early stages

of GBS and lag behind the clinical evolution. In AIDP, the earliest features are prolonged F-wave latencies, prolonged distal latencies, and

reduced amplitudes of compound muscle action potentials (CMAPs),

probably owing to the predilection for involvement of nerve roots

and distal motor nerve terminals early in the course. Later, slowing

of conduction velocity, conduction block, and temporal dispersion

may be appreciated (Table 447-1). Occasionally, sensory nerve action

potentials (SNAPs) may be normal in the feet (e.g., sural nerve) when

abnormal in the arms. This is also a sign that the patient does not

have one of the more typical “length-dependent” polyneuropathies.

As mentioned, in AMAN and AMSAN, the principal EDx finding

is reduced amplitude of CMAPs (and also SNAPS with AMSAN)

without conduction slowing or prolongation of distal latencies, which

early on is caused by conduction block but later can be due to axonal

degeneration.

Diagnosis GBS is a descriptive entity. The diagnosis of AIDP is

made by recognizing the pattern of rapidly evolving paralysis with

areflexia, absence of fever or other systemic symptoms, and characteristic antecedent events. In 2011, the Brighton Collaboration

developed a new set of case definitions for GBS in response to needs

of epidemiologic studies of vaccination and assessing risks of GBS

(Table 447-3). These criteria have subsequently been validated.

Other disorders that may enter into the differential diagnosis include

acute myelopathies (especially with prolonged back pain and sphincter disturbances); diphtheria (early oropharyngeal disturbances);

Lyme polyradiculitis and other tick-borne paralyses; porphyria

(abdominal pain, seizures, psychosis); vasculitic neuropathy (check

erythrocyte sedimentation rate, described below); poliomyelitis and

acute flaccid myelitis (wild-type poliovirus, West Nile virus, enterovirus D68, enterovirus A71, Japanese encephalitis virus, and the wildtype poliovirus); CMV polyradiculitis (in immunocompromised

patients); critical illness neuropathy or myopathy; neuromuscular

junction disorders such as myasthenia gravis and botulism (pupillary

reactivity lost early); poisonings with organophosphates, thallium, or

arsenic; paralytic shellfish poisoning; or severe hypophosphatemia

(rare). Cases of acute flaccid myelitis may pose particular challenges

stnairavdnasepytbuS otseidobitnaotuaGgI

Guillain-Barré syndrome

Acute inflammatory demyelinating polyneuropathy

Facial variant: Facial diplegia and paresthesia

Acute motor axonal neuropathy

More and less extensive forms

Acute motor-sensory axonal neuropathy

Acute motor-conduction-block neuropathy

Pharyngeal-cervical-brachial weakness

None

GM1, GD1a

GT1a>GQ1b>>GD1a

GQ1b, GT1a

Miller Fisher syndrome

Incomplete forms

Acute ophthalmoparesis (without ataxia)

Acute ataxic neuropathy (without ophthalmoplegia)

CNS variant: Bickerstaff’s brainstem encephalitis

Galactose

KEY

Glucose

N-Acetylgalactosamine

N-Acetylneuraminic acid

Cer Ceramide

GM1 Cer

GD1a Cer

Cer

GT1a

GQ1b

FIGURE 447-1 Spectrum of disorders in Guillain-Barré syndrome and associated antiganglioside antibodies. IgG autoantibodies against GM1 or GD1a are strongly

associated with acute motor axonal neuropathy (AMAN), as well as the more extensive acute motor-sensory axonal neuropathy (AMSAN), and the less extensive acute

motor-conduction-block neuropathy. IgG anti-GQ1b antibodies, which cross-react with GT1a, are strongly associated with Miller Fisher syndrome, its incomplete forms

(acute ophthalmoparesis [without ataxia] and acute ataxic neuropathy [without ophthalmoplegia]), and its more extensive form, Bickerstaff’s brainstem encephalitis.

Pharyngeal-cervical-brachial weakness is categorized as a localized form of acute motor axonal neuropathy or an extensive form of Miller Fisher syndrome. Half of patients

with pharyngeal-cervical-brachial weakness have IgG anti-GT1a antibodies, which often cross-react with GQ1b. IgG anti-GD1a antibodies have also been detected in a

small percentage of patients. The anti-GQ1b antibody syndrome includes Miller Fisher syndrome, acute ophthalmoparesis, acute ataxic neuropathy, Bickerstaff’s brainstem

encephalitis, and pharyngeal-cervical-brachial weakness. The presence of clinical overlap also indicates that Miller Fisher syndrome is part of a continuous spectrum with

these conditions. Patients who have had Guillain-Barré syndrome overlapped with Miller Fisher syndrome or with its related conditions have IgG antibodies against GM1

or GD1a as well as against GQ1b or GT1a, supporting a link between AMAN and anti-GQ1b syndrome. (From N Yuki, H-P Hartung: Guillain-Barré syndrome. N Engl J Med

3504 PART 13 Neurologic Disorders

in distinguishing these from GBS because sphincter disturbances are

often absent.

Laboratory tests are helpful primarily to exclude mimics of GBS.

CSF pleocytosis is seen with poliomyelitis, acute flaccid myelitis, and

Lyme and CMV polyradiculitis. EDx features may be minimal early in

GBS, and the CSF protein level may not rise until the end of the first

week. If the diagnosis is strongly suspected, treatment should be initiated without waiting for evolution of the characteristic EDx and CSF

findings to occur. GBS patients with risk factors for HIV or with CSF

pleocytosis should have a serologic test for HIV.

TREATMENT

Guillain-Barré Syndrome

In the vast majority of patients with GBS, treatment should be

initiated as soon after diagnosis as possible. Each day counts;

~2 weeks after the first motor symptoms, it is not known whether

immunotherapy is still effective. If the patient has already reached

the plateau stage, then treatment probably is no longer indicated,

unless the patient has severe motor weakness and one cannot

exclude the possibility that an immunologic attack is still ongoing.

Either high-dose intravenous immune globulin (IVIg) or plasmapheresis (PLEX) can be initiated, as they are equally effective for

typical GBS. A combination of the two therapies is not significantly

better than either alone. IVIg is often the initial therapy chosen

because of its ease of administration and good safety record. IVIg

is usually administered as five daily infusions for a total dose of

2 g/kg body weight. There is some evidence that GBS autoantibodies are neutralized by anti-idiotypic antibodies present in IVIg preparations, perhaps accounting for the therapeutic effect. A course

of PLEX usually consists of ~40–50 mL/kg plasma exchange (PE)

4–5 times over 7–10 days. Meta-analysis of randomized clinical

trials indicates that treatment reduces the need for mechanical ventilation by nearly half (from 27 to 14% with PLEX) and increases the

likelihood of full recovery at 1 year (from 55 to 68%). Functionally

significant improvement may occur toward the end of the first

week of treatment or may be delayed for several weeks. The lack of

noticeable improvement following a course of IVIg or PLEX is not

an indication to treat with the alternate treatment. However, there

are occasional patients who are treated early in the course of GBS

and improve, who then relapse within a month. Brief retreatment

with the original therapy is usually effective in such cases. Glucocorticoids have not been found to be effective in GBS. Occasional

patients with very mild forms of GBS, especially those who appear

to have already reached a plateau when initially seen, may be managed conservatively without IVIg or PLEX.

In the worsening phase of GBS, most patients require monitoring

in a critical care setting, with particular attention to vital capacity,

heart rhythm, blood pressure, nutrition, deep-vein thrombosis prophylaxis, cardiovascular status, early consideration (after 2 weeks

of intubation) of tracheotomy, and chest physiotherapy. As noted,

~30% of patients with GBS require ventilatory assistance, sometimes for prolonged periods of time (several weeks or longer).

Frequent turning and assiduous skin care are important, as are daily

range-of-motion exercises to avoid joint contractures and daily

reassurance as to the generally good outlook for recovery.

Prognosis and Recovery Approximately 85% of patients with

GBS achieve a full functional recovery within several months to a

year, although minor findings on examination (such as areflexia) may

persist and patients often complain of continued symptoms, including

fatigue. The mortality rate is <5% in optimal settings; death usually

results from secondary pulmonary complications. The outlook is

worst in patients with severe proximal motor and sensory axonal

damage. Such axonal damage may be either primary or secondary in

nature (see “Pathophysiology,” above), but in either case, successful

regeneration cannot occur. Other factors that worsen the outlook for

recovery are advanced age, a fulminant or severe attack, and a delay

in the onset of treatment. Between 5 and 10% of patients with typical GBS have one or more late relapses; many of these cases are then

classified as chronic inflammatory demyelinating polyneuropathy

(CIDP).

CHRONIC INFLAMMATORY

DEMYELINATING POLYNEUROPATHY

CIDP is distinguished from GBS by its chronic course. In other

respects, this neuropathy shares many features with the common

demyelinating form of GBS, including elevated CSF protein levels

and the EDx findings of acquired demyelination. Most cases occur in

adults, and males are affected slightly more often than females. The

incidence of CIDP is lower than that of GBS, but due to the protracted

course, the prevalence is greater. As with GBS, CIDP and its variants

can be triggered by use of immune checkpoint inhibitors used to treat

various cancers.

Clinical Manifestations Onset is usually gradual over a few

months or longer, but in a few cases, the initial attack is indistinguishable from that of GBS. An acute-onset form of CIDP may mimic GBS

but should be considered if it deteriorates >9 weeks after onset or

relapses at least three times. Symptoms are both motor and sensory

in most cases. Weakness of the limbs is usually symmetric but can be

strikingly asymmetric in multifocal acquired demyelinating sensory

and motor (MADSAM) neuropathy variant (Lewis-Sumner syndrome)

in which discrete peripheral nerves are involved. There is considerable

TABLE 447-2 Principal Antiglycolipid Antibodies Implicated in

Immune Neuropathies

CLINICAL

PRESENTATION ANTIBODY TARGET USUAL ISOTYPE

Acute Immune Neuropathies (Guillain-Barré Syndrome)

Acute inflammatory

demyelinating

polyneuropathy (AIDP)

No clear patterns IgG (polyclonal)

GM1 most common

Acute motor axonal

neuropathy (AMAN)

GD1a, GM1, GM1b,

GalNAc–GD1a (<50%

for any)

IgG (polyclonal)

Miller Fisher syndrome

(MFS)

GQ1b (>90%) IgG (polyclonal)

Acute pharyngeal

cervicobrachial

neuropathy (APCBN)

GT1a (? most) IgG (polyclonal)

Chronic Immune Neuropathies

Chronic inflammatory

demyelinating

polyneuropathy

(CIDP) (75%)

Approximately 10% to

CNTN1 or NF155, less

often to NF140/186 and

Caspr1, and even more

rarely to P0, myelin P2

protein, or PMP22

IgG4 with CNTN1, NF155,

NF140/186, Caspr1

Rare IgM with NF155

CIDP-M (MGUS

associated) (25%)

Neural binding sites IgG, IgA (monoclonal)

Chronic sensory > motor

neuropathy

SGPG, SGLPG (on MAG)

(50%)

IgM (monoclonal)

Uncertain (50%) IgM (monoclonal)

Multifocal motor

neuropathy (MMN)

GM1, GalNAc–GD1a,

others (25–50%)

IgM (polyclonal,

monoclonal)

Chronic sensory ataxic

neuropathy

GD1b, GQ1b, and other

b-series gangliosides

IgM (monoclonal)

Abbreviations: CIDP-M, CIDP with a monoclonal gammopathy; Caspr1, contactin

associated protein-1; CNTN1, contactin-1; MAG, myelin-associated glycoprotein;

MGUS, monoclonal gammopathy of undetermined significance; NF140/186,

neurofascin 140/186; NF155, neurofascin 155; SGPG, sulfoglucuronyl paragloboside;

SGLPG, sulfoglucuronyl lactosaminyl paragloboside.

Source: Reproduced with permission from HJ Willison, N Yuki: Peripheral

neuropathies and anti‐glycolipid antibodies. Brain 125:2591, 2002.

3505 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies CHAPTER 447

variability from case to case. Some patients experience a chronic

progressive course, whereas others, usually younger patients, have a

relapsing and remitting course. A small proportion have cranial nerve

findings, including external ophthalmoplegia. Some have only motor

findings, and a small proportion present with a relatively pure syndrome of sensory ataxia. The latter can be seen in the chronic inflammatory sensory polyradiculopathy (CISP) variant of CIDP in which

demyelination predominantly occurs at the sensory roots or with the

distal acquired demyelinating symmetric (DADS) variant.

Approximately, 10% of cases are associated with IgG4 isotype

antibodies directed against contactin-1 (CNTN1) or neurofascin 155

(NF155), with early axonal damage, severe distal motor involvement,

or sensory ataxia with tremor. Less commonly, IgM anti-NF140/186

CIDP associated with sensory ataxia but without tremor, low-amplitude

CMAPs (conduction block or axonal degeneration), and nephrotic

syndrome have also been reported. Anti-contactin associated protein-1

(Caspr1) antibodies occur in CIDP associated with severe neuropathic

pain.

CIDP tends to ameliorate over time with treatment; the result is that

many years after onset, nearly 75% of patients have reasonable functional status. Death from CIDP is uncommon.

Diagnosis The diagnosis rests on characteristic clinical, CSF, and

electrophysiologic findings. The CSF is usually acellular with an

Macrophage

scavenging

Motor

neuron

Axon

Kv Caspr

Juxtaparanode

Axon

Myelin

Schwann-cell

microvilli

Paranode Node

Nav Cytoskeleton

KEY

IgG anti-GM1 or

anti-GD1a antibodies

C3 MAC

Unidentified antigen

Myelin

Nerve

injury

Macrophage

GM1,

GD1a

MAC

Axon

MAC

Myelin

Macrophage

Axon

Complement

activation

Antibody

binding

Axon

Macrophage

Myelin

FIGURE 447-2 Possible immune mechanisms in Guillain-Barré syndrome (GBS). Panel A shows the immunopathogenesis of AIDP. Although autoantigens have yet to be

unequivocally identified, autoantibodies may bind to myelin antigens and activate complement. This is followed by the formation of membrane-attack complex (MAC) on

the outer surface of Schwann cells and the initiation of vesicular degeneration. Macrophages subsequently invade myelin and act as scavengers to remove myelin debris.

Panel B shows the immunopathogenesis of acute axonal forms of GBS (acute motor axonal neuropathy [AMAN] and acute motor-sensory axonal neuropathy [AMSAN]).

Myelinated axons are divided into four functional regions: the nodes of Ranvier, paranodes, juxtaparanodes, and internodes. Gangliosides GM1 and GD1a are strongly

expressed at the nodes of Ranvier, where the voltage-gated sodium (Nav) channels are localized. Contactin-associated protein (Caspr) and voltage-gated potassium (Kv)

channels are respectively present at the paranodes and juxtaparanodes. IgG anti-GM1 or anti-GD1a autoantibodies bind to the nodal axolemma, leading to MAC formation.

This results in the disappearance of Nav clusters and the detachment of paranodal myelin, which can lead to nerve-conduction failure and muscle weakness. Axonal

degeneration may follow at a later stage. Macrophages subsequently invade from the nodes into the periaxonal space, scavenging the injured axons. (From N Yuki, H-P

Society.)

3506 PART 13 Neurologic Disorders

elevated protein level, sometimes several times normal. As with GBS,

a CSF pleocytosis should lead to the consideration of HIV infection,

leukemia or lymphoma, and neurosarcoidosis. EDx findings reveal

variable degrees of conduction slowing, prolonged distal latencies,

distal and temporal dispersion of CMAPs, and conduction block as

the principal features. In particular, the presence of conduction block

is a certain sign of an acquired demyelinating process. Evidence of

axonal loss, presumably secondary to demyelination, is present in

>50% of patients. Serum protein electrophoresis with immunofixation

is indicated to search for monoclonal gammopathy and associated

conditions (see “Monoclonal Gammopathy of Undetermined Significance,” below). MRI can demonstrate enlarged nerves, clumping of

cauda equina, and enhancement. Ultrasound is cheaper and often more

readily available and can likewise show enlargement of nerves at the

roots or more distally. Studies have shown that imaging completements

EDx findings and increases sensitivity. In all patients with presumptive

CIDP, it is also reasonable to exclude vasculitis, collagen vascular disease (especially SLE), chronic hepatitis, HIV infection, amyloidosis,

and diabetes mellitus. Other associated conditions include inflammatory bowel disease and lymphoma.

Pathogenesis Biopsy in typical CIDP reveals little inflammation

and onion-bulb changes (imbricated layers of attenuated Schwann cell

processes surrounding an axon) that result from recurrent demyelination and remyelination (Fig. 447-1). The response to therapy suggests

that CIDP is immune-mediated; CIDP responds to glucocorticoids,

whereas GBS does not. Passive transfer of demyelination into experimental animals has been accomplished using IgG purified from the

serum of some patients with CIDP, lending support for a humoral autoimmune pathogenesis. A minority of patients have serum antibodies

TABLE 447-3 Brighton Criteria for Diagnosis of Guillain-Barré Syndrome (GBS) and Miller Fisher Syndrome

Clinical case definitions for diagnosis of GBS

Level 1 of diagnostic certainty

Bilateral AND flaccid weakness of the limbs

AND

Decreased or absent deep tendon reflexes in weak limbs

AND

Monophasic illness pattern and interval between onset and nadir of weakness

between 12 h and 28 days and subsequent clinical plateau

AND

Electrophysiologic findings consistent with GBS

AND

Cytoalbuminologic dissociation (i.e., elevation of CSF protein level above laboratory

normal value AND CSF total white cell count <50 cells/μL)

AND

Absence of an identified alternative diagnosis for weakness

Level 2 of diagnostic certainty

Bilateral AND flaccid weakness of the limbs

AND

Decreased or absent deep tendon reflexes in weak limbs

AND

Monophasic illness pattern and interval between onset and nadir of weakness

between 12 h and 28 days and subsequent clinical plateau

AND

CSF total white cell count <50 cells/μL (with or without CSF protein elevation above

laboratory normal value)

If CSF not collected or results not available, electrophysiologic studies consistent

with GBS

AND

Absence of identified alternative diagnosis for weakness

Level 3 of diagnostic certainty

Bilateral and flaccid weakness of the limbs

AND

Decreased or absent deep tendon reflexes in weak limbs

AND

Monophasic illness pattern and interval between onset and nadir of weakness

between 12 h and 28 days and subsequent clinical plateau

AND

Absence of identified alternative diagnosis for weakness

Clinical case definitions for diagnosis of Miller Fisher syndrome

Level 1 of diagnostic certainty

Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes, and

ataxia

AND

Absence of limb weakness

AND

Monophasic illness pattern and interval between onset and nadir of

weakness between 12 h and 28 days and subsequent clinical plateau

AND

Cytoalbuminologic dissociation (i.e., elevation of cerebrospinal protein above

the laboratory normal and total CSF white cell count <50 cells/μL)

AND

Nerve conduction studies are normal, OR indicate involvement of sensory

nerves only

AND

No alterations in consciousness or corticospinal tract signs

AND

Absence of identified alternative diagnosis

Level 2 of diagnostic certainty

Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes

and ataxia

AND

Absence of limb weakness

AND

Monophasic illness pattern and interval between onset and nadir of

weakness between 12 h and 28 days and subsequent clinical plateau

AND

CSF with a total white cell count <50 cells/μL) (with or without CSF protein

elevation above laboratory normal value)

Nerve conduction studies are normal, OR indicate involvement of sensory

nerves only

AND

No alterations in consciousness or corticospinal tract signs

AND

Absence of identified alternative diagnosis

Level 3 of diagnostic certainty

Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes

and ataxia

AND

Absence of limb weakness

AND

Monophasic illness pattern and interval between onset and nadir of

weakness between 12 h and 28 days and subsequent clinical plateau

AND

No alterations in consciousness or corticospinal tract signs

AND

Absence of identified alternative diagnosis

Abbreviation: CSF, cerebrospinal fluid.

Source: From JJ Sejvar et al: Guillain-Barré syndrome and Fisher syndrome: Case definitions and guidelines for collection, analysis, and presentation of immunization safety

data. Vaccine 29:599, 2011. Validation study published by C Fokke et al: Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain 137:33, 2014.

3507 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies CHAPTER 447

against P0, myelin P2 protein, or PMP22 (proteins whose genes are

mutated in certain forms of hereditary Charcot-Marie-Tooth neuropathy). As previously mentioned, antibodies of IgG4 isotype directed

against CNTN1, NF155, NF140/186, and Caspr1 have been associated

with early nodal and paranodal damage with and a poor response to

IVIg. CNTN1 and its partner Caspr1 interact with NF155 at paranodal axoglial junctions. Passive transfer of IgG4 CNTN1 antibodies

produces paranodal damage and ataxia in rodents. It is also of interest

that a CIDP-like illness developed spontaneously in the nonobese diabetic (NOD) mouse when the immune co-stimulatory molecule B7-2

(CD86) was genetically deleted; this suggests that CIDP can result from

altered triggering of T cells by antigen-presenting cells.

As many as 25% of patients with clinical features of CIDP also have

a monoclonal gammopathy of undetermined significance (MGUS),

discussed below. Cases associated with monoclonal IgA or IgG kappa

usually respond to treatment as favorably as cases without a monoclonal gammopathy. Patients with IgM-kappa monoclonal gammopathy and antibodies directed against myelin-associated glycoprotein

(MAG) have a distinct demyelinating polyneuropathy with more

sensory findings, usually only distal weakness, and a poor response to

immunotherapy.

TREATMENT

Chronic Inflammatory Demyelinating

Polyneuropathy

Most authorities initiate treatment for CIDP when progression is

rapid or walking is compromised. If the disorder is mild, management can be expectant, awaiting spontaneous remission. Controlled

studies have shown that high-dose IVIg, subcutaneous Ig (scIg),

PLEX, and glucocorticoids are all more effective than placebo.

Initial therapy is usually with IVIg, administered as 2.0 g/kg

body weight given in divided doses over 2–5 days; three monthly

courses are generally recommended before concluding a patient

has failed treatment. If the patient responds, the infusion intervals

can be gradually increased or the dosage decreased (e.g., starting at

1 g/kg every 3–4 weeks). Patients who require more frequent IVIg,

experience side effects with IVIg (headaches), have poor venous

access, or find it more convenient are treated with scIg (2–3 times

a week such that the total dosage per month is the same or slightly

higher than the monthly dosage of IVIg). PLEX, which appears to

be as effective as IVIg, is initiated at 2–3 treatments per week for

6 weeks; periodic retreatment may also be required. Treatment with

glucocorticoids is another option (60–80 mg prednisone PO daily

for 1–2 months, followed by a gradual dose reduction of 10 mg

per month as tolerated), but long-term adverse effects including

bone demineralization, gastrointestinal bleeding, and cushingoid

changes are problematic. As many as one-third of patients with

CIDP fail to respond adequately to the initial therapy chosen; a

different treatment should then be tried. Patients who fail therapy

with IVIg, scIg, PLEX, and glucocorticoids may benefit from

treatment with immunosuppressive agents such as azathioprine,

methotrexate, cyclosporine, and cyclophosphamide, either alone or

as adjunctive therapy. CIDP associated with anti-CNTN1, NF155,

NF140/186, and Caspr1 antibodies (IgG4 subclass antibodies) is

typically refractory to IVIg, but several studies suggest a response

to rituximab. Use of these therapies requires periodic reassessment

of their risks and benefits. In patients with a CIDP-like neuropathy

who fail to respond to treatment, it is important to evaluate for

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes; see below).

MULTIFOCAL MOTOR NEUROPATHY

Multifocal motor neuropathy (MMN) is a distinctive but uncommon

neuropathy that presents as slowly progressive motor weakness and

atrophy evolving over years in the distribution of selected nerve trunks,

associated with sites of persistent focal motor conduction block in the

same nerve trunks. Sensory fibers are relatively spared. The arms are

affected more frequently than the legs, and >75% of all patients are

male. Some cases have been confused with lower motor neuron forms

of amyotrophic lateral sclerosis (Chap. 437). Less than 50% of patients

present with high titers of polyclonal IgM antibody to the ganglioside

GM1. It is uncertain how this finding relates to the discrete foci of

persistent motor conduction block, but high concentrations of GM1

gangliosides are normal constituents of nodes of Ranvier in peripheral

nerve fibers. Pathology reveals demyelination and mild inflammatory

changes at the sites of conduction block.

Most patients with MMN respond to high-dose IVIg or scIg (dosages as for CIDP, above); periodic retreatment is required (usually at

least monthly) to maintain the benefit. Some refractory patients have

responded to rituximab or cyclophosphamide. Glucocorticoids and PE

are not effective.

NEUROPATHIES WITH MONOCLONAL

GAMMOPATHY

■ MULTIPLE MYELOMA

Clinically overt polyneuropathy occurs in ~5% of patients with the

commonly encountered type of multiple myeloma, which exhibits

either lytic or diffuse osteoporotic bone lesions. These neuropathies

are sensorimotor, are usually mild and slowly progressive but may be

severe, and generally do not reverse with successful suppression of the

myeloma. In most cases, EDx and pathologic features are consistent

with a process of axonal degeneration.

In contrast, myeloma with osteosclerotic features, although representing only 3% of all myelomas, is associated with polyneuropathy

in one-half of cases. These neuropathies, which may also occur with

solitary plasmacytoma, are distinct because they (1) are demyelinating or mixed axonal and demyelinating by EDx, have elevated CSF

protein, and clinically resemble CIDP; (2) often respond to radiation

therapy or removal of the primary lesion; (3) are associated with different monoclonal proteins and light chains (almost always lambda as

opposed to primarily kappa in the lytic type of multiple myeloma); (4)

are typically refractory to standard treatments of CIDP; and (5) may

occur in association with other systemic findings including thickening of the skin, hyperpigmentation, hypertrichosis, organomegaly,

endocrinopathy, anasarca, and clubbing of fingers. These are features

of POEMS syndrome. Levels of vascular endothelial growth factor

(VEGF) are increased in the serum, and this factor is thought to somehow play a pathogenic role in this syndrome. Treatment of the neuropathy is best directed at the osteosclerotic myeloma using surgery,

radiotherapy, chemotherapy, or autologous peripheral blood stem cell

transplantation.

Neuropathies are also encountered in other systemic conditions

with gammopathy, including Waldenström macroglobulinemia, primary systemic amyloidosis, and cryoglobulinemic states (mixed essential cryoglobulinemia, some cases of hepatitis C).

■ MONOCLONAL GAMMOPATHY OF

UNDETERMINED SIGNIFICANCE

Chronic polyneuropathies occurring in association with MGUS are

usually associated with the immunoglobulin isotypes IgG, IgA, and

IgM. Most patients present with isolated sensory symptoms in their

distal extremities and have EDx features of an axonal sensory or

sensorimotor polyneuropathy. These patients otherwise resemble

idiopathic sensory polyneuropathy, and the MGUS might just be coincidental. They usually do not respond to immunotherapies designed

to reduce the concentration of the monoclonal protein. Some patients,

however, present with generalized weakness and sensory loss and EDx

studies indistinguishable from CIDP without monoclonal gammopathy (see “Chronic Inflammatory Demyelinating Polyneuropathy,”

above), and their response to immunosuppressive agents is also similar.

An exception is the syndrome of IgM-kappa monoclonal gammopathy associated with an indolent, long-standing, sometimes static

3508 PART 13 Neurologic Disorders

sensory neuropathy, frequently with tremor and sensory ataxia. Most

patients are men and aged >50 years. In the majority, the monoclonal

IgM immunoglobulin binds to a normal peripheral nerve constituent, MAG, found in the paranodal regions of Schwann cells. Binding

appears to be specific for a polysaccharide epitope that is also found in

other normal peripheral nerve myelin glycoproteins, P0 and PMP22,

and also in other normal nerve-related glycosphingolipids (Fig. 447-1).

In the MAG-positive cases, IgM paraprotein is incorporated into the

myelin sheaths of affected patients and widens the spacing of the

myelin lamellae, thus producing a distinctive ultrastructural pattern.

Demyelination and remyelination are the hallmarks of the lesions, but

axonal loss develops over time. These anti-MAG polyneuropathies are

typical refractory to immunotherapy. In a small proportion of patients

(30% at 10 years), MGUS will in time evolve into frankly malignant

conditions such as multiple myeloma or lymphoma.

VASCULITIC NEUROPATHY

Peripheral nerve involvement is common in polyarteritis nodosa

(PAN), appearing in half of all cases clinically and in 100% of cases

at postmortem studies (Chap. 363). The most common pattern is

multifocal (asymmetric) motor-sensory neuropathy (mononeuropathy

multiplex) due to ischemic lesions of nerve trunks and roots; however,

some cases of vasculitic neuropathy present as a distal, symmetric

sensorimotor polyneuropathy. Symptoms of neuropathy are a common

presenting complaint in patients with PAN. The EDx findings are those

of an axonal process. Small- to medium-sized arteries of the vasa nervorum, particularly the epineural vessels, are affected in PAN, resulting

in a widespread ischemic neuropathy. A high frequency of neuropathy

occurs in eosinophilic granulomatosis with polyangiitis (Churg-Strauss

syndrome [CSS]).

Systemic vasculitis should always be considered when a subacute or

chronically evolving mononeuropathy multiplex occurs in conjunction

with constitutional symptoms (fever, anorexia, weight loss, loss of

energy, malaise, and nonspecific pains). Diagnosis of suspected vasculitic neuropathy is made by a combined nerve and muscle biopsy, with

serial section or skip-serial techniques.

Approximately one-third of biopsy-proven cases of vasculitic neuropathy are “nonsystemic” in that the vasculitis appears to affect only

peripheral nerves. Constitutional symptoms are absent, and the course

is more indolent than that of PAN. The erythrocyte sedimentation rate

may be elevated, but other tests for systemic disease are negative. Nevertheless, clinically silent involvement of other organs is likely, and vasculitis is frequently found in muscle biopsied at the same time as nerve.

Vasculitic neuropathy may also be seen as part of the vasculitis

syndrome occurring in the course of other connective tissue disorders.

The most frequent is rheumatoid arthritis, but ischemic neuropathy

due to involvement of vasa nervorum may also occur in mixed cryoglobulinemia, Sjögren’s syndrome, granulomatosis with polyangiitis

(formerly known as Wegener’s), hypersensitivity angiitis, SLE, and

progressive systemic sclerosis.

Some vasculitides are associated with antineutrophil cytoplasmic

antibodies (ANCAs), which in turn are subclassified as cytoplasmic

(cANCA) or perinuclear (pANCA). cANCAs are directed against

proteinase 3 (PR3), whereas pANCAs target myeloperoxidase (MPO).

PR3/cANCAs are associated with eosinophilic granulomatosis with

polyangiitis, whereas MPO/pANCAs are typically associated with

microscopic polyangiitis, CSS, and less commonly PAN. Of note,

MPO/pANCA has also been seen in minocycline-induced vasculitis.

Management of these neuropathies, including the “nonsystemic”

vasculitic neuropathy, consists of treatment of the underlying condition as well as the aggressive use of glucocorticoids and cyclophosphamide. Use of these immunosuppressive agents has resulted in

dramatic improvements in outcome, with 5-year survival rates now

>80%. Clinical trials found that the combination of rituximab and

glucocorticoids is not inferior to cyclophosphamide and glucocorticoids. Thus, combination therapy with glucocorticoids and rituximab

is recommended as the standard initial treatment, particularly for

ANCA-associated vasculitis. Mepolizumab, an anti-IL-5 monoclonal

antibody, when added to standard care, is also effective for treatment

of eosinophilic granulomatosis with polyangiitis.

ANTI-Hu PARANEOPLASTIC NEUROPATHY

(CHAP. 94)

This uncommon immune-mediated disorder manifests as a sensory

neuronopathy (i.e., selective damage to sensory nerve bodies in dorsal root ganglia). The onset is often asymmetric with dysesthesias

and sensory loss in the limbs that soon progress to affect all limbs,

the torso, and the face. Marked sensory ataxia, pseudoathetosis, and

inability to walk, stand, or even sit unsupported are frequent features

and are secondary to the extensive deafferentation. Subacute sensory

neuronopathy may be idiopathic, but more than half of cases are

paraneoplastic, primarily related to lung cancer, and most of those

are small-cell lung cancer (SCLC). Diagnosis of the underlying SCLC

requires awareness of the association, testing for the paraneoplastic

antibody, and often positron emission tomography (PET) scanning for

the tumor. The target antigens are a family of RNA-binding proteins

(HuD, HuC, and Hel-N1) that in normal tissues are only expressed by

neurons. The same proteins are usually expressed by SCLC, triggering

in some patients an immune response characterized by antibodies and

cytotoxic T cells that cross-react with the Hu proteins of the dorsal root

ganglion neurons, resulting in immune-mediated neuronal destruction. An encephalomyelitis may accompany the sensory neuronopathy

and presumably has the same pathogenesis. Neurologic symptoms

usually precede, by ≤6 months, the identification of SCLC. The sensory

neuronopathy runs its course in a few weeks or months and stabilizes,

leaving the patient disabled. Most cases are unresponsive to treatment

with glucocorticoids, IVIg, PE, or immunosuppressant drugs.

■ FURTHER READING

Amato AA, Ropper AH: Sensory ganglionopathy. N Engl J Med

383:1657, 2020.

Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed.

New York, McGraw-Hill, 2016, pp 320–383.

Beachy N et al: Vasculitic neuropathies. Semin Neurol 39:608, 2009.

Bunschoten C et al: Progress in diagnosis and treatment of chronic

inflammatory demyelinating polyradiculoneuropathy. Lancet Neurol

18:784, 2019.

Fatemi Y et al: Acute flaccid myelitis: A clinical overview for 2019.

Mayo Clin Proc 94:875, 2019.

Guidon AC, Amato AA: COVID-19 and neuromuscular disorders.

Neurology 94:959, 2020.

Leonard SE et al: Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol 15:671, 2019.

Maramattom BV et al: Guillain-Barre Syndrome following

ChAdOx1-S/nCoV-19 vaccine. Ann Neurol 90:312, 2021.

Puwanant A et al: Clinical spectrum of neuromuscular complications

after immune checkpoint inhibition. Neuromuscul Disord 29:127,

2019.

Toscano G et al: Guillain-Barré syndrome associated with SARSCoV-2. N Engl J Med 382:2574, 2020.

Uncini A, Vallat J-M: Autoimmune nodo-paranodopathies of

peripheral nerve: The concept is gaining ground. J Neurol Neurosurg

Psychiatry 89:627, 2018.

Wijdicks EF, Klein CJ: Guillain-Barré syndrome. Mayo Clin Proc

92:467, 2017.

3509 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction CHAPTER 448

Myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder

characterized by weakness and fatigability of skeletal muscles. The

underlying defect is a decrease in the number of available acetylcholine

receptors (AChRs) at NMJs due to an antibody-mediated autoimmune

attack. Treatment now available for MG is highly effective, although a

specific cure has remained elusive.

■ PATHOPHYSIOLOGY

At the NMJ (Fig. 448-1, Video 448-1), acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta).

When an action potential travels down a motor nerve and reaches the

448

nerve terminal, ACh from 150 to 200 vesicles is released and combines

with AChRs that are densely packed at the peaks of postsynaptic folds.

The AChR consists of five subunits (2α, 1β, 1δ, 1γ, or ε) arranged

around a central pore. When ACh combines with the binding sites on

the α subunits of the AChR, the channel in the AChR opens, permitting

the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is

sufficiently large, it initiates an action potential that is propagated along

the muscle fiber, triggering muscle contraction. This process is rapidly

terminated by hydrolysis of ACh by acetylcholinesterase (AChE),

which is present within the synaptic folds, and by diffusion of ACh

away from the receptor.

In MG, the fundamental defect is a decrease in the number of

available AChRs at the postsynaptic muscle membrane. In addition,

the postsynaptic folds are flattened, or “simplified.” These changes

result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate

potentials that may fail to trigger muscle action potentials. Failure of

transmission results in weakness of muscle contraction.

The amount of ACh released per impulse normally declines on

repeated activity (termed presynaptic rundown). In the myasthenic

Myasthenia Gravis and

Other Diseases of the

Neuromuscular Junction

Anthony A. Amato

Agrin

Voltage-gated

K+ channel

ChAT Choline acetyltransferase

Acetylcholine receptor

SNARE proteins

Syntaxin-1

SNAP 25

Synaptotagmin

Synaptobrevin

Axon

Myelin

sheath

Acetate

Choline

ChAT

Ca+ ions

AChE

Voltage-gated

Na+ channels

Voltage-gated

Ca+ channel

Myofibril

Active zone

FIGURE 448-1 Illustrations of (A) a normal presynaptic neuromuscular junction, (B) a normal postsynaptic terminal, and (C) a myasthenic neuromuscular junction. AChE,

acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a reduced number of acetylcholine

receptors (AChRs); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 448-1 also. (From AA Amato, J Russell: Neuromuscular Disorders,

2nd ed. New York, McGraw-Hill, 2016, Figures 25-3 [p 588], 25-4 [p 589], and 25-5 [p 590]; with permission.)

3510 PART 13 Neurologic Disorders

patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and

fewer muscle fibers by successive nerve impulses and hence increasing

weakness, or myasthenic fatigue. This mechanism also accounts for the

decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.

MG is an autoimmune disorder most commonly caused by antiAChR antibodies. The anti-AChR antibodies reduce the number of

available AChRs at NMJs by three distinct mechanisms: (1) accelerated

turnover of AChRs by a mechanism involving cross-linking and rapid

endocytosis of the receptors; (2) damage to the postsynaptic muscle

membrane by the antibody in collaboration with complement; and

(3) blockade of the active site of the AChR (i.e., the site that normally

binds Ach). An immune response to muscle-specific kinase (MuSK),

a protein involved in AChR clustering at the NMJ, can also result in

MG, with reduction of AChRs demonstrated experimentally. AntiMuSK antibody occurs in ~10% of patients (~40% of AChR antibody–

negative patients), whereas 1–3% have antibodies to another protein at

the NMJ—low-density lipoprotein receptor-related protein 4 (LRP4)—

that is also important for clustering of AChRs. The pathogenic antibodies are IgG and are T-cell dependent. Thus, immunotherapeutic

strategies directed against either the antibody-producing B cells or

helper T cells are effective in this antibody-mediated disease.

How the autoimmune response is initiated and maintained in MG

is not completely understood, but the thymus appears to play a role

in this process. The thymus is abnormal in ~75% of patients with

AChR antibody–positive MG; in ~65%, the thymus is “hyperplastic,”

with the presence of active germinal centers detected histologically,

although the hyperplastic thymus is not necessarily enlarged. An

additional 10% of patients have thymic tumors (thymomas). Musclelike cells within the thymus (myoid cells), which express AChRs on

their surface, may serve as a source of autoantigen and trigger the

autoimmune reaction within the thymus gland.

■ CLINICAL FEATURES

MG has a prevalence as high as 200 in 100,000. It affects individuals in

all age groups, but peak incidences occur in women in their twenties and

thirties and in men in their fifties and sixties. Overall, women are affected

more frequently than men, in a ratio of ~3:2. The cardinal features are

weakness and fatigability of muscles. The weakness increases during

repeated use (fatigue) or late in the day and may improve following rest or

sleep. The course of MG is often variable. Exacerbations and remissions

may occur, particularly during the first few years after the onset of the

disease. Unrelated infections or systemic disorders can lead to increased

myasthenic weakness and may precipitate “crisis” (see below).

The distribution of muscle weakness often has a characteristic pattern. The cranial muscles, particularly the lids and extraocular muscles

(EOMs), are typically involved early in the course of MG; diplopia

and ptosis are common initial complaints. Facial weakness produces a

“snarling” expression when the patient attempts to smile. Weakness in

chewing is most noticeable after prolonged effort, as in chewing meat.

Speech may have a nasal timbre caused by weakness of the palate or

a dysarthric “mushy” quality due to tongue weakness. Difficulty in

swallowing may occur as a result of weakness of the palate, tongue,

or pharynx, giving rise to nasal regurgitation or aspiration of liquids

or food. Bulbar weakness and more frequent episodes of respiratory

depression can be especially prominent in MuSK antibody–positive

MG. In ~85% of patients, the weakness becomes generalized, affecting

the limb muscles as well. If weakness remains restricted to the EOMs

for 3 years, it is likely that it will not become generalized, and these

patients are said to have ocular MG. The limb weakness in MG is often

proximal and may be asymmetric. Despite the muscle weakness, deep

ACh

(acetylcholine) Vesicle SNARE proteins

Syntaxin-1

SNAP 25

Synaptotagmin

Synaptobrevin

Vesicle

fusion

Agrin

Dystroglycan

Lrp4

MuSK

Dok-7

Rapsyn

Na+ channels Myofibril

ACh

receptor

AChE

α α γ

ACh

AChE

Vesicle SNARE proteins

Syntaxin-1

SNAP 25

Synaptotagmin

Vesicle Synaptobrevin

fusion

Agrin

Dystroglycan

Lysis of

ACh receptors

Na+ channel

Myofibril

AChR autoantibody

Complement

α α α α

FIGURE 448-1 (Continued)

3511 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction CHAPTER 448

tendon reflexes are preserved. If ventilatory weakness becomes requires

respiratory assistance, the patient is said to be in crisis.

■ DIAGNOSIS AND EVALUATION (TABLE 448-1)

The diagnosis is suspected on the basis of weakness and fatigability

in the typical distribution described above, without loss of reflexes or

impairment of sensation or other neurologic function. The suspected

diagnosis should always be confirmed definitively before treatment is

undertaken; this is essential because (1) other treatable conditions may

closely resemble MG and (2) the treatment of MG may involve surgery

and the prolonged use of drugs with potentially adverse side effects.

Ice-Pack Test If a patient has ptosis, application of a pack of ice

over a ptotic eye often results in improvement if the ptosis is due to an

NMJ defect. This is hypothesized to be due to less depletion of quanta

of AChR in the cold and reduced activity of AChE at the NMJ. It is a

quick and easy test to do in the clinic or at the bedside of a hospitalized

patient.

Autoantibodies Associated with MG As previously mentioned,

anti-AChR antibodies are detectable in the serum of ~85% of all myasthenic patients but in only ~50% of patients with weakness confined to

the ocular muscles. The presence of anti-AChR antibodies is virtually

diagnostic of MG, but a negative test does not exclude the disease.

The measured level of anti-AChR antibody does not correspond well

with the severity of MG in different patients. Antibodies to MuSK are

present in ~40% of AChR antibody–negative patients with generalized

MG. MuSK antibodies are rarely present in AChR antibody–positive

patients or in patients with MG limited to ocular muscles. These

antibodies may interfere with clustering of AChRs at NMJs. A small

proportion of MG patients without antibodies to AChR or MuSK

have antibodies to LRP4. Interestingly, antibodies against agrin also

have been found in rare patients with MG. Agrin is a protein derived

from motor nerves that normally binds to LRP4 and is important for

normal clustering of AChRs at NMJ. Additionally, anti-striated muscle

antibodies directed against titin and other skeletal muscle components

are found in ~30% of myasthenics without thymoma, 24% of thymoma

patients without myasthenia, and 70–80% of patients with both

myasthenia and thymoma. Furthermore, antibodies directed against

Netrin-1 receptors and Caspr2 (contactin-associated protein-like 2)

often coexist and are associated in patients with thymoma who have

MG and neuromyotonia or Morvan’s syndrome.

Electrodiagnostic Testing Repetitive nerve stimulation may provide helpful diagnostic evidence of MG. Anti-AChE medication should

be stopped 6–12 h before testing. It is best to test weak muscles or

proximal muscle groups. Electrical stimulation is delivered at a rate of

two or three per second to the appropriate nerves, and action potentials

are recorded from the muscles. In normal individuals, the amplitude of

the evoked muscle action potentials does not change by >10% at these

rates of stimulation. However, in myasthenic patients, there is a rapid

reduction of >10% in the amplitude of the evoked responses.

Anticholinesterase Test Drugs that inhibit the enzyme AChE

allow ACh to interact repeatedly with the limited number of AChRs

in MG, producing improvement in muscle strength. Edrophonium

is used most commonly for diagnostic testing because of the rapid

onset (30 s) and short duration (~5 min) of its effect. An objective end

point must be selected to evaluate the effect of edrophonium, such as

weakness of EOMs, impairment of speech, or the length of time that

the patient can maintain the arms in forward. An initial IV dose of

2 mg of edrophonium is given. If definite improvement occurs, the

test is considered positive and is terminated. If there is no change,

the patient is given an additional 8 mg IV. The dose is administered

in two parts because some patients react to edrophonium with side

effects such as nausea, diarrhea, salivation, fasciculations, and rarely

with severe symptoms of syncope or bradycardia. Atropine (0.6 mg)

should be drawn up in a syringe and ready for IV administration if

these symptoms become troublesome. The edrophonium test is now

reserved for patients with clinical findings that are suggestive of MG

but who have negative antibody, electrodiagnostic testing, or ice-pack

test. False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis (Chap. 437), and

in placebo-reactors. False-negative or equivocal tests may also occur.

Pulmonary Function Tests (Chap. 284) Measurements of ventilatory function are valuable because of the frequency and seriousness

of respiratory impairment in myasthenic patients.

Differential Diagnosis Other conditions that cause weakness of

the cranial and/or somatic musculature include the nonautoimmune

congenital myasthenia, drug-induced myasthenia, Lambert-Eaton

myasthenic syndrome (LEMS), neurasthenia, hyperthyroidism (Graves’

disease), botulism, intracranial mass lesions, oculopharyngeal dystrophy, and mitochondrial myopathy (Kearns-Sayre syndrome, progressive external ophthalmoplegia). Treatment with immune checkpoint

inhibitors for cancer may also result in autoimmune MG. Myositis and

myocarditis are also often found in combination with MG as a complication of checkpoint inhibitors (Chap. 365). Symptoms typically begin

after the first or second cycle of treatment, with ptosis, diplopia, and

bulbar and occasionally extremity weakness. Patients usually improve

when the immune checkpoint inhibitor is discontinued and a short

course of glucocorticoids or intravenous immunoglobulin (IVIg) is

administered. Treatment with penicillamine (used for scleroderma or

rheumatoid arthritis) has also been associated with MG. Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness

in myasthenic patients; very large doses can cause neuromuscular

weakness in normal individuals.

The congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of disorders of the NMJ that are not autoimmune but

rather are due to genetic mutations in which virtually any component

of the NMJ may be affected. Alterations in function of the presynaptic

nerve terminal, in the various subunits of the AChR, AChE, or the

other molecules involved in end-plate development or maintenance,

have been identified in the different forms of CMS. These disorders

share many of the clinical features of autoimmune MG, including

weakness and fatigability of proximal or distal extremity muscles

TABLE 448-1 Diagnosis of Myasthenia Gravis (MG)

History

Diplopia, ptosis, dysarthria, dysphagia, dyspnea

Weakness in characteristic distribution: proximal limbs, neck extensors,

generalized

Fluctuation and fatigue: worse with repeated activity, improved by rest

Effects of previous treatments

Physical examination

Evaluation for ptosis at rest and following 1 min of exercise, extraocular

muscles and subjective diplopia, orbicularis oculi and oris strength, jaw

opening and closure

Assessment of muscle strength in neck and extremities

Weakness following repeated shoulder abduction

Vital capacity measurement

Absence of other neurologic signs

Laboratory testing

Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular

MG; definite diagnosis if positive; negative result does not exclude MG; ~40%

of AChR antibody–negative patients with generalized MG have anti-MuSK

antibodies and ~2% have LRP-4 antibodies

Repetitive nerve stimulation: decrement of >10% at 3 Hz: highly probable

Single-fiber electromyography: blocking and jitter, with normal fiber density;

confirmatory, but not specific

Edrophonium chloride (Enlon®) 2 mg + 8 mg IV; highly probable diagnosis if

unequivocally positive

Ice-pack test looking for improvement in ptosis is very sensitive

For ocular or cranial MG: exclude intracranial lesions by CT or MRI

Abbreviations: AChR, acetylcholine receptor; CT, computed tomography; LRP4,

lipoprotein receptor-related protein 4; MRI, magnetic resonance imaging; MuSK,

muscle-specific tyrosine kinase.

3512 PART 13 Neurologic Disorders

and often involving EOMs and the eyelids similar to the distribution

in autoimmune MG. CMS should be suspected when symptoms of

myasthenia have begun in infancy or childhood, but they can present

in early adulthood. As in acquired autoimmune MG, repetitive nerve

stimulation is associated with a decremental response. Some forms

(e.g., AChE deficiency, prolonged open channel syndrome) have a feature of after-discharges that are not seen in MG. An additional clue is

the absence of AChR and MuSK antibodies, although these are absent

in ~10% of generalized MG patients (so-called double seronegative

MG).

The prevalence of CMS is estimated at ~3.8 per 100,000. The most

common genetic defects occur in the ε subunit of the AChR, accounting for ~50% of CMS cases, with mutations in the genes encoding for

rapsin, COLQ, DOK7, agrin, and GFPT together accounting for ~40%.

In most of the recessively inherited forms of CMS, the mutations are

heteroallelic; that is, different mutations affecting each of the two alleles

are present. Features of the most common forms of CMS are summarized in Table 448-2. Molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic

counseling. Some forms of CMS improve with AChE inhibitors, while

others (e.g., slow channel syndrome, AChE deficiency, DOK7-related

CMS) actually worsen. Fluoxetine and quinidine can be useful for slow

channel syndrome, and albuterol for mutations affecting AChE, DOK7,

rapsyn, and agrin. Additionally, ephedrine and 3,4-diaminopyridine

(3,4-DAP) may be of benefit in some forms of CMS.

LEMS is a presynaptic disorder of the NMJ that can cause weakness

similar to that of MG. The proximal muscles of the lower limbs are

most commonly affected, but other muscles may be involved as well.

Cranial nerve findings, including ptosis of the eyelids and diplopia,

occur in up to 70% of patients and resemble features of MG. However,

TABLE 448-2 Congenital Myasthenic Syndromes (CMS)

CMS SUBTYPE GENE CLINICAL FEATURES

ELECTROPHYSIOLOGIC

FEATURES

RESPONSE TO

ACHE INHIBITORS TREATMENT

Presynaptic Disorders

CMS with paucity of ACh

release

CHAT; CHT AR; early onset, respiratory failure at

birth, episodic apnea, improvement

with age

Decremental response

to RNS

Improve AChE inhibitors; 3,4-DAP

Synaptic Disorders

AChE deficiency COLQ AR; early onset; variable severity;

axial weakness with scoliosis; apnea;

+/– EOM involvement, slow or absent

pupillary responses

After discharges on

nerve stimulation and

decrement on RNS

Worsen Albuterol; ephedrine; 3,4-

DAP; avoid AChE inhibitors

Postsynaptic Disorders Involving AChR Deficiency or Kinetics

Primary AChR deficiency AChR subunit

genes

AR; early onset; variable severity;

fatigue; typical MG features

Decremental response

to RNS

Improve AChE inhibitors; 3,4-DAP

AChR kinetic disorder:

slow channel syndrome

AChR subunit

genes

AD; onset childhood to early adult; weak

forearm extensors and neck; respiratory

weakness; variable severity

After discharges on

nerve stimulation and

decrement on RNS

Worsen Fluoxetine and quinidine;

avoid AChE inhibitors

AChR kinetic disorder:

fast channel syndrome

AChR subunit

genes

AR; early onset; mild to severe; ptosis,

EOM involvement; weakness and

fatigue

Decremental response

to RNS

Improve AChE inhibitors; caution with

3,4-DAP

Postsynaptic Disorders Involving Abnormal Clustering/Function of AChR

DOK 7 AR; limb girdle weakness with ptosis

but no EOM involvement

Decremental response

to RNS

Variable Albuterol; ephedrine; may

worsen with AChE inhibitors

Rapsyn AR; early onset with hypotonia,

respiratory failure, and arthrogryposis

at birth to early adult onset resembling

Decremental response

to RNS

Variable Albuterol

Agrin AR; limb girdle or distal weakness,

apnea

Decremental response

to RNS

Variable Albuterol; may worsen with

AChE inhibitors

MuSK AR; congenital or childhood onset of

ptosis, EOM and progressive limb girdle

weakness

Decremental response

to RNS

Variable Variable response to AChE

inhibitors and 3,4-DAP

Positive response to

albuterol

LRP4 AR; congenital onset with hypotonia;

ventilatory failure, mild ptosis, and EOM

weakness

Decremental response

to RNS

Worsen Worsen with AChE inhibitors

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