PATHOPHYSIOLOGY OF PERIPHERAL NEUROPATHIES

Peripheral nerve pathology can be divided into two categories based on location of primary
pathologic process:
I. Interstitial: external to axon, Schwann cell and perineural cells.
II. Parenchymal: includes axon, Schwann cell and perineural cells, usually metabolic
derangement or may be secondary to interstitial damage.

Connective tissue components:

I. Endoneurium: consists of basal lamina surrounding Schwann cells. External to
lamina is narrow zone of collagen fibrils which is endoneurium proper and contains
few cells.
II. Perineurium: ensheathes fascicles and ganglia and consists of lamellae of flattened
cells. Larger diameter fascicles are covered by more layers. Perineurium provides
diffusion barrier with tight junctions and metabolic activity.
III. Epineurium: areolar connective tissue around fascicles.
IV. Arrangement at spinal roots:
A. Endoneurium continues to junction with CNS.
B. Perineurium merges with pia mater.
C. Epineurium merges with dura mater.
V. Changes following degeneration:
A. Basal lamina and endoneurium persist, viable for years for reinnervation.
B. Little change in perineurium and epineurium.

Vascular supply:
I. Only epineurium and perineurium have arterioles (50-400 microns) in diameter.
Only these layers are affected by necrotizing angiopathies (PNA, Wegeners, Churg-
Strauss, RA).
II. Endoneurial capillaries have tight junctions and form 'blood nerve barrier'.
III. Diseases by vessel size:
A. Large vessel: occlusive or embolic disorders.
B. Medium vessel: vasculitis.
C. Capillary vessel: microangiopathy.
IV. Necrotizing angiopathy (as in mononeuritis multiplex):
A. Produces central fascicular axonal loss.
B. Watershed regions affected first, segments in midproximal portion of
limbs.
C. Produces axonal> demyelinating damage.

Examples: Nerve compression- affects parenchyma indirectly (see below).

Page 1 of 4
Examples: Inflammatory-demyelinating
I. Edema around capillaries and beneath perineurium
II. Mononuclear cells about endoneural capillaries.
III. Macrophage contact with Schwann cells leading to demyelination (see below).

Examples: Sarcoidosis
I. Granulomas may involve perineurium, extending to endoneurium and epineurium.
II. Lesions are focal, affecting short lengths of fascicles.
III. Damage caused by uncertain mechanism.

Examples: Amyloidosis
I. Polymerized amyloid in epineurium, perineurium and endoneurium.
II. Damage caused by compression or ischemia (vessel involvement by amyloid).
Axonopathies are consequent to trauma or presumed metabolic abnormalities.
After acute transection Wallerian degeneration follows.

I. Distal segment normal both structurally and electrically 36-48 hours after
transection.
II. At 96 hours all fibers show separation of myelin at nodes and at Schmidt-Lanterman
incisures.
III. Previously flat layers of myelin become ovoids in beaded pattern along nerve fibers.
IV. Axoplasm becomes 'watery' in appearance and devoid of organelles.
V. Ovoids become smaller as early sign of early degradation.
VI. At about 6 days macrophages continue process of degradation.
VII. Increase in Schwann cell nuclei with intact basement membrane may be signal of
early regeneration changes. Depending upon etiology (e.g., crush injury)
degeneration and regeneration may proceed simultaneously.

Wallerian degeneration may occur under many conditions:

I. Physical trauma: transsection, compression, tear, radiation, burn, repeated mild
trauma.
II. Ischemic transection: vasculitis, granulomas, amyloidosis.
III. Secondary to active segmental demyelination: due to immunologic-mediated 'by-
stander effect', or demyelinating internal (axonal) strangulation.

Features of axonal degeneration may be seen in metabolic/toxic conditions (natural and

experimental) or secondary to interstitial causes. The following features are not seen in HSMN
I&II, other hereditary neuropathies and experimental lead neuropathy.

I. Axons show spherical enlargements in both PNS and CNS segments.

II. There is sequestration of neurofilaments and microtubules associated with
enlargements.
III. Accumulation of microfilaments may be related to changes in axoplasm transport.
IV. Distal/proximal locus of spherical enlargements varies among different
experimental toxic models.

Page 2 of 4
Demyelination results from many causes and has different mechanisms. In focal compression
the following occurs:

I. Focal compression causes stretching of paranodal myelin such that there is

telescoping of myelin on one side of the lesion. The myelin can rupture at these
points.
II. Degeneration and regeneration of myelin can follow.

In acute demyelination associated with inflammatory processes the following occurs:

I. Macrophages penetrate basal lamina of Schwann cells at internodes. Mildest

change is retraction of myelin at nodes. Finger-like macrophage processes then
enter between layers of myelin and peel them off. Myelin ovoids form and myelin
is engulfed by macrophages.
II. Satiated macrophages rapidly leave via blood stream and leave behind Schwann
cells with varying amounts of myelin and frequent bare axons. If severe, axons may
degenerate.
III. Demyelination is usually segmental, associated with inflammatory perivascular
infiltrates of mononuclear cells.
IV. Remyelination may occur rapidly.

In chronic acquired demyelinating disorders, such as CIDP, the following is observed:

I. There are varying amounts of mononuclear infiltrates with subperineurial edema

but with minimal inflammation.
II. There is segmental demyelination with varying degrees of remyelination. There is
varying degree of fiber loss.

The effects on conduction of an axonopathy reflect distal to proximal or 'dying back' pathology,
causing absent or low amplitude responses. Large diameter fibers are most susceptible to
injury and sensory more than motor.

I. Compound AP composed of slower/smaller fibers in acrylamide model.

II. Smaller diameter fibers and sensory fibers show more frequent 'terminal end
disconnection' (dying back) in acrylamide model.

Demyelination causes slowing of conduction or block.

I. In normals, during saltatory conduction, latency of exit current depends upon time
for AP to reach node (source of inward current) and hence time interval of jumps
(intranodal conduction) is equal.
II. With demyelination, intranodal conduction is slowed to variable degree at each
internode (variable degree of demyelination), and hence timing of jumps is variable,
causing slowed conduction. Process may be segmental.

Page 3 of 4
III. With severe demyelination (bare axons) conduction may be continuous (non-
saltatory) over some segments. Process may reflect activity of extranodal Na
channels.
IV. Lowered axoplasmic resistance and increased capacitance due to reduced or absent
myelin may cause AP to fail, causing blocking.
V. Above processes very temperature dependent, with blocking seen in vitro with 0.5
degree C changes.

Page 4 of 4
 EMG CONFERENCE
J.W. Albers, M.D., Ph.D.
October 7, 1986

AXONAL VS. DEMYELINATING POLYNEUROPATHY

I. Introduction

The peripheral nervous system includes the cranial, spinal, and peripheral nerves, and
the peripheral component of the autonomic nervous system. Polyneuropathy refers to
diffuse disease of the peripheral nerves and results from multiple causes. Although
detailed investigation sometimes does not reveal the etiology of a polyneuropathy,
improved diagnostic techniques over the past 25 years have extended our
understanding of polyneuropathy.

Peripheral nerve disease may be classified in a variety of ways, including clinical,

electrophysiologic, metabolic, morphometric, or pathologic. The following classification
is derived from clinical, electrodiagnostic, and conventional laboratory information,
although electrodiagnostic findings are emphasized.

II. Evaluation of Peripheral Neuropathy

A. Clinical

1. History

a) Onset and temporal profile of motor, sensory, or autonomic

involvement

b) Type and distribution of sensory abnormalities (paresthesia,

hyperesthesia, hyperpathia)

c) Distribution of weakness (e.g. distal and/or proximal)

d) Industrial and medical history for drug or toxin exposures

e) Careful family history with attention to bony deformities (e.g. pes

cavus and hammer toes)

f) Social habits including recreational drug use

g) Antecedent illness or symptoms or underlying disease

Page 1 of 13
 2. Clinical Evaluation

a) Distinguish involvement of nerve, plexus, or root

b) If sensory, which modalities (superficial: light touch, pain,

temperature; deep: joint, vibration, deep pain; cortical:
discriminative)

c) Sensory loss may involve all modalities, or may be selective.

When selective, two patterns of peripheral loss are recognized.

(1) One consisting of reduced pain and temperature

sensation, involving small myelinated or unmyelinated
fibers

(2) Another involving abnormal touch - pressure, joint

position and two-point discrimination in which large
myelinated fibers are involved

3. Laboratory Evaluation

a) CSF examination

b) Conventional studies of blood and urine (YTS, BUN, LFTs, thyroid

function studies, SPEP, IEP, ESR, ANA, BI2, porphyrin screen,
heavy metals).

c) Rectal and nerve biopsy

B. Electrodiagnostic Evaluation

1. Nerve conduction studies reflect the integrity of the large myelinated

nerve fibers.

a) Conduction velocity frequently used to denote presence or

absence of neuropathy is sensitive primarily to demyelinating
disease and may remain essentially normal when 90% of the
axons are not functioning.

b) Distal latencies are markedly prolonged in demyelination and are

mildly prolonged in axonal degeneration, particularly if there is
"dying back" or axonal stenosis.

c) Motor and sensory evoked amplitudes are most sensitive to

axonal degeneration.

Page 2 of 13
2. Complete electrodiagnostic examination requires:

a) Motor and sensory conduction studies (multiple nerves)

b) Upper and lower extremity evaluation

c) Demonstration of symmetry

d) Needle electromyography of proximal and distal muscles

(distribution of abnormalities useful in identifying disorders
confused with or superimposed upon polyneuropathy, e.g.

(1) Severe, asymmetric leg involvement, sparing foot intrinsic

muscles would be inconsistent with polyneuropathy.

(2) Marked predilection of paraspinal muscles would be

unusual in polyneuropathy but suggests polyradiculopathy.

3. Although strategy may vary depending upon severity, a relatively

standardized electrodiagnostic evaluation is outlined in Table I.

4. Establishing a differential diagnosis using electrodiagnosis:

a) Identifying the presence or absence of findings suggestive of

demyelination is the single most important goal.

b) Confusion related to superimposed focal entrapment is the most

important error.

c) Chronic axonal stenosis or selective loss of large myelinated fibers

may erroneously suggest demyelination.

5. Findings characteristic of pure axonal lesions

a) Reduced sensory and motor evoked amplitudes (see Figure 1).

b) Absence of conduction block and/or abnormal temporal

dispersion

(1) Best evaluated using motor conduction studies

(2) Area calculations most sensitive but amplitude criteria

easier

(3) Proximal to distal CMAP ratio normally > 0.7

(4) Be alert for anomalous innervation.

Page 3 of 13
 c) Mild slowing of conduction velocity and distal latency

(1) CV typically > 75% of the lower limit of normal

(2) DL less than 120% of the upper limit of normal

(3) F-response latency less than 120% of upper limit of normal

(but may be absent)

d) Evidence of partial denervation on needle EMG

(1) Needle EMG may demonstrate evidence of chronic axonal

degeneration prior to changes in nerve conduction studies.

(2) The intrinsic foot muscles are particularly, sensitive to

early axonal degeneration.

6. Findings characteristic of (suggestive of) acquired demyelination.

a) Reduced conduction velocity disproportionate of amplitude loss

b) Acquired demyelination usually multifocal, resulting in:

(1) Abnormal temporal dispersion

(2) Partial conduction block

c) Prolonged distal latency

7. Findings characteristic of (suggestive of) hereditary demyelination

a) Reduced conduction velocity, prolonged distal latency

b) Demyelination uniform, involving entire nerve

c) Therefore, fibers involved homogeneously, resulting in:

(1) No abnormal increase in temporal dispersion

(2) No conduction block

Page 4 of 13
 8. Distinction between presence or absence of demyelination not always
clear

a) Overlap common

b) Suggestive criteria shown in Table II

9. Correlation of electrodiagnostic and clinical findings

a) Quantitative sensory evaluation of normal subjects demonstrates

a significant correlation between the results of sensory evoked
amplitude and distal conduction velocity and touch-pressure, two-
point discrimination, and vibratory sensation.

b) No relationship is demonstrated for pain (pin) or temperature

sensation.

c) There also is a significant correlation between the clinical grading

of ankle reflexes and the sural evoked amplitude.

III. Polyneuropathy Classification Based Upon Electrodiagnostic Findings

A. Comments

1. n.b. The emphasis is upon demonstrating sensory and/or motor

predilection, plus evidence of presence or absence of demyelination.

2. Many etiologies could arguably fit in several of the groups.

B. Classification

1. Demyelinating, hereditary (non-acquired), mixed sensorimotor

polyneuropathy

a) HMSN type I (Charcot-Marie-Tooth Disease)

b) HMSN type III (Dejerine-Sottas hypertrophic neuropathy)

c) HMSN type IV (Refsum's atactica polyneuritiformis)

d) Metachromatic Leukodystrophy

e) Krabbe's Globoid Cell Leukodystrophy

2. Demyelinating, acquired sensorimotor (or motor > sensory)

polyneuropathy

Page 5 of 13
a) Acute inflammatory demyelinating polyradiculoneuropathy (AIDP,
Guillain-Barré Syndrome, post-infectious neuritis)

b) Chronic inflammatory demyelinating polyradiculoneuropathy

(CIDP, chronic relapsing polyradiculoneuropathy)

c) Vaccine related AIDP (?)

d) Diphtheritic neuropathy

e) Chronic dysimmune polyneuropathy (subset of "2b")

(1) Monoclonal gammopathies of undetermined significance

(MGUS)

(2) Osteosclerotic myeloma

(3) Multiple myeloma (large proportion are axonal)

(4) Waldenstrom’s macroglobulinemia

(5) Castleman's disease

(6) Other lymphoproliferative disorders

(7) SLE/vasculitis

(8) Lymphoma

(9) AIDS

(10) Uremic associated CIDP

f) Diabetic polyneuropathy

g) Multifocal demyelinating neuropathy with conduction block

h) Other disorders that fulfill demyelination criteria (but may not

have actual demyelination)

(1) Arsenical polyneuropathy during acute stages

(2) Cytosine arabinoside (ara-C)

(3) Doxorubicin

(4) Amiodarone

(5) Perhexiline maleate

Page 6 of 13
 (6) Hexane

3. Axonal, motor > sensory

a) Acute intermittent porphyria

b) HMSN type II (axonal Charcot-Marie-Tooth disease)

c) Dapsone

d) Vincristine

e) Disulfiram

f) Insulin

g) MISSING TEXT HERE

4. Axonal, predominant sensory polyneuropathy or neuronopathy

a) Paraneoplastic

b) Congenital sensory

c) Cis-platinum

d) Metronidazole

e) Pyridoxine

5. Axonal, sensory > motor polyneuropathy

a) Friedreich's ataxia

b) Leprosy

c) Rheumatoid arthritis

d) Sarcoidosis

e) B12 deficiency

f) Nitrous oxide

g) Amyloid

Page 7 of 13
 6. Axonal, mixed sensorimotor polyneuropathy

a) Most toxic/metabolic neuropathies

b) Uremic polyneuropathy

c) Nitrofurantoin

d) Thalidomide

e) Mercury

f) Chronic alcohol

g) INH

h) Organophosphorus compounds

(1) Tri-ortho-cresyl-phosphate ("ginger-jake paralysis")

(2) Parathion

i) Acrylamide

C. Sources of Error

1. Errors of omission (drawing conclusions based upon a limited data base)

2. Overemphasis upon value of "conduction velocity"

a) Evoked amplitudes are most sensitive indicators of axonal

degeneration.

3. Failure to measure and maintain limb temperature

a) Surface temperature of 34°C (32-36°C) optimal

b) Conduction velocity increases by 2 m/s/°C with increasing

temperature

c) Distal latency decreases by 0.2 m/s/°C with increasing

temperature

d) Sensory amplitudes decrease with increasing temperature and

increase with decreasing temperature

(1) Decreased temperature results in less temporal dispersion.

Page 8 of 13
e) Warming best accomplished by submerging limb; hydrocollator
packs also effective. Heaters maintain temperature but limited
use in raising temperature.

Page 9 of 13
 TABLE I
Polyneuropathy Protocol
A. Conduction Studies

1. Test most involved site if mild or moderate, least involved if severe.

2. Peroneal motor (EDB); stimulate at ankle and knee. Record F-response latency
following distal antidromic stimulation.

3. If abnormal, tibial motor (abd hallucis); stimulate at ankle; record F-response

latency.

4. If no responses:

a. Peroneal motor (anterior tibial); stimulate fibula and knee.

b. Ulnar motor (hypothenar); stimulate below elbow and wrist. Record F-

response latency.

5. Sural sensory (ankle); stimulate 14 cm from recording electrode; perform

conduction velocity unless amplitude super-normal. If not clearly normal
because of age or technical factors, consider:

a. Needle recording

b. Averaging

6. Median sensory (index); stimulate wrist and elbow. If antidromic response is

absent or a focal entrapment is suspected, record from the wrist stimulating the
palm.

7. Additional peripheral nerves can be evaluated if findings equivocal. Definite

abnormalities should result in:

a. Evaluation of opposite extremity

b. Proceed to evaluation of specific suspected abnormality

8. Skin potential responses (measure of autonomic function)

Page 10 of 13
B. Needle Examination

1. Anterior tibial, medial gastrocnemius, first dorsal interosseous (hand), and

lumbar paraspinal muscles

2. If normal, intrinsic foot muscles should be examined

3. An abnormalities should be confirmed by examination of at least one

contralateral muscle

Page 11 of 13
 TABLE II
Electrodiagnostic Criteria Suggestive of Demyelination

Demonstrate at least one of the following in 2 or more nerves (exceptions noted):

A. Conduction velocity less than 95% of lower limit of normal if amplitude exceeds 50% of lower
limit of normal, less than 85% if amplitude less than 50% of lower limit of normal.

B. Distal latency exceeding 110% of upper limit of normal if amplitude normal, exceeding 120%
of upper limit of normal if amplitude less than lower limit of normal.

C. Evidence of unequivocal temporal dispersion or a proximal to distal amplitude ratio less than
0.7.1,2

D. F-response latency exceeding 120% of upper limit of normal).1,3

1
Excluding isolated ulnar or peroneal nerve abnormalities at the elbow or knee respectively.
2
Excluding the presence of anomalous innervation (e.g. median to ulnar nerve crossover).
3
Excluding isolated median nerve abnormality at the wrist.

Page 12 of 13
 FIGURE 1
Models of Normal and Pathologic Nerve Conduction
A. B.

C. Legend:
A. Normal nerve consisting of 8 axons and
respective nerve fiber. Individual muscle
fiber action potentials are shown
following distal (top) and proximal
(bottom) stimulation. Summated CMAPs
are shown for each condition.

B. Results following severe axonal loss

(removed 75% fibers).

C. Results following multifocal demyelination

with conduction slowing and some
conduction block in some axons.

* Homogenous demyelination would

resemble “A” with prolonged latencies
and reduced CV but no increase in
temporal dispersion.

Page 13 of 13
INVITED REVIEW The acquired demyelinating polyneuropathies include acute (AIDP, Guil-
lain-Barre syndrome, GBS) and chronic (CIDP, dysproteinemic) forms
which differ primarily in their temporal profile. They are inflammatory-demy-
elinating diseases of the peripheral nervous System and likely have an im-
munologic pathogenesis. Although these neuropathies usually have a char-
acteristic presentation, the electromyographer plays a central role in their
recognition, since the demyelinating component of the neuropathy, which
greatly reduces the differential diagnosis, is often first identified in the elec-
tromyography laboratory. In AIDP, the electromyographer, in addition to es-
tablishing the diagnosis, can sometimes predict the prognosis. Recognition
of the chronic and dysproteinemic forms of acquired demyelinating poly-
neuropathy is important since they are treatable. The dysproteinemic forms
also may be associated with occult systemic disorders that also may re-
quire treatment, independent of the neuropathy.
MUSCLE & NERVE 12:435-451 1989

ACQUIRED INFLAMMATORY
DEMYELINATING POLYNEUROPATHIES:
CLINICAL AND ELECTRODIAGNOSTIC
FEATURES
JAMES W. ALBERS, MD, PhD, and JOHN J. KELLY, Jr, MD

Polyneuropat~iies arc frequently (I
nostic pi O M C I T ~ S , ~c5pec
~) i a ~ ~1 0y1 c~iiii(i‘iiis w h o tlo
not regiilarly deal with iiciii o r
o r who lac k .idccjiiCitc n c ~ i om r
siippoi I. In( t cnsed diagnostic yicld 111 polyiicur OF)-
‘ithies results frorn idc~ritifrc,it~on of the cliiiic,rl
and clectrotliagiio5tie c t i d r ‘ictcv i5tic5 ol tlciriyc~liii-
ntion.”“ Sonic investigators2’ If’ ~ i , i \ c r5tiin,ited
t h a t up to 25% of idiopithic neuiopntliics drc ‘111-
toimmuiic iri ri‘iturc, t l i c majorit y 1)ciiig of the tle-
myelinatirig type, irit luding ‘tc utc m c l c h r onic
forms tlif feririg prirn,irily in their tcnipornl pio-
file. Uot ti ar e inflanirn,itoi y-tterxiycliri,itirig ciiwasc4
o f peripher a1 nerves arid nerve’ I oot5, nlt hougli
there may be cxteri~ivcSCY ondai y ‘ixorid dcgcncr-
__ __
From the Neuromuscular Sectiori of the Ileparttnenls of Neurology anc
Physical Medicine arid Rehabilitation, The liriiversity of Mictiigan. Ann
Arbor. Michigan (Dr. Albers) arid Departrnent of Neurology, Tufts-New
England Medical Center, Boston, Massachusetts (Dr. Kelly).
Acknowledgement. We thank Pamela Wilson foi her skillful secretarial as
sistance in the ptepxration of this manuscript
Presented in part at the Amcrican Association of Clectromyography ar:d
Electrodiagnosis Tenth Annual Continuirig Education Course. Irnmuno
logic Disorders of Peripheral Nerves, Sail Antonio, Texas, October 15,
1987.
Address reprint requests to Dr Albers at the Department of Neurology,
The University of Michigan Medical Center, 1500 Easi Medical Center
Drive, 1C32510032 Uti, Ann Arbor, Michigan. 48109 0032.
Accepted for publication May 18, 1988
0148 -639X11206/0435 $04 00117
0 1989 John Wiley & Sons, lric
‘ition. Specific etiologies have not been identified,
but ininiunologic rncchanisrns dmost cer tairily are
involvcct. A ~ n ~ i j o ativanc
r e has heen the recogni-
tion a i i d iiiicter~tariclirigof ctcmyelinating n e ~ iop- i
‘ i t k i i o r i ~ s o ica t e d with plasma (ell dysc rasias. Al-
though lewer in riurnber, they are important
Ixx < I I I S C the c i r c ulntiiig rrionoclonal protein itself
likely dnmage5 iici vc fibers. Under standing the
iriec h a n i ~ n i sinvolved rnny help clarify the nicc ha-
i i 5 r i i s of other obscure neuropathies, as well. 1lie
evnluatiori of patients with suspected acute inflam-
malory dcniyclinating polyneuropathy (AIDI’,
(;iiillaiii-lSarrk syndrome, GISS), or c hronic in-
flarnriiatoi y tlernyelinating polyneuropath y (CIDP)
iricliitics clct trodiagnostic examination, such as
th‘it shown in Table I . Ihis examination is di-
rcc tcd tow,ird detec ting evidence of segnierital or
rnirltifocal ttcrnyelinatiori.
ACUTE INFLAMMATORY DEMYELINATING
POLYNEUROPATHY
Clinical Features. T h e incitlcrice of AIIIP is 0.5-
1. ~ ~ / r ~ i i l l i o i i / r i i ~ ~increasirig
ritl~, slightly with advanc-
ing agc until about 75 ycary, nnd tlirniniShirig
thereaf~er.” I’here are 1 1 0 known genetic o r geo-
graphic predilections, although incitlerice is
slightly tiig~rcr for men tIiari for woincn 1)1‘1g-
riostic t i iter ia ai e ( t c w iptive arid based upon r cc-
ogiiition of ;I relatively ( hnracteristic clinical
pic ture.” ‘1 ypic a1 firitlings i n c ~ u d erapicily progres-

Inflammatory Demyelinating Polyneuropathy MUSCLE & NERVE June 1989 435

 Table 1. Suspected inflammatory-demyelinating polyneuropathy suggested electrodiagnostic protocol

Conduction Studiesa
1 . Test most involved site when mild or moderate, least involved if severe.
2. Evaluate the peroneal motor (extensor digitorum brevis); stimulate ankle, fibular head, and knee. Measure the F response
latency.b
3. If abnormal, evaluate the tibial motor (abductor hallucis); stimulate ankle and knee. Measure the F response latency.
4. If no responses, evaluate the
a. Peroneal motor (anterior tibial); stimulate fibula head and knee.
b. Ulnar motor (hypothenar); stimulate clavicle, elbow, below elbow, and wrist. Measure the F response latency.
c. Median motor (thenar); stimulate elbow and wrist. Measure the F response latency.
5.Evaluate the sural sensory (ankle); stimulate 14 cm from recording electrode; perform conduction velocity unless the
arnplitude is supernormal.
6 . Evaluate the rnedian sensory (index); stimulate the wrist and elbow. If antidromic response is absent or focal entrapment is
suspected, record from the wrist while stimulating the palm.
7 . Additional peripheral nerves can be evaluated if findings are equivocal. Definite abnormalities should result in
a. Evaluation of contralateral extremity
b . Proceeding to evaluation of specific suspected abnormality
8 . If promiriarit cranial involvement:
a. Evaluate the facial motor (orbicularis oculi): stimulate at the angle of jaw.
b. Conduct blink reflex studies (orbicularis oculi): stimulate the supraorbital nerve.
Needle Examination
1 Exarriine the anterior tibial, medial gastrocnemius, vastus lateralis, biceps brachii, interosseous (hand), and lumbar paraspirial
muscles
2 Any abnormality should be confirmed by exarrination of at least one contralateral muscle

Source Modified and reprinted from Ref 2 with the permission of John Wdey & Sons Inc Copyright 0 1985
VVords in parentheses indicate recording site for conduclion studies
bA// F response latericy measurements are for distal stimulafion sites on/)

sive weakness, often with bulbar and respiratory
iiivolvemeiit; liyporef-lexia o r areflexia; slightly di-
minished sensation; autonomic dysfunction; and
cerebrospinal fluid (CSF) protein elevation with-
out p]eocytosis."7.48,"8.88.""
An antecedent event, most commonly a respi-
ratory tract infection or gastroenteritis, is evident
within 1 nionth (an average of 15 days) in over
(iO% of' ~ i a t i e n t sOther
.~ antecedent events include
other infections (e.g., hepatitis 13, Epstein--Barr
virus, cytornegalovirus, toxoplasmosis), immuniza-
tioii,83 malignant disease, and surgery.5 AIDP also
has been associated with acquired HIVl infec-
tions, Lyrne disease, Hodgkin's disease, and non-
Hodgkin's lymphoma.59
Initial manifestations include syrrinietrical mo-
tor and/or sensory syniptorns.4 -I'he niost common
complaint is leg weakness,5 and many patierits
demonstract spread in a distal-to-proximal fash-
ion. Prominent. facial weakness occurs in about
50% of patient^,^ anti unilateral facial involverrielit
tias been described in up to 10% of patients,4 con-
sistent with an isolated mononeuropathy superim-
posed on a generalized polyneuropathy. Other
cranial nerve involvement leads to weakness of
mastication, swallowing, and, rarely, eye move-
ments." Despite common sensory symptoms, ob-
jective sensory loss is infrequent. ''' When present,
large myelinated fiber modalities (vibratory and
joint position sensations) are involved. Back arid
extremity pain are frequent complaints during the
early stages of the illness and may be severe.
Autonomic nervous system involvement in-
cludes bowel and bladder impairment, cardiac
dysrhythmia, labile heart rate and blood pressure
resulting in hypertension or hypotension, and
impaired thermoregulation."~~ The syndrome of
inappropriate antidiuretic hormone secretion
(SIADH) has been associated with AIDP, perhaps
related to abnormalities of autonomic afferents
arising from vascular stretch receptors."8375
The Fisher syndrome is considered a variant of
AIDP, consisting of ophthalmoplegia, ataxia, and
areflexia.?' I The temporal profile arid CSF h i d -
ings are indistinguishable from AIUP, and elec-
trodiagnostic studies in some patierits show a de-
myelinating polyneuropathy.35 Although some
consider the syndrome a brainstem encephalitis,"'
others") propose peripheral explanations for all of
the clinical signs.
The interval from the first neurologic syrnp-
tom to peak impairment is less than 20 days in
over 75% of patient^,^ arid 50% of patients reach
their nadir by 2 weeks.'" Progression exceeding 4
weeks should be viewed cautiously and alternative
diagnoses considered. Diaphragm and intercostal

436 Inflammatory Demyelinating Polyneuropathy MUSCLE & NERVE June 1989

muscle involvement leads to respiratory paralysis
in about 30% of patients. Mechanical ventilation
usually is initiatcd between 6 and 18 days after on-
set (mean of 10 days).4 Initial improvement is ob-
served within 40 days in over 80% of the patient^,^
and the overall prognosis is quite good, with most
patients demonstratin substantial clinical recov-
ery within G 111ontlis.~3 0
‘The question of relapse in AIDP is difficult be-
cause of potential confusion with other disorders
associated with relapsing polyneuropathy, includ-
ing acute intermittent porphyria,3 systemic lupus
erythematosus, and the chronic relapsing forms of
inflammatory polyneuropathy . Distinct relapses in
patients with otherwise typical AIDP do occur, al-
though the rate is probably less than 5%. In the
multicentcred, randomized trial of plasma ex-
change in the treatment of AIDP,90 four relapses
were reported out of 254 patients during the
study period.
Electrophysiologic Findings. A variety of elec-
trodiagnostic firidings has been report-
,d,‘,29,5 1,62,63,74,78.79
perhaps due to the temporal
changes that occur in response to cumulative de-
myelination and axonal degeneration. The syn-
drome also may encompass patients with primary
axonal degeneration as well as patients with severe
distal conduction block resembling axonal
degeneration.“0fH’Nevert.heless, the majority of
patients demonstrate an evolving picture of a de-
myelinating polyneuropathy with superimposed
axonal degeneration.‘ A model of peripheral nio-
tor nerve, useful in predicting the electrophysio-
logic firidings in multifocal demyelination, is de-
ST I M U L AT E
ULNAR NERVE
RECORD F R O M
HYPOTHEN A R
MUSCLES
I -
FIGURE 1. Abnormal temporal dispersion with partial conduction block of ulnar compound muscle action potential, recording from hy-
pothenar muscles of patient with acute inflammatory demyelinating polyneuropathy.
Inflammatory Dernyelinating Polyneuropathy
scribed in the Appendix. Included is a discussion
of the importance of abnormal temporal disper-
sion in distinguishing acquired from hereditary
demyelinating polyr~europathies.~~
Studies performed early in the course of
AIDP, when the diagnosis may be unclear, often
demonstrate only delayed or absent F responses
or H reflexes. Occasionally F responses appear
normal but are difficult to elicit. During subse-
quent examinations, evidence of segmental con-
duction block and conduction slowing become ap-
parent, with abnormal temporal dispersion of
evoked responses, reduced conduction velocity,
and prolonged distal latency. ItlenLification of ab-
normal temporal dispersioii and partial conduc-
tion block is the most reliable electrodiagnostic in-
dicator of an acquired demyelinating. folyneurop-
athy “ but not diagnostic of AIIII’.’’* A charac-
teristic motor conduction recording fiwn a patient
with AIDP is shown in Fig. I . The electrodiagnos-
tic recognition of primary dem yelination is inipre-
cise and depends upon identifying abnormalities
that cannot be explained by axonal involvement
alone. This differentiation is most straightforward
in acute disorders in previously well individuals
without other sources of conduction slowing. Cri-
teria suggestive of acute dernyelination (Table 2)
have been modified from those initially proposed
by Kelly,@‘ recognizing that the distinction be-
tween “demyelination” and “axonal degeneration”
is not always clear.
Evidence of segmental demyelination is pres-
ent in about 50% of patients during the fjrst 2
weeks of illness.1.2 This increases t o 85%’during
the third week of illness. Throughout the course
Jy5mu
2ms
Wrist
LIJ5mV
& = ;I”bsow
-
J Imv
MUSCLE & NERVE June 1989 437
 Table 2. Criteria suggestive of demyelination in the electrodiagnostic evaluation of acute inflammatory polyneuropathy

Demonstrate at least three of the following in motor nerves (exceptions noted below)
1 Conduction velocity less than 90% of lower limit of normal if amplitude exceeds 50% of lower limit of normal, less than 80% if
amplitude lcss than 50% of lower limit of normal (two or more nerves) a
2 Distal latency exceeding 115% of upper limit of riormal if amplitude normal exceeding 125% of upper limit of normal if
amplitude less than lower limit of normal (two or more nerves)
3 Evidence of unequivocal temporal dispersion or a proximal to-distal amplitude ratio less than 0 7 (one or more nerves)
4 F-response latency exceeding 125% of upper limit of nurmal (one or more nerves) a

Source: Modifred arid reprmted from Ref. 2 with the permission of John Wiley & Sons, Inc., Copyright 0 1985.
"€xclud!ng isolated ulnar of peroneal nerve abnomalities at the elbow or knee, respectively.
bExcluding rsoiated median nerve abnormahty at the wrist.
'€xcluding the presence of anomalous innervation (e g., median to ulnar nerve crossover)

of' AIDP, 10%of patients never fulfill electrodiag-
nostic criteria for rlerriyelinat.ion tle(:i>useresponses
are unobtainable. A 4 b o ~ 3%
~ tof patients sr.utlied se-
quentially dernonstrate evidence of axonal degen-
eration only. Motor nerve abnormalities peak be-
tween the third and fourth weeks, although indi-
vidual patients may demonstrate absent cvoked
responses within days of onset, presumably re-
flecting distal conduction block, and/or axonal de-
generation. Conversely. some patients demon-
strate progressive amplitude loss through i.hc fifth
or sixth weeks. Patients having only prolonged di-
stal latencies during the first 3 weeks of illness5'
may demonstrate partial conduction block and con-
duct.ioIi velocity slowing in the following weeks.
The degree of conduction block, not the
amourit of motor conduction slowing, best corre-
lates with clinical impairment. Sequential CI\?IAP
amplitude recordings for proximal and distal
stimulation for one patient are shown in Fig. 2.
The reduced CMAP amplitude with proximal
stiniulation (clavicle) cannot be explained by t.em-
pcml dispersion alone and likely represents par-
tial condiiction block. Early recordings demon-
strated progressively decreasing amplitudes, re-
flecting axonal degeneration o r progressive con-
duction block. During subsequent recordings
when the neurologic impairment was unchanged,
the evokctl amplitude with distal stimulation im-
proved dramatically. This rapid improvement
cannot be explained by axonal regeneration or
collateral rcinnervation but is explainable by re-
versal of distal conduction block.
During the first few weeks of illness, motor ab-
normalities ar-e much ~iiorecornnion than sensory
abnormalities. Motor and sensory evoked ampli-
tudes expressed as ii percentage of the normal
mean were averaged for 70 patients with AIDP
(34 patients had sequential evaluations) versus
time after disease onset and are shown in Fig. 3.2
Although almost of patients have SOIIIC ino-
tor conduction abnormalities during the first few
weeks of illness, only 2570 of patients have sensory
abnormalities during the same interval. Ry the
third week, however, almost 80% of palierits had
abnorrnal sensory studies. Motor abnormalities for
a given patient tended to be homogeneous, with
the lower limbs showing greater involvement than
the uppcr limbs. Conversely, sensory studies fre-
quently demonstrated abnormalities of individual
nerves. Sural and median sensory conduction
studies are shown in Table 3 . During initial evalu-
ation, a common finding was an abnormal median
sensory response with normal sural nerve conduc:-
tion studies.'9 'I'he median sensory nerve action
potential (SNAP) usually was absent or markedly
reduced in amplitude with prolonged distal la-
tency. Patients wit.h an abnormal surd and normal
median sensory conduction study, a firidirig char-
acteristic of most mild, chronic polyneuropathies.
were uncornmon. This finding of a normal, rela-
tively spared sural response in the presence of an
abnormal median sensory response, in association
with the appropriate clinical syndrome, is chariic-
teristic of AIDP.
Several explanations exist for the discrepancy
between motor and sensory studies as well as the
discrepancy between the sural and median sensory
conduction studies. Neurornuscular transmission
failure following a distal axonal lesion would re-
sult in reduc-ed CMAP amplit.udes prior to reduc:-
tion in SNAP amplitutles. If the aniount of rriyeliri
protected the axon or preserved conduction, the
larger myelinated sensory fibers would be prefer-
entially preserved relative to the smaller motor fi-
bers. This also could explain prolonged sural
nerve function compared to median sensory func-
tion, because the sural recording is obtained from
the more proxirnal nerve as compared with the
terminal median sensory fibers. This distal predi-
lection is consistent wirh reported centripetal de-
rriyelinatiori in sonic patients" and also consistent

438 Inflammatory Demyelinating Polyneuropathy MUSCLE 13NERVE June 1989

 AMPLITUDE
(MV) 4
14-- wrist
13 -. elbow

I?-- clavicle
11..

to--

9 -.

8.-

7 ..
6 --

5--

4 --
3--

2 -.

I
25 50 1W 150 200 250 300 333

TIME FROM ONSET (DAYS)

FIGURE 2. Serial ulnar compound muscle action potential amplitudes with proximal and distal stimulation, recording from the hypothe-
nar muscles of a patient with acute inflammatory demyelinating polyneuropathy. Amplitudes (mV) are expressed as a function of time
from disease onset. (Reprinted with permission from Albers JW: Electromyography in the prognosis of nerve injury. American Academy
of Neurology Special Course #22: Clinical Electromyography, 1980.)

with the observations of Sumner,H9who found, us-

ing a humorally induced demyelination in rat sci-
atic nerve, that smaller diameter myelinated fibers

t
T T were affected earlier and more completely than
larger diameter fibers. Nerve roots were highly
5 80
W permeable to antiserum: and distal motor nerve
3
r- twigs and cummon compression sites were identi-
2 60
fied as potential areas of vulnerability because of
5
-I an impaired blood-nerve barrier.
f 40 Electromyography (EMG) has a secondary role
0
in evaluating patients with AIDP. Decreased nio-
B
w 20
0 tor unit action potential (MUAP) recruitment,
b without evidence of conliguration abnormalities or
W

e
- I 2 3 4 5 6-10
TIME (Weeha)
11-15 16-25 26-35 36 50
abnormal spontaneous activity, is the initial find-
ing, reflecting the clinical distribution of weakness.
FIGURE 3. Motor- (open bar) and sensory- (shaded bar) evoked Occasionally, myokymic discharges are observed
response amplitudes expressed as a percentage of the normal during the first few weeks of illness.'s They may
mean as a function of time after disease onset in 70 patients be found in facial or extremity muscles and may
with acute inflammatory demyelinating polyneuropathy. The re-
be present in the absence of clinical myokymia. Fi-
sponses are significantly ( P < 0.05) different for weeks 1, 2, and
3. No significant differences exist thereafter. (Reprinted from brillation potentials and positive waves appear be-
Ref. 2 by permission of John Wiley & Sons, Inc, Copyright Q tween 2 and 5 weeks, sirnultarieously in proxiiiial
1985.) and distal muscles (Fig. 4), consistent with either

Inflammatory Devyelmating Polyneuropathy MUSCLE & NERVE June 1989 439

 Table 3. Comparison of median and sural sensory conduction studies in patients with acute Inflammatory demyehnating
polyneuropathy results at the time of initial and follow-up evaluation
All studies (ri =
Both normal 30 (35%)
Both abnormal 20 (23%)
Median abnormal and sural rormal 36 (42%)
Median normal and sural abnormal 0 (0%)
Source Mod/f/edand reprmted from Ref 2 w/th the permission of John Wdey & Sons Inc Copyright
random axonal degeneration at any point along
the axon or predominant distal involvement.
Proximal fibrillation potentials are maximal be-
tween 6 and 10 weeks, with distal fibrillation po-
tentials persisting for many months. 'l'he amount
of abriorrrial spontaneous activity ranges from
none to extensive denerviition with profuse ( 4 t )
positive waves and fibrillation potentials. The
early reduction in fibrillation potentials in proxi-
mal compai-ed with distal muscles likely reflects
reinnervation from axonal sprouting or regenera-
tion in proximal compared with distal muscles.
This can be explained both by the greater proba-
bility of' regeneration in a short axon and by the
increased likelihood of' collateral reinnervation
from a greater number of surviving axoris.
Prognostic Indicators. Clinical and CSP findings
are poor predictors of outmme in patients with
A prolonged interval to onset of- recovery
indicates a poor prognosis, t i 0 LIS does rapid evolu-
,
tion of weakness and ventilator dependency."5
m 2
3
s
2
F
z upon both the extent and rate of respiratory dete-
gl
In
J
H
0 ally are needed if the forced vital capacity falls
5 0
a I 2 3 4 5 6-10 11-15 1625 2635
TIME rweoksl
FIGURE 4. Abnormal spontaneous activity in proximal (open
bar) and distal (striped bar) muscles as a function of time after
disease onset in 70 patients with acute inflammatory demyeli-
nating polyneuropathy. Fibrillation potential scores range from 0
to 4+, with 0 = none and 4+ = profuse fibrillation potentials in
all areas of muscle. (Reprinted from Ref. 2 by permission of
John Wiley & Sons, Inc., Copyright B 1985.)
440 Inflammatory Demyelinating Polyneuropathy
86) Initial eval first 3 weeks (n = 39) Follow-UP(n = 39)
11 (28%) 13 (33%)
9 (23%) 13 (33%)
19 (49%) 13 (33%)
0 (0%) 0 (0%)
1985
Nevertheless, some ventilaltor-dcpendent patients
recover promptly arid comlpletely, whereas seem-
ingly identical patients havq: a prolonged recovery.
The most powerful predicwr of poor outcome is
reduced ChilAP amplitude to less than 10% of the
lower limit of nornial.6G Neurologic recovery is
positively and significant11 correlat.ed with pre-
served mean CMAP anipliitude, when the studies
are performed between weeks 3 and 5. .I'hese
findings support the hypothesis that evidence sug-
gestive of predominant demyelination is corre-
lated with relatively rapid recovery. whereas find-
ings suggestive of severe ;ixonal destruction are
correlated with slow rec~very."~'" The amount of-
fibrillation is a relatively poor predictor of prog-
nosis when used alone.
Treatment. The supportive treatment of patients
with AIDP involves maintenance of respiralory
function and prevention of' circulatory failure arid
throniboembolism.' T h e advent of respiratory
intensive care units has been important in preserv-
ing life, although a mortality rate of approxi-
mately 5%' persists even with aggressive pulmon-
ary treatment. Most dcatbs follow medical compli-
cations of respiratory parxlysis, including pneu-
rnonia.42Approximately half. of patient deaths are
sudden, presurndb\y related lo cardiac dysrhyth-
mias or hypotension. All p;i.tients require observa-
tion for respiratory deterio-ration. 'L'he decision of
whether o r not to intubate a patient depends
rioration. General thresholds are difficult to de-
fine, but intubation and rebpirator support gener-
36-50
below 13 mlikg. Elective inrubation should be per-
formed if there is a rapid decline of vital capa(:ity,
early signs of h ypoxia, aspiration with poor tra-
cheopulmonary toilet, pullnonary infection with
shunting, or signs of' respiratory distress or fa-
tigue. Arterial Mood p s e s represent a poor mea-
sure of respiratory function. detcriorating 1at.e in
the clinical course. ,4 low 1 1 0 2 and low or normal
MUSCLE 8, NERVE June 1989
PCO, indicates shunting from early atelectasis and
often precedes respiratory h i l ~ i r e .Hypercapnia is
a late finding of respiratory failure and dangerous
criterion for elective intubation. Prolonged intuba-
tion without tracheostoniy is now possible with
soft endotrachial tubes, although met.iculous tra-
cheopulmonary toilet is hcilitated by trache-
ostomy, and the use of' a talking tracheostoniy may
facilitate psychological care.
Autonomic instability requires monitoring in
an intensive care setting. Hypotension is best man-
aged by increasing fluids, and sympathominietics
usually are avoided. Hypertension is best not
treated unless severe. When necessary, rnedica-
tions with a short half-life such as nitroprusside or
propanalol are preferred. T h e most common car-
diac dysrhythmias are a second- or third-degree
AV block. Temporary pacemaker insertion is an
effective treatment.
Additional medical management includes
proper bladder care, prompt identification and
treatment of superimposed infection, restriction
of fluids in patients who are hyponatremic, and
antiembolism protection, including low-dose hepa-
rin (5000 units subcutaneous twice daily) and anti-
embolus stockings in quadriparetic patients. Ap-
propriate laboratory studies should be performcd,
nionitoring for occult blood loss, anemia and
thrombocytopenia, infection, and electrolyte im-
balance.
Corticosteroids are of unproven efficacy in
AIDP, and their use is corirroversial. The most re-
cent controlled studyg9 reported that prednisone
may have slowed the recovery rate and increased
the chance of relapse. Anecdotal reports24 exist of
single patients who responded dramaLically to sle-
roids.
T h e potential importance of humoral factors
in the pathogenesis of AIDP suggested that thera-
peutic plasma exchange (.l'PE) might modify the
disease course." The niulticeri~er randomized
trial of TPE in the treatment of ,41DP9" dcmon-
strate'd significant benefit of TPE when compared
with conventional medical treatment, excluding
steroids. Hy all criteria, 'L'PE had a beneficial ef-
fect. T h e median time on a respirator was re-
duced by 1 1 days and the time to unassisted am-
bulation shortened by an average of 73 days lor
respirator-dependent patients who received TPE.
Similar- rcsults have tieen reported in two ad-
ditional controlled, randornized trials. "." Two
smaller controlled trials were inconclusivc, al-
though the trends favored the TPE group."'."3
TPE is not effective for all patients. Patient age
Inflammatory Dernyeltnating Polyneuropathy
and the CMAP amplitudes are important predic-
tors of early r e s ~ ~ ~ ~ i ~ s i " eTPE
, i ~ sappears
s . ~ 4 partic-
ularly effect.ive for pat.ients w h o begin treatment
within 7 days of disease onset, although early, ag-
gressive TPE may be associated with initial im-
provetrierit followed by relapse, perhaps related to
termination of treatment too early in the course of
the disease."
CHRONIC INFLAMMATORY DEMYELINATING
POLYNEUROPATHY
Clinical Features. CIDP is a chronic progressive
or relapsing disorder' of peripheral nerves that
c:linic:ally resembles AIDP. Reliable incidence esti-
niat.es are unavailable, although it is probably less
than that of AIDP. Because of the prolonged
course, however, I he prevalence probably exceeds
t.hat of AIDP. CIDP occurs in both sexes and all
ages wilt1 little evidence of peaks other than a pre-
dominance in the fifth and sixth decade^.^'
Diagnostic criteria differ o n l y slightly for those
used for AIDP. At present, the only reliable
method for differentiating the two disorders is by
an arbitrary clinical judgment regarding the tem-
poral evolution of neurologic symptoms. Patients
with CIDP usually have an interval between onset
and peak impairment exceeding 4 weeks, and the
average duration from onset to peak deficit aver-
ages approxiniately 3 months, with a range of 3
weeks to 16 months."
CIDP is characterized by sensory loss and
weakness, areflexia, elevated CSF protein, and
electrodiagriostic evidence of multifocal demyeli-
nation with or without superimposcd axorial
degeneration.~5~'fi~''1'I'he etiology is unknown, but
the results of nerve biopsy and reports of re-
sponse to s t e r o i c ~ s , ' ~a' ~ a~t l i i o p r i n e , ' ~ .or
~~
TPE":' ,84,85,92 suggest an immunologic etiology."
~~
An identifiable antecedent event is rare compared
with AIDP, although CIDP has been associated
witti iiniiiune complexes of tiepatitis B virus.41
Symmetric sensory aridior motor symptoms are
the initial manifestation, and weakness usually be-
gins in the legs. Karely, asymmetric findings are
present, consistent with rnultifocal demyeliriatirig
mononeuropathies.~'Cranial nerve involvenient is
common, especially orbicularis oculi weakness, but
less prominent than iii AIDP. Maximal weakness
usually is distal, and 15 of the 23 patients de-
scribed by Prineas arid McLeod" were nonambu-
latoi-y during their most severe episode. Occa-
sional patients require respiratory support, either
during an exacerbation or during the terminal
phase. Muscle wast.ing may bc severe but often is
MUSCLE & NERVE June 1989 441
rnild compared with the degrec and severity of
muscle weakness. Sensory symptoms and signs usu-
ally are mild but may be associated with a sensory
ataxia. All modalities of sensation may be affect-
ed." although large fiber loss predominates. Mus-
cle stretch reflexes are usually absent at some time
during the illness; rare patients fulfill all other di-
agnostic criteria but have hypoactive, preserved
reflexes. Autonomic involvement is uncommon.
The clinical course in CIDP is variable. The
term chronic relapsing polyneuropathy (CRP) has
been used to describe patients with clear relapses
and remissions. Dyck and associates26 estimated
that approximately 50% of-patients had a progres-
sive course (slow or stepwise), one-third had a re-
lapsing course, arid the remaining patients experi-
enced a monophasic illness with the peak deficit
remaining or developing after 6 months. W-ith
current treatments, many patients who may have
had progressive disease seemingly respond to
treatment but relapse when therapies are tapered
or discontinued. The distinction between therapy-
associated relapse in CIDP and idiopathic relapse
in CRP is unclear.
In CRP, the average interval between relapses
is about 10 months, although relapses have been
reported 3 1 years after initial attacks.77 Patients
with CRP may remit after many years, without
further exacerbations. In early reports of outcome
for 53 patients with CIDP who were followed for
an average of 7 years, 9 died (6 from the disease),
6 were confined to wheelchair or bed, 36 had a
mild to moderately severe impairment, and only 2
had complete resolution.26 Recent experience sug-
gests that more patients experience remission,
with fewer patients demonstrating progressive de-
terioration. This may reflect earlier detection and
treatment or recognition of milder cases.
Electtophysiologic Features. The electrodiagnos-
tic findings in CIDP resemble those described late
in the course of AIDP and are consistent with
multifocal demyelination with variable amounts of
superimposed axonal degeneration. The chronic
progressive, stepwise progressive, and relapsing
forms cannot be differentiated electrophysiologi-
cally. Electrodiagnostic criteria suggestive of de-
myelination in CIDP ('Table 4) differ slightly from
those described for AIDP. These differences re-
flect the possible development of axonal stenosis
or regeneration, changes that may result in sub-
stantial conduction slowing without segmental de-
myelination. Nevertheless, electrodiagnostic evi-
dence of demyelination is present in virtually all
patients with CIDP, and many consider this part
of the diagnostic criteria. Motor conduction ve-
locities may be markedly reduced, F response la-
tencies very prolonged (or absent), and temporal
dispersion more prominent than observed in
AIDP, although individual variations are large.
The combination of absent or abnormal SNAPS
with normal sural responses occurs but is uncom-
mon in CIDP compared with AIDP. EMG abnor-
malities are present in most patients with CIDP.
Like AIDP, needle examination is useful for de-
fining the chronicity and extent of axonal degen-
eration.
Treatment. T h e supportive care of patients with
CIDP is identical to that described for AIDP. Un-
like AIDP, corticosteroids are of demonstrated
benefit in controlled trials of both the CRP and
CIDp.8,26,27,77,91Many prednisone treatment pro-
tocols exist, including high-dose daily or alternate-
day schedules, with slow taper depending upon
clinical response. Azathioprine also has been re-
ported to be effective in several case reports and
small clinical trials of CIDP patients,94 including
patients previously steroid unresponsive or intoler-
ant.72
Isolated case re orts described TPE as benefi-
in (;IDp."',5Y,6r84 A consecutive patient trial
of TPE demonstrated substantial clinical improve-
ment within 3 weeks in about 50% of progressive
CIDP patients." The temporal association be-
tween improvement and TYE in patients with

Table 4. Criteria suggestive of dernyelination in the electrodiagnostic evaluation of chronic inflammatory polyneuropathy

Evaluation should satisfy at least three of the following in motor nerves (exceptions noted below)
1 Conduction velocity less than 75% of the lower limit of normal (two or more nerves) a
2 Distal latency exceeding 130% of upper limit of normal (two or more nerves)
3 Evidence of unequivocal temporal dispersion or conduction block on proximal stimulation consisting of a proximal-to-distal
amplitude ratio less than 0 7 (one or more nerves)
4 F-response latency exceeding 130% of upper limit of normal (one or more nerves) a

"Exciudmg /solafed ulnar or peroneai nerve abnormalmes at the elbow or knee, respectwely
'Excludmg /so/atedm e d m nerve abnormahty at the wnst
'Excludmg the presence of anomalous innervation (e g medmn to ulnar nerve crossover)

442 Inflammatory Demyelinating Polyneuropathy MUSCLE & NERVE June 1989

longstanding, progressive deterioration seemed
more than coincidental. A subsequent prospective
double-blind trial in which patients with static or
progressive CIDP were randomized to TPE or
sham exchange groups demonstrated significant
improvement in electrodiagnostic and clinical
measurements after 3 weeks, favoring patients re-
ceiving TPE?
DYSPROTElNEMlCOR PARANEOPLASTIC
NEUROPATHIES
A subset of patients with acquired dcmyelinating
polyneuropathy exists which differs from CIDP
only by the presence of an underlying systemic ill-
ness. Because the systemic illness may not be ap-
parent when the polyneuropathy is diagnosed,
these patients often are classified as having CIDP
or even RIDP, although most clinicians restrict
these terms lo exclude patients with systemic ill-
ness. Included are atients with Waldenstrorn's
* n a c r ~ ) ~ l o ~ ~ u I i n eganirria
~ i i a , ' ~ heavy chain dis-
ease:" cryoglob~linemia,~~ lymphoma,"' systemic
UPU US erythematosus,26Castleman's disease,l4 and
HIVI
Acquired demyelinating polyneuro athy rarely
can be due to an occult malignancy.'' The poly-
neuropathy with malignancy can be motor domi-
nant, distal and/or proximal in distribution, evolve
rapidly or slowly, and develop a relapsing or re-
mitting course. EMG and pathologic studies are
the same as in idiopathic cases. The etiology is as-
sumed to be an irnmunologic process triggered by
the underlying malignancy. The association is
rare, however, and there is no reason to routinely
evaluate all patients for a malignancy. Far more
common is the association of an acquired demyeli-
nat.ing polyneuropathy and a plasma cell dyscrasia
syndrome. Because of the high prevalence com-
pared with other systemic disorders, these syn-
dromes will be described further below.
Demyelinating Polyneuropathy Encountered in the
Plasma Cell Dyscrasia Syndromes. All idiopathic
polyneuropathy patients, anti particularly those
with presumed CIDP, should be evaluated for
possible occult plasma cell dy~crasias.'~'4 sug-
gested approach is detailed in Table 5. Up to 10%
of patients with idiopathic polyneuropathy harbor

Table 5. Flow chart for evaluation of polyneuropathy patient

Regular neuropathy evalution + SPEP

I
.1 J .1
Step 1 SPEP abnormal SPEP nornial SPEP normal

Ster, 2
v
Serum + urine IEP
or IF, 24 hr urine protein
(neuropathy severe) (neuropathy mild)
5
Treat symptoms + follow
(if neuropathy worsens)

4 J
If M protein found If no M protein found
1
i Consider sural nerve biopsy for amyloid
Step 3 Rematology evaluation and irnrnunofluorescence, consider
(bone marrow, rectal metastatic skeletal survey

--i
2 nerve biopsy,
skeletal survey, etc.) If positive

Step 4
I
Diagnosis made > If MGUS
If negative

I
Continue evaluation for idiopathic PN

6
Treat accordingly
__- Follow and reassess every year, treatment
as needed

SPEP = serum protein electrophoresis. IEP = ,mmunoelectrophoresrs, IF - imrnunohxation, MGUS ~ monocbnal gammopathy
Source Reprinted with permission from Kelly JJ Polyneuropathies associated with plasma cell dyscrasias, in Brown MJ fed) Seminars in neurobgy
Neuropathy 7 30-39 1987

Inflammatory Demyelinatiny Polyneuropathy MUSCLE & NERVE June 1989 443

 Table 6. Features of polyneuropathy M protein syndromes

Type of Sensory Autonomic CSF protein

polyneuropathy Topography Weakness loss loss Course elevation Pathology EMG

MGUS (IgM) Distal, symmetric ++ +++ 0 Chronic ++ SD Slow CV

MGUS Distal, rarely ++ ++ + Chronic ++ SD Slow or mildly slow
UgG, IgA) proximal CV
AL Distal, symmetric +/++ +++ ++ Chronic +
~ AD Mildly slow CV
QSM Distal, symmetric +++ +r 0 Chronic + +i+ + + SD Slow CV
(AD)
WM Distal, symmetric ++ ++ 0 Chronic ++ SD Slow CV

Note 0 = none. 2 = equivocal or occasional, + = minimal, ++ = moderate, +++

= marked, MGUS = monoclonal gammopathy, AL = amyloidosis,
OSM = osteosclerotic myeloma WM = Waldenstrom’s macroglobulinemia. SO = segmental demyelination, AD = axonal degeneration. CV = conduction
velocity
Source Reprinled with permission from Kelly JJ Polyneuropathies associated with plasma cell dyscrasias, in Brown MJ (ed) Seminars in neurology
Neuropathy 7 30-39, 1987

an occult plasma cell dyscrasia which may directly
relate to the etiopathogenesis of the neuropathy
and respond to treatment. These patients are of
investigational importance because the mono-
clonal protein may cauSe the polyneuropathy. The
features of the polyneuropathy in the different
plasma cell dyscrasia syndromes are summarized
in Table 6.
Primary systemic amyloidosis of the amyloiti
light-chain type forms an important subset of the
plasma cell dyscrasia syndromes. The polyneurop-
athy, however, is axonal and usually involves srnall
fibers without evidence of conduction slowing,
and therefore should not be confused with the de-
rnyelinating dysimniune polynenropathies. Simi-
larly, typical multiple myeloma is associated with a
very high monoclonal protein l e ~ e l ,widespread
lytic skeletal lesions, anemia, and hypercalcemia.
It is rarely associated with p o l y n e u r ~ p a t h y . ~ ~ of int.erest because one-half of these patients have
When it is, polyneuropathy is heterogeneous in
type with little relationship to the status of the niy-
elotna.
Monoclonal Gammapathy of Undetermined Signifi-
cance. In evaluating patients with presumed
CIDP, a monoclonal gammopathy occasionally is
identified. This hematologic disorder, referred to
as monoclonal gammopathy of undetermined sig-
nificance (MCUS), was formerly called “benign
monoclonal gammopathy” but was renamed be-
cause up to 20% of these patients develop more
serious hematologic disease or secondary changes
elsewhere, including n e ~ r o p a t h y By
. ~ ~definition,
these patients have a low monoclonal protein con-
centration (<3 g/dl), no malignant plasma cell in-
filtration of the bone marrow, and no bony lesions
(Table 7). This group accounts for about one-half
of plasma cell dyscrasia, polyneuropathy patients
(Table 8).
Patients with MGUS-associated neuropathy in-
clude IgM and non-IgM types. The IgM group is
a characteristic polyneuropathy , and the n1ono-
clonal immunoglobulin possesses antinerve activ-
ity, most commonly directed at an antigen on the

Table 7. Hematologic diagnostic criteria of M protein syndromes

Syndrome Anemia M protein serum M protein urine Bone marrow Skeletal survey Tissue biopsy

MGUS No +* ? 2 Normal -
AL +
+/-t ++ + + Normal ++ (amyloid)
MM -t++ +++*’ ++ +++ Abnormal (Iytic) + + + (myeloma)
OSM No +*h No ++i+++ Abnormal (sclerotic) + ++ (sclerotic myeloma)
WM +++ +++** ? ++I+++ f ~

GAMMA-HCD +++ + + ++ N ~

Note. -t = equivocal or occasional, + = rare, t +

= common, + + + = almost always or severely abnormal, MM = multiple myeloma, Gamma-HCD =
gamma heavy-chain disease, other abbreviations same as Table 6.
* Less than 3 g per deciliter
If More than 3 y per deciliter
A = Almost always lambda light chain.
Source. Reprintcd with permission from Kelly JJ: Polyneuropathies associafed with plasma cell dyscrasias, in Brown MJ (ed) Seminars in neurology.
Neuropathy 7.30-39, 1987.

444 Inflammatory Demyelinating Polyneuropathy MUSCLE & NERVE June 1989

 Table 8. Final hematologic diagnosis in 28 patients with
polyneuropathy and M proteins
Monoclonal gammopathy of undetermined significance
Arnyloidosis light-chain type
Myeloma (including osteosclerotic cases)
Waldenstrom s rnacroglobulinemia
Gamma heavy-chain disease
Total
Source Repnnted with permmion from Ref 46
myelin sheath.36*" The vast majority of patients
with antinerve-reactive IgM polyneuropathy have
a slowly progressive, sensory polyneuropathy
which superficially resembles the sensory neuron-
opathy syndrome seen with cancer. These neurop-
athies, however, tend to be much more chronic
and indolent, and weakness and atrophy may de-
velop when the neuropathy is advanced. Pansen-
sory impairment with sensory ataxia occurs. Other
cases are very mild and nonprogressive over sev-
eral years. Electrodiagnostic findings differentiate
these patients from those with pure sensory neu-
ronopathy. Motor conduction is markedly slowed
in the range associated with segmental demyelin-
ati~n,~ and
' CMAP amplitudes are reduced. Nee-
dle EMG confirms loss of motor axons. T h e CSF
protein is usually markedly elevated unless the
polyneuropathy is very mild.
Nerve biopsy demonstrates combined axonal
degeneration and demyelination. Direct immuno-
fluorescent staining for immunoglobulin^^^ shows
deposition of monoclonal IgM (Fig. 5) on the my-
elin sheath. The monoclonal protein is almost
always of the kappa light-chain type. Studies
have demonstrated in vitro reactivity of this im-
munoglobulin with myelin-associated glycoprotein
(MAG) and other carbohydrate epitopes of glyco-
proteins or glycolipids on the myelin shcath.40
Treatment with immunosuppressives and T'PE
decreases the itnniunoglobulin level and patients
may improve (Ref. 87 and Kelly et al., unpub-
lished). Injection of serum from these patients
into animal nerves causes focal d e m y e l i n a t i ~ n . ~ ~and may be sclerotic or mixed sclerotic and lytic
Karely, other IgM polyneuropathies are associated
with axonal degeneration, and IgM is deposited
on axons and perineurial tissue. Studies have
shown in vitro reactivity with axonal pellets and
axonal antigens such as chondroitin sulfate.86
Patients with nonreactive IgM neuropathies
form a more heterogeneous group. Some closely
resemble MAG-reactive polyneuropathies, and
some resemble axonal neuropathy. They may re-
Inflammatory Dernyelinating Polyneuropathy
spond to immunosuppression. T h e mechanism of
nerve fiber damage is unknown.
Patients with the IgG or IgA polyneuropathies
16
7
are a heterogeneous group, and a relationship, if
any, between the gammopathy and polyneuropa-
1 thy is not clear. Nevertheless, such patients may
1 have an unequivocal demyelinating polyneuropa-
28 thy indistinguishable from patients with GIDP- or
IgM-associated dysimmune neuro athy . Response
to immunosuppression is variable.7!
Osteosclerotic Myeloma. Osteosclerotic myeloma
differs from typical multiple myeloma.45Less than
3% of patients with osteosclerotic myeloma ac-
count for about two-thirds of cases of polyneurop-
athy in large myeloma series; about one-half of all
osteosclerotic myeloma patients have a polyneu-
ropathy. Osteosclerotic myeloma is more indolent
than multiple myeloma, occurs at a younger age,
and is associated with longer survival. The poly-
neuropathy tends to be slowly progressive, distal,
symmetric, and mainly motor, without autonomic
dysfunction. CSF protein is very high, and there is
frequently papilledema.
Electrodiagnostic findings"343s45 include
marked slowing of motor nerve conduction veloc-
ities, partial conduction block, and prolonged or
absent F-response latencies. SNAPS are decreased
or absent. EMG needle examination shows acute
and chronic neurogenic changes. Most patients
have nionoclonal protein of the lgG or IgA and
lambda light-chain type, but occasionally, kappa
light-chains are present. There are no reports of
direct immunofhorescent staining of nerves from
these patients, and the monoclonal protein is not
MAG-rea~tive.~'Microinjection of the serum into
animal nerves does not cause focal demyelination
or conduction The key to diagnosis is rec-
ognition of the monoclonal protein and bony le-
sions.
The polyneuropathy resembles monophasic
CIDP, and consideration of this diagnosis man-
dates protein studies and a metastatic skeletal sur-
vey. Bony lesions occur in the proximal skeleton
(Fig. 6). Biopsy of any suspicious lesion is manda-
tory. Treatment depends on the nature of the
plasmacytoma. If solitary, surgical extirpation or
radiation therapy is indicated, and patients im-
prove following effective treatment. Many, or pos-
sibly all, eventually relapse. If lesions are multiple,
chemotherapy occasionally provides benefit.21
Some patients' develop widespread findings
with polyneuropathy, organomegaly, endocrinop-
MUSCLE & NERVE June 1989 445
FIGURE 5. lmmunofluorescent staining shows intensely stained deposits of IgM especially along the outer lamellae of the myelin
sheaths of myelinated axons. Less intense staining is seen around t h e axon. (Reprinted from Ref. 37 with permission.)

FIGURE 6. Osteosclerotic lesions in patients with polyneuropathy (A) Mixed lytic and sclerotic lesion of the left ilium in a 56-year-old
woman (B) Multiple sclerotic lesions involving vertebral bodies, sacrum, ischium, and pelvis in a 42-year-old man (C) “Ivory” L-3 ver-
tebra in a 47-year-old woman. (Reprinted from Ref. 45 with permission )
athy, M protein, and skin changes (POEMS syn-
drome). This multisystem disorder also has been
called “Crow - Fukase syndrome” and “Takatsuki’s
sy~idrome”.’~ None of these terms is satisfactory
because they are too restrictive. Most of these pa-
tients have monoclonal proteins of the IgG or lgA
type with lambda light-chains. One-half to two-
thirds have osteosclerotic lesions. ‘I’he common
denominator may be the lambda light-chain or
some other secretory product of the plasma cell le-
sion. Thus, osteosclerotic myeloma may be one
end of a spectrum, with POEMS at the other.

CONCLUSION
Patients with acquired demyelinating polyneurop-
athies comprise a substantial portion of those
patients with undiagnosed polyneuropathies pre-
senting for evaluation. -1’heir importance is dis-
proportionate to their numbers, since many are
treatable, some are associated with unrecognised
systemic disorders, and most provide clues to the
etiopathogenesis of other obscure neuropathies.
Although their relationship is unclear, the acute,
chronic, and dysimmune infiammator y dernyeli- ‘=I
2~
nating polyneuropathies have characteristic pre-
sentations, some of which are easily recognized.
Not surprisingly, the electromyographer plays a
central role in the evaluation of these patients and
is in a position to recognize the patterns of in-
volvement and suggest possible diagnostic alterna-
tives. Thus, the ability to identify an acquired
demyelinating polyneuropathy, coupled with a
thorough knowledge of these syndromes, is ini-
portant for any electromyographer who studies
neuromuscular patients.

APPENDIX
Motor Nerve Model: Prediction of Electrodiagnostic
Findings in M’ltifocal Demyelinationm A silnple
model of the peripheral motor nerve can pre-
dict electrodiagnostic
” findinns
” in acute inflamma-
tory demyelinating polyneuropathy (AIDP). ’lhis
model, together with empiric electrodiagnostic
observations, can be used to anticipate the elec-
trodiagnostic findings for acute, multifocal demy-
elination. ‘I’he model is represented in Figs. 7-9,
consisting of eight axons of variable diameter,
ranging from the largest (top) to smallest (bot-
tom). Individual muscle fiber action potentials
(MFAPs) are shown to the right of each axon fol-
lowing stimulation of all axons (arrow). Conduc-
tion is fastest in the largesl and slowest in the
smallest axon; the difference in conduction bc-
tween the largest and smallest fibers constitutes
(CMAP) shown below each nerve in the schematic screen. Indi-
vidual axons are of slightly different sizes and therefore conduct
at different rates. Muscle fibers are denoted bv solid bars to the
right of each axon Arrows represent stimulation sites Upper re-
cording resultant CMAP following distal nerve stimulation
Lower recording: resultant CMAP following proximal nerve stim-
ulation. (Reprinted from Ref. 1 with the permission of Butter-
worths, Copyright 6 1987).
the range of conduction velocities. Individual
MFAPs dre summed to obtain a compound muscle
action potential (CMAP), shown below the mod-
eled Ilene. In the figures, the simulated CMAP is
demonstrated for distal nerve stiniulation (upper
half of each figure) and proximal nerve stimula-
tion (lower half of each figure). Latencies could be
calculated and a conduction velocity for the fastest
axon determined using the distance between stim-

Inflammatory Demyelinating Polyneuropathy MUSCLE & NERVE June 1989 447


FIGURE 8. Computerized model of axonal degeneration in pe-
ripheral motor nerve described in Fig. 7, following random loss
of 75% of axons. Resultant CMAP after distal (upper screen)
and proximal (lower screen) stimulation. Arrows represent stim-
ulation sites. (Reprinted from Ref. 1 with the permission of But-
terworths, Copyright 6 1987).
ulation sites. In this model of normal nerve (Fig.
7), the CMAP amplitude can be iiieasured follow-
ing proximal and distal stimulation. The reduced
CMAP amplitude following proximal stimulation
reflects the expected temporal dispersion of indi-
vidual MFAPs and would be increased if either
the distance between stimulation sites or the range
of conduction velocities were increased.
Following extensive axorial dcgerieratiori (Fig.
8), CMAP amplitude diminishes for both proximal
arid distal st.irriulation with little change in distal
latency or conduction velocity. If' the largest axon
had remained intact, conduction velocity anti tlis-
448 Inflammatory Demyelina:,ng Poiyneuropathy
1-1
FIGURE 9. Computerized model of multifocal demyelination in
peripheral motor nerve described in Fig. 7. Resultant CMAP af-
ter distal (upper screen) and proximal (lower screen) stimula-
tion. Arrows represent stimulation sites. The diminished CMAP
amplitude with proximal stimulation results from temporal dis-
persion of individual muscle fiber action potentials and conduc-
tion block in some axons. (Reprinted from Ref. 1 with the per-
mission of Butterworths, Copyright 0 1987.)
tal latency would have been unchanged. The
greatest abnormality relative to axonal degenera-
tion would result if only the smallest fiber re-
mained. Both conduction velocity and distal la-
tency would be abnormal, but the magnitude of
abnormality would be small compared with the re-
duced CMAP amplitude.
For comparison, random, multifocal demyeli-
nation is denionstrated in Fig. 9. I n the model,
propagation is slowed across a single dernyeli-
riated node, arid conduction is blocked if two ad-
MUSCLE & NERVE June 1989
jacent nodes a1-e dcrnyclinated. With distal stimu-
lation, CMAP amplitude is slightly reduc:ctl arid
duration slightly increased because of increased
dispersion. Dist.al latency is slightly prolonged be-
c;iuse the largest two fibers are cicmyelinated dis-
tally bui. the third largest fiber is intact. Proximal
stimulation results in pronounced temporal dis-
persion of the (;MAP, explained by the variable
amounts of demyclination i r i some axons corn-
pared with the others, producing an incrcasc in
the range of conduction velocity. ‘This results in
the initial component of the CMAP (rcpresenting
the fastest conduction time) being greatly sepa-
rated from the trailing portion of the CMAP
(representing the slowest conducting axon). l h e
CMAP amplitude with proximal stimulation is
reduced to a great-er extent than can be ex-
plained by temporal dispersion alone, because of
conduction block in two of the axons. T h e likcli-
hood of continuous propagation along the nerve
dccreares with increasing iiber length because of
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