Download Peripheral Nervous System Complications of Infectious

Peripheral Nervous System Complications
of Infectious Diseases
A. Arturo Leis, MD
John J. Halperin, MD
Taylor B. Harrison, MD
Dianna Quan, MD
AANEM 59th Annual Meeting
Orlando, Florida
Copyright © October 2012
American Association of Neuromuscular
& Electrodiagnostic Medicine
2621 Superior Drive NW
Rochester, MN 55901
Printed by Johnson Printing Company, Inc.
1
Dr. Quan has indicated that her material references an “off-label” use of a commercial product.
Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for
the specific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may
be used if, in the judgment of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance
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counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041.
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Peripheral Nervous System Complications
of Infectious Diseases
Table of Contents
Course Committees & Course Objectives
4
Faculty5
Neuromuscular Manifestations of West Nile and Polio Virus Infection
A. Arturo Leis, MD
7
Peripheral Nervous System Complications of Neuroborreliosis
John J. Halperin, MD
15
Polyneuropathies Associated With Infectious Disease
Taylor B. Harrison, MD
21
Varicella Zoster Virus and Postherpetic Neuralgia: A New Era?
Dianna Quan, MD
31
CME Questions
35
No one involved in the planning of this CME activity had any relevant financial relationships to disclose.
Authors/faculty have nothing to disclose
Chair: Taylor B. Harrison, MD
The ideas and opinions expressed in this publication are solely those of the specific authors
and do not necessarily represent those of the AANEM.
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Objectives
Objectives - Participants will acquire skills to discuss the clinical presentation, diagnosis, management, and outcomes of varied peripheral nervous
system complications associated with infectious diseases. The course will focus on (1) anterior horn cell disorders, (2) Lyme disease, (3) infectious
polyneuropathies, and (4) complications of varicella zoster infection.
Target Audience:
• Neurologists, physical medicine and rehabilitation and other physicians interested in neuromuscular and electrodiagnostic medicine
• Health care professionals involved in the management of patients with neuromuscular diseases
• Researchers who are actively involved in the neuromuscular and/or electrodiagnostic research
Accreditation Statement - The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical
education (CME) for physicians.
CME Credit - The AANEM designates this live activity for a maximum of 3.25 AMA PRA Category 1 CreditsTM. If purchased, the AANEM designates
this enduring material for a maximum of 5.75 AMA PRA Category 1 CreditsTM. This educational event is approved as an Accredited Group Learning
Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of
the Royal College of Physicians and Surgeons of Canada. Physicians should claim only the credit commensurate with the extent of their participation
in the activity. CME for this course is available 10/2012 - 10/2015.
CEUs Credit - The AANEM has designated this live activity for a maximum of 3.25 AANEM CEUs. If purchased, the AANEM designates this
enduring material for a maximum of 5.75 CEUs.
2011-2012 Course Committee
Shawn J. Bird, MD, Chair
Philadelphia, PA
Shashi B. Kumar, MD
Tacoma, WA
Marcy C. Schlinger, DO
Bath, MI
Lawrence W. Frank, MD
Elmhurst, IL
A. Arturo Leis, MD
Jackson, MS
Nizar Souayah, MD
Westfield, NJ
Taylor B. Harrison, MD
Atlanta, GA
Benjamin S. Warfel, II, MD
Lancaster, PA
2011-2012 AANEM President
John C. Kincaid, MD
Indianapolis, IN
Peripheral Nervous System Complications
of Infectious Diseases
Faculty
A. Arturo Leis, MD
Taylor Bartlett Harrison, MD
Dr. Leis is a clinical professor of Neurology at the University of
Mississippi and a senior scientist at the Center for Neuroscience
and Neurological Recovery. He completed his medical degree
from the University of Arizona, a neurology residency at the
University of Texas-Houston, and a clinical neurophysiology
and electrophysiology fellowship at the University of Iowa. Dr.
Leis also completed two mini-fellowships in epilepsy at Wake
Forest University. He has published more than 100 abstracts and
80 articles and chapters in peer-reviewed journals. He authored
the Atlas of Electromyography, © 2000, and the Atlas of Nerve
Conduction Studies and Electromyography, © 2012 (Oxford
University Press, New York). Dr. Leis’ major research focus is
neuromuscular disorders, including West Nile virus infection and
silent period studies.
Dr. Harrison is an assistant professor in Emory University’s Department of Neurology. He is the lab director for the Grady Memorial Health Systems EMG Laboratory and the program director
for Emory’s Clinical Neurophysiology fellowship program. His
medical degree was earned at the University of Louisville, with
his residency and fellowship training completed at Emory. His
clinical interests lie in clinical neurophyisology and neurological
complications of infectious diseases, with a focus on neurological
morbidity related to HIV/AIDS.
John J. Halperin MD
Dr. Quan received her medical degree from Columbia University and her neurology residency and neuromuscular disorders
and electrodiagnosis fellowship training at the University of
Pennsylvania. She is currently an associate professor of neurology at the University of Colorado Denver School of Medicine
in Aurora, where she is program director for the neuromuscular
medicine fellowship and director of the EMG laboratory. She has
been an active member of the AANEM and the American Academy of Neurology and serves as a medical editor for the online eMedicine Textbook of Neurology and a frequent ad hoc reviewer
for Muscle & Nerve. Her interests include peripheral neuropathy,
amyotrophic lateral sclerosis, and postherpetic neuralgia.
Department of Neurology
University of Mississippi
Jackson, MS
Department of Neurosciences
Overlook Medical Center
Summit, New Jersey
Dr. Halperin chairs the Neurosciences Department at Overlook
Medical Center, is the Neurosciences medical director for the
Atlantic Health System, and is professor of neurology at the
Mount Sinai School of Medicine in New York. He received his
medical degree from Harvard, completing his neurology residency
and fellowship at Massachusetts General Hospital in Boston. A
Fellow of the American Academy of Neurology, the American
College of Physicians, the AANEM, and the Royal College of
Physicians of Edinburgh, Dr. Halperin has authored or coauthored
more than 150 papers and chapters and edited four books and
monographs. He has served on the Muscle & Nerve editorial
board and currently is on the editorial boards of Neurology and
The Neurologist. His clinical interests are in neuromuscular
disease and neuroimmunology, focusing on nervous system
manifestations of Lyme disease.
Department of Neurology
Emory University
Atlanta, Georgia
Dianna Quan, MD
Department of Neurology
University of Colorado Denver
Aurora, Colorado
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PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Neuromuscular Manifestations
of West Nile and Polio Virus Infection
A. Arturo Leis, MD
Clinical Professor of Neurology
Methodist Rehabilitation Center
Jackson, Mississippi
INTRODUCTION
West Nile virus (WNV), a mosquito-borne RNA flavivirus and
human neuropathogen, was first isolated from a febrile woman
in the West Nile region of Uganda, Africa, in 1937. During the
1940s and 1950s, transmission of WNV by mosquitoes was
demonstrated, the close antigenic relationship with flaviviruses
was described, and neutralizing antibody was found in many
residents of East-Central Africa. The virus also became recognized
as a cause of human meningitis or encephalitis in elderly patients
during an outbreak in Israel in 1957, although central nervous
system (CNS) involvement in middle-aged and younger subjects
remained unusual and outcome in the younger age group was
generally excellent. During the 1960s to 1970s, birds were
identified as a major host, horses were commonly infected, and
there were large human epidemics in Africa and the Middle East.
Europe also experienced its first WNV outbreak. During the 1980s
and 1990s, there were major outbreaks in Africa, the Middle East,
Europe, and Russia, although the Romania epidemic in 1996
marked the geographic transition of WNV epidemics from rural
areas to urban industrialized areas.1
The poliovirus has caused paralysis and death for much of human
history.2 The virus caused major epidemics in Europe in the
1880s and soon after outbreaks appeared in the United States. By
1910, frequent epidemics became regular events throughout the
developed world, particularly in cities during the summer months.
At its peak in the 1940s and 1950s, polio infected millions
of people and paralyzed or killed over half a million people
worldwide every year. There are still an estimated 1 million polio
survivors in the United States, although the exact incidence and
prevalence of postpolio syndrome (PPS) is unknown. Researchers
estimate that PPS affects up to 40% of polio survivors.3
West Nile virus gained entry into North America in 1999 in the
New York City outbreak.4 The viral strain introduced into the
United States likely originated from a strain that was circulating in
Israel during 1998. In the past decade, WNV has spread and is now
widely established from Canada to Venezuela.5 In 2011, human
cases were reported in Albania, Greece, Israel, Italy, Romania,
Russia, and Mexico. Hence, the geographic range of WNV now
includes six of seven continents, including Africa, Asia, Europe,
Australia (subtype Kunjin), North America, and South America.
In contrast, polio cases have decreased by over 99% since 1988,
from an estimated 350,000 cases then to 1,352 reported cases in
2010. The reduction is the result of the global effort to eradicate
the disease. In 2012, only three countries (Afghanistan, Nigeria
and Pakistan) remain polio-endemic, down from more than 125 in
1988. Persistent pockets of polio transmission in northern Nigeria
and the border between Afghanistan and Pakistan are the current
focus of the polio eradication initiative. As long as a single child
remains infected, children in all countries are at risk of contracting
polio. In 2009-2010, 23 previously polio-free countries were
reinfected due to imports of the virus.2,3
Before 1996, WNV was known to cause high fever, chills,
malaise, headache, backache, arthralgia, myalgias, retro-orbital
pain, and a maculopapular rash, but neurological symptoms were
uncommon. However, since the New York City outbreak, severe
neurological illness, including encephalitis and meningitis, has
been reported much more frequently, together with neuromuscular
manifestations. The diagnosis of WNV infection should be
considered in any patient with an unexplained acute febrile or
neurological illness during the summer months, particularly
if recently exposed to mosquitoes. In such cases serum should
be tested for class M immunoglobulin (IgM) antibody to WNV,
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NEUROMUSCULAR MANIFESTATIONS OF WEST NILE AND POLIO VIRUS INFECTION
which indicates a recent infection. If there are signs of CNS
involvement, cerebrospinal fluid (CSF) should be analyzed and
also tested for WNV IgM antibody. Cerebrospinal fluid findings
typically show increased leukocytes (usually > 200 cells/mm3),
increased protein, and normal glucose. Almost half of WNV
meningitis patients may have at least 50% neutrophils in their
initial CSF specimen, followed by a shift to lymphocytosis.6
Imaging studies in WNV infection are frequently normal,
although they may be useful in excluding other etiologies of
acute myelomeningoencephalitis. When abnormal, findings are
generally nonspecific and without mass effect. T2-weighted
magnetic resonance imaging (MRI) signal abnormalities have
been reported in brainstem, deep grey structures (basal ganglia
or thalami), and cerebellum. However, other imaging series have
found no definite predilection for any specific area of the brain
parenchyma. In patients with WNV-associated limb paralysis,
abnormal signal intensity may be more pronounced in the spinal
cord ventral horns with enhancement around the conus medullaris
and cauda equina. However, followup MRIs may show complete
resolution of signal abnormalities.
Neuromuscular manifestations are now recognized as a prominent
feature in patients with WNV neuroinvasive disease (encephalitis,
meningitis). In the 1999 New York City outbreak, more than 50%
of patients with confirmed WNV encephalitis had severe muscle
weakness as a cardinal sign.4 Weakness was an apparent risk factor
predicting death in patients with WNV encephalitis. In the 2002
and 2003 WNV epidemics in the United States, neuromuscular
manifestations were a well-recognized feature associated with
increased morbidity and mortality.7 In Colorado, the state with
the most reported cases of WNV infection (2,943) and fatalities
(63) during the 2003 epidemic, as many as 50% of patients with
encephalitis had evidence of acute flaccid paralysis.
WEST NILE VIRUS POLIOMYELITIS
In the original New York City outbreak, several case series
attributed neuromuscular complications, particularly acute
flaccid paralysis, to peripheral neuronal processes, namely
Guillain-Barré syndrome (GBS), motor axonopathy, or severe
axonal polyneuropathy.4,8 In the 2002 epidemic, more cases of
WNV-associated acute flaccid paralysis were also seen across
the Southern United States. These patients had asymmetric
acute flaccid paralysis, absent deep tendon reflexes in affected
limbs, preserved sensation, bowel or bladder dysfunction,
and respiratory distress. Electrodiagnostic (EDX) studies in
these subjects revealed markedly decreased or absent motor
responses in the paretic limbs, preserved sensory responses, and
widespread asymmetric muscle denervation, without evidence
of demyelination or myopathy. The clinical and EDX findings
were classic for poliomyelitis and inconsistent with GBS or other
peripheral nerve disorders. These cases were first reported in
2002, with clinical, laboratory, and electrophysiologic guidelines
to help physicians discern poliomyelitis from GBS (Table 1).9
Subsequently, clinical, laboratory, and neurophysiologic findings
suggested that WNV-associated acute flaccid paralysis was
a poliomyelitis syndrome with involvement of anterior horn
cells (ANCs) of the spinal cord.9-12 Soon thereafter pathologic
confirmation of WNV poliomyelitis was obtained (Figure 1,
A-C),13 Indeed, postmortem examinations of patients with WNV
infection from the 2002 epidemic showed that poliomyelitis was
8
Table 1. Characteristics in West Nile virus-associated poliomyelitis
compared with typical Guillain-Barré syndrome
Guillain-Barré
syndrome
Weeks after acute
Timing of onset Acute phase of infection
infection
Fever,
Present
Absent
leukocytosis
Generally symmetric;
Asymmetric; monoplegia
Weakness
proximal and distal
distribution
to quadriplegia
muscles
Some myalgias,
Sensory
infrequent numbness,
Sensory loss, painful
symptoms
paresthesias, or sensory distal paresthesias
loss
Bowel and
Often involved
Rarely involved
bladder
Encephalopathy Often present
Absent
No pleocytosis,
Pleocytosis, elevated
elevated protein
CSF profile
protein
(albuminocytologic
dissociation)
Demyelination (marked
Anterior horn cell or
slowing of conduction
motor axon loss
Electrodiagnosti
velocity, conduction
(reduced/absent CMAPs,
c features
block, temporal
preserved SNAPs,
dispersion); reduced
asymmetric denervation)
SNAPs
West Nile poliomyelitis
CMAP = compound muscle action potential, CSF = cerebrospinal fluid,
SNAP = sensory nerve action potential
Modified from Leis and colleagues.9
____________________________________________________
the major CNS finding in each case. This is in agreement with
the neuropathology of experimental or naturally occurring WNV
infection in monkeys, horses, and birds. In these vertebrates,
WNV shows a pronounced tropism for gray matter of the spinal
cord, causing poliomyelitis. In contrast, peripheral nerves are not
commonly involved.
Most investigators actively involved in WNV clinical research
now accept poliomyelitis to be the most common cause of WNVassociated acute flaccid paralysis in humans. Moreover, the
Centers for Disease Control now classifies WNV infection into
WNV fever and neuroinvasive disease, with further subdivision
of the latter group into encephalitis, meningitis, and poliomyelitis.
Patients with the poliomyelitis presentation commonly have
associated signs of meningitis, encephalitis, or respiratory distress
from involvement of spinal motor neurons supplying the phrenic
nerves to the diaphragm, but acute flaccid paralysis also may
occur in the absence of fever or meningoencephalitis. Recovery
from neurological sequelae of WNV neuroinvasive disease may
be slow and incomplete, with a poorer prognosis for recovery
of physical function in patients with acute flaccid paralysis. The
initial four patients treated by the author in 2002 with acute flaccid
paralysis and profound loss of AHCs in paretic limbs, based on
EDX studies, remain weak in affected limbs almost a decade after
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Table 2. Baseline-to-peak amplitudes of motor (m, in mV) and
sensory (s, in μV) responses in a 50-year-old man with West Nile
poliomyelitis of the right upper limb
The patient initially presented with acute flaccid paralysis and areflexia
in the right arm, without pain or paresthesias. Sensory examination was
normal. Initial electrodiagnostic studies showed markedly reduced motor
responses in the monoplegic right limb (particularly in proximal muscles),
with normal sensory responses. Note persistently reduced proximal motor
responses 1 year after the acute illness.
Nerve
Median
(m)
Median
(s)
Figure 1. Spectrum of pathological findings in West Nile virus poliomyelitis:
(A) Chromatolytic neuron with eccentric nucleus and distended cell body.
Chromatolysis is usually triggered by damage to the cell body or axon.
Neuronal recovery through regeneration can occur after chromatolysis, but
most often it is a precursor of cell death (apoptosis). The event of
chromatolysis is also characterized by a prominent migration of the nucleus
towards the periphery of the cell and increase in the size of the cell body
(hematoxylin-eosin, original magnification ×400). (B) Activated microglial
cells surround and ingest a dead neuron (neuronophagia), which is typical
of viral infections (hematoxylin-eosin, original magnification ×400). (C)
Blood vessel at the interface between ventral horn gray matter and
adjacent white matter surrounded by a dense cuff of chronic inflammatory
cells (perivascular inflammation); (wm = white matter; gm = gray matter)
(hematoxylin-eosin, original magnification ×100). (D) Cervical sympathetic
ganglia. Microglial nodules are clustered around eosinophilic husks of
dying ganglion cells. Microglial cells are consuming the pyknotic
sympathetic neurons (neuronophagia) (hematoxylin-eosin, original
magnification ×400).
Modified from Fratkin and colleagues.13
Stimulati Recordin
Recording
on site site
g site
Initial
study
3-month followup
6-month followup
R
L
R
L
R
L
Wrist
APB
2
11.4
3.8
11.2
6.3
-
Wrist
Digit II
33.4
35.4
27.2
32.8
38.1
-
Ulnar (m)
Wrist
ADM
1.6
7.5
2.1
12.1
3.9
-
Ulnar (s)
Musculoc
utaneous
(m)
Musculoc
utaneous
(s)
Axillary
(m)
Wrist
Digit V
28.8
27.6
21.8
23.5
30.7
-
Erb’s
point
Biceps
0.2
7.6
0.2
7
0.6
-
Arm
Forearm
27.1
32.6
21.4
-
22
-
Deltoid
0.4
5.3
0.2
7.3
1.4
-
Dorsum
hand
31.9
31.8
39.8
40.3
39.4
-
Erb’s
point
Radial (s) Forearm
ADM = abductor digiti minimi, APB = abductor pollicis brevis, R = right, L = left
Bold data are abnormal.
Modified from Leis and Stokic.16
____________________________________________________________________________________________________
____________________________________________________________________________________________________
the acute WNV illness. However, each of these patients had needle
electromyographic (EMG) evidence of profound denervation in
muscles of the most affected limbs with few or no voluntarily
recruited motor unit potentials (MUPs) and absent or markedly
reduced motor responses with normal sensory responses on
nerve conduction studies.9,10 Table 2 shows motor and sensory
amplitudes in one of these patients, a 50-year-old man with WNV
poliomyelitis limited to the right upper limb. Followup nerve
conduction studies at 3, 6, and 12 months continued to show
markedly reduced motor responses in proximal muscles with
normal sensory responses. Followup needle EMG examinations
also showed persistent profound denervation in shoulder girdle
muscles with only a single voluntarily recruited MUP in deltoid
and biceps (Figure 2). This patient never regained the ability to
abduct or forward elevate the arm past the horizontal position.
In contrast, limbs with lesser degrees of ANC loss, based on the
presence of recordable motor responses and preserved innervation
on needle EMG, had better recovery of function. Indeed, after
performing EDX evaluations on many WNV patients with
varying degrees of acute flaccid paralysis observations suggest
that prognosis for recovery of function is greatly dependent on the
degree of motor neuron loss; limbs with absent motor responses
and no voluntary needle EMG activity have a poorer longterm
prognosis while those with relatively preserved motor responses
and some voluntary activity have a more favorable outcome.
Figure 2. Needle electromyographic examination in a 50-year-old man
with West Nile virus poliomyelitis limited to the right upper limb. Needle
examination of the biceps muscle at 1 year followup showed persistent
profound denervation with only a single voluntarily recruited rapidly firing
motor unit potential. Similar denervation was noted in other shoulder
girdle muscles. Clinical followup 5 years later revealed persistent severe
weakness in proximal upper limb muscles.
__________________________________________________________
OTHER SPINAL CORD NEUROPATHOLOGY
IN WEST NILE VIRUS INFECTION
Although the anterior horns are the major site of spinal cord
pathology, autopsy series show that pathologic changes may
extend beyond the spinal cord gray matter with focal inflammatory
changes involving the adjacent white matter.13 This may explain
the infrequent occurrence of WNV-associated transverse myelitis
with clinical involvement of spinal sensory and motor pathways
(Leis, personal observation). In addition, neuronophagia,
neuronal disappearance, and pathologic alterations have been
described in dorsal root ganglia and sympathetic ganglia.13
Involvement of dorsal root ganglia may explain some of the
sensory deficits and reduced sensory nerve action potentials on
EDX testing that occasionally are reported in patients with WNV
infection.7 However, sensory loss attributed to WNV has not been
a prominent clinical finding. Another often overlooked finding is
9
NEUROMUSCULAR MANIFESTATIONS OF WEST NILE AND POLIO VIRUS INFECTION
the disappearance of neurons in the sympathetic ganglia (Figure1,
D), which offers a plausible explanation for the autonomic
instability observed in some patients, including labile vital signs,
hypotension, and potentially lethal cardiac arrhythmias.13 Such
data suggest that autonomic instability may play a role in the
morbidity and mortality of human WNV infection.
WEST NILE VIRUS SPINAL NERVE ROOT
INVOLVEMENT
Inflammatory changes in spinal cord gray matter also may
extend into the spinal nerve roots to cause a myeloradiculitis.7
Involvement of ventral spinal roots may contribute to the
asymmetric acute flaccid paralysis seen in many patients
with WNV infection. Magnetic resonance imaging findings
showing apparent enhancement of ventral nerve roots support
the concept that anterior radiculopathy should be considered,
in addition to AHC pathology, when assessing patients with
WNV-associated acute flaccid paralysis. However, acute isolated
radiculopathy as the sole neuromuscular manifestation of WNV
infection is not common, although confusion may arise when
acute flaccid paralysis due to poliomyelitis is limited to one
limb (monoparesis).9,10 In one series that included 10 patients
with WNV poliomyelitis, four patients had monoparesis.14
The author has also encountered several patients with WNV
and asymmetric weakness in the arms or legs who initially
were thought to have cervical or lumbosacral radiculopathies.
WEST NILE VIRUS PERIPHERAL NERVE
INVOLVEMENT
West Nile virus can involve peripheral nerves although this
manifestation is much less frequent than originally assumed
during the 1999 outbreak, when weakness and acute flaccid
paralysis were attributed to GBS or axonal polyneuropathy. In
one series of 64 patients with WNV infection, three patients had
mixed axonal degenerating and demyelinating processes and one
had a pure demyelinating neuropathy.15 In addition, there are case
reports of patients with true GBS, unilateral brachial plexopathy,
and bilateral diaphragmatic paralysis attributed to loss of
motor neurons or motor axons supplying the phrenic nerves.
Lymphocytic infiltration of nerves and occasional degenerating
axons also has been described, suggesting that WNV may reach
the CNS via peripheral nerves. Indeed, recent evidence suggests
that axonal transport may mediate WNV entry into the CNS to
induce acute flaccid paralysis. However, most autopsy series do
not suggest that WNV exhibits a predilection for peripheral nerves.
Similarly, WNV infection in monkeys, horses, and birds does not
commonly involve peripheral nerves. In addition, it should be
recognized that prolonged critical illness can be associated with
an axonal sensorimotor polyneuropathy, termed critical illness
polyneuropathy, which can confound the interpretation of WNVassociated polyneuropathy.
NEUROMUSCULAR JUNCTION AND
SKELETAL MUSCLE IN WEST NILE
VIRUS INFECTION
West Nile virus has been reported to be linked to a defect in
neuromuscular transmission.16,17 The author has described six
10
cases of myasthenia gravis (MG) that developed after acute WNV
infection. All patients had serologically confirmed WNV infection
that manifested as neuroinvasive disease with poliomyelitis.
None had clinical evidence of MG prior to WNV. In all cases,
classic MG symptoms (intermittent ptosis, diplopia, dysarthria,
dysphagia, fatigue, generalized weakness, and respiratory
distress) either began or worsened within several months (range
3-7 months) of WNV infection. However, residual deficits
(disabling fatigue and persistent asymmetric weakness) from
neuroinvasive WNV often confounded or delayed the diagnosis
of MG. All patients had markedly elevated antibodies against the
acetylcholine receptor and one had a thymoma. Treatment varied;
one patient was managed with only acetylcholinesterase inhibitors
(pyridostigmine), one with pyridostigmine and prednisone, and
four with pyridostigmine, multiple immunosuppressive drugs,
and intravenous immunoglobulin (IVIg) or plasmapheresis
for recurrent MG crises.17 Myopathy also is an uncommon
manifestation of WNV infection, although there are several
reports of rhabdomyolysis with creatine kinase (CK) levels as
high as 45,000 U/L (normal < 220 U/L). 7 However, in one of these
reports, postmortem examination confirmed poliomyelitis with
striking loss of motor neurons in the anterior horn and brainstem,
and only mild inflammation without necrosis in skeletal muscle. In
one series, muscle biopsies on four patients with WNV with acute
asymmetric paralysis showed scattered necrotic muscle fibers
invaded by macrophages (two patients), normal muscle fibers with
inflammatory cells surrounding small blood vessels (one patient),
and a normal muscle biopsy (one patient).12 In one of the patients
with scattered necrotic muscle fibers, immunohistochemistry with
polyclonal antibodies against flaviviruses did not detect WNV
on biopsied muscle. These investigators acknowledged that the
scattered necrotic muscle fibers were an unlikely explanation for
the severe paralysis observed.12 In the most comprehensive series
of rhabdomyolysis in patients with WNV neuroinvasive disease,
nine of 244 hospitalized patients had rhabdomyolysis (median
age 70 years, CK levels ranged from 1 to 42K IU).18 However,
six of nine patients had history of recent falls prior to admission.
The authors concluded that although the temporal relationship of
rhabdomyolysis and WNV illness suggested a common etiology,
these patients presented with complex clinical conditions that may
have led to development of rhabdomyolysis from other causes.
In addition, it is now commonly recognized that critical illness
can be associated with a diffuse myopathy, termed critical illness
myopathy, which can cause generalized weakness, respiratory
failure, and inability to wean from the respirator. Accordingly,
the role played by direct WNV invasion of muscles and the
clinical significance of WNV-associated myositis remains to
be elucidated.
West Nile virus has also been reported to cause myocarditis,
and cardiomyopathy, which can predispose to fatal arrhythmia.
However, cardiac arrhythmias have also been reported to occur
across the spectrum of WNV disease, including in cases of
WNV fever not associated with myocarditis. Since statistics
on the incidence of WNV myocarditis as the cause of cardiac
arrhythmias are lacking, it is possible that autonomic instability
caused by direct WNV infection of neurons controlling cardiac
function may also have precipitated cardiac arrhythmias.13
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
WEST NILE VIRUS AND AUTOIMMUNE
DISEASE
An unresolved issue that may have important neuromuscular
implications is whether WNV infection can induce autoimmune
disease. Support for this contention arises from the numerous
reports of WNV patients with various neuromuscular diseases
that have a presumed autoimmune mechanism, including GBS,
other demyelinating neuropathies,15 myasthenia gravis,17 brachial
plexopathies, and stiff-person syndrome.19 In the latter case, stiffperson syndrome with antibodies to glutamic acid decarboxylase
developed several weeks after WNV fever. However, longterm
followup of patients with WNV infection should clarify whether
there is an increased incidence of autoimmune diseases.
SPECTRUM OF NEUROMUSCULAR
SYMPTOMS AND SIGNS IN WEST NILE
VIRUS INFECTION
In the author’s initial series of 54 WNV patients who had extensive
EDX evaluation and a few autopsies, neuromuscular manifestations
included: acute flaccid paralysis with electrophysiologic or
pathologic features of poliomyelitis (n = 19), clinical findings of
autonomic instability (cardiac dysrythmias, marked fluctuations
in blood pressure, gastrointestinal complications including
gastroparesis) or pathologic alterations in sympathetic ganglia (n =
7), brainstem dysfunction (n = 4) including three cases of seventh
nerve palsies (two delayed several weeks after acute illness and
one with acute illness), myopathy (n = 3, in two attributed to
critical illness myopathy and one case of rhabdomyolysis with
acute renal failure), diffuse axonal polyneuropathy (n = 2, one
attributed to critical illness polyneuropathy and one to acute
polyneuropathy associated with WNV), new onset myasthenia
gravis (n = 2), transverse myelitis with involvement of sensory
and motor pathways (n = 1), gait apraxia (n = 1), and optic nerve
involvement (n = 1). In the latter case, full-field pattern reversal
visual evoked potential studies showed a monocular abnormality
that suggested a conduction defect in the visual pathways anterior
to the optic chiasm. In nine patients, the chief complaint was
severe or disabling fatigue without objective muscle weakness
on clinical examination or abnormalities on neurophysiologic
studies. The specific physiologic mechanism for WNV fatigue
remains unknown. In the PPS, poliovirus-induced lesions in
the reticular activating system are thought to contribute to the
subjective fatigue. In patients with WNV infection, prolonged
fatigue is common after the acute illness, affecting nearly twothirds of patients.1 At 1 year followup, fatigue was the most
common persistent symptom in patients hospitalized from the
1999 New York outbreak, affecting 67 % of patients whereas
muscle weakness was found in 44% of patients. Thus, physicians
should be aware that fatigue and subjective weakness may be the
major complaint in patients with WNV infection, particularly
in those with WNV fever. In addition, the author observed two
patients that developed severe, but reversible, muscle weakness
that recovered completely within weeks. Both patients were
hospitalized for their weakness. Weakness involved both lower
limbs in one patient (paraparesis) and one upper limb in the
other (monoparesis). Their neurophysiologic studies were
unremarkable after recovery of function, in agreement with the
clinical examination. The reversible muscle weakness likely
reflects transient AHC dysfunction during the phase of acute
WNV illness, with full recovery of function occurring within
several weeks. Although rapid reversal of paralysis has rarely
been reported with WNV infection, this phenomenon is not new
and was first observed in patients with poliomyelitis caused by
the poliovirus.20 Jacob von Heine (1799-1878) recognized the
transitory nature of some attacks of paralysis early in the 19th
century, and he attributed the rapid improvement to fluid exudate
and edema in the spinal cord that was reabsorbed.20 Therefore,
in acute WNV infection, as in acute poliovirus infection,
reversible paralysis may reflect transient AHC dysfunction.
In two other patients, the author observed that WNV infection
caused exaggerated weakness in previously weak limbs (from
lumbar spinal stenosis) suggesting that preexisting dysfunction
may predispose AHCs to additional injury during acute WNV
infection. It is speculated that AHCs that have survived an initial
insult, or incorporated too many muscle fibers from denervated
motor units beyond the metabolic capability, may be especially
prone to injury.
WEST NILE VIRUS IMMUNITY AND
PATHOGENESIS
Although postmortem examinations have confirmed WNV
poliomyelitis and encephalitis, the precise mechanisms that
underlie destruction of neurons remain to be fully elucidated. The
increased risk of severe WNV infection in immunosuppressed
and elderly patients suggests that an intact immune system is
essential for control of WNV. West Nile virus-specific antibodies
are responsible for reducing viremia and preventing development
of severe disease, while different T-lymphocyte populations play
an important role in clearing infection from tissues and preventing
viral persistence. However, the possible pathologic effect of
the immune system in WNV neuroinvasive disease cannot be
overlooked. There is evidence that bystander neuronal death may
occur as a result of a cascade of immunobiochemical events in the
spinal cord that impaired glutamate transport and allowed excess
glutamate to accumulate extracellularly around motor neurons.
West Nile virus neuroinvasive disease is also characterized by
increased production of proinflammatory cytokines derived
from infected cells and upregulation of other proinflammatory
genes. These cytokines and other proinflammatory factors are
either neurotoxic or attract leukocytes into the affected area,
which further contribute to WNV-induced neurotoxicity. Hence,
WNV-induced inflammation is now recognized as a major
contributor of neuropathogenesis. The concept of a pathologic
effect of the immune system in WNV neuroinvasive disease
provides a framework for the development of anti-inflammatory
drugs as much needed interventions to limit the cascade of
immunobiochemical events leading to neurotoxicity.
TREATMENT FOR NEUROINVASIVE WEST
NILE INFECTION
At present, no specific therapy has been approved for human
use in WNV infection. However, the merging knowledge about
the pathogenesis of WNV infection has direct therapeutic
implications. Treatment strategies that control the previously
described cascade of events leading to neuronal death may prove
beneficial. Promising therapies include the use of interferon and
11
NEUROMUSCULAR MANIFESTATIONS OF WEST NILE AND POLIO VIRUS INFECTION
interferon inducers, which have been shown to reduce mortality in
mice infected by subcutaneous injection of WNV. Other potential
therapies include ribavirin, nucleic acids, RNA interference,
antisense oligomers, peptides, imino sugars, and mycophenolic
acid (for a review, see Diamond).21 These agents act through
distinct mechanisms and are moving through various stages of
preclinical development.
(Table 1). Poliovirus poliomyelitis should also be considered in
the differential diagnosis if the patient resides in or travels to a
polio-endemic region. However, in 2012 only three countries
(Afghanistan, Nigeria, and Pakistan) remain polio-endemic.2
In addition, poliovirus infection mainly affects infants or
young children whereas WNV primarily affects middle-aged to
elderly adults.
The role of corticosteroids in WNV neuroinvasive disease is
controversial, with concern that immunosuppressive effects
may worsen outcome. However, high-dose steroids have been
used successfully in anecdotal reports to treat WNV-associated
acute flaccid paralysis and to shorten the acute phase of WNV
meningoencephalitis. The author also has administered high-dose
intravenous steroids to two patients with acute flaccid paralysis
and brainstem involvement, including progressive seventh nerve
palsies, who showed clear improvement in brainstem symptoms
and facial paralysis within 24 hours of treatment. However,
both cases were characterized by an atypical temporal pattern of
progressive symptoms or new deficits occurring several weeks
after the onset of the acute illness. In most cases, WNV is thought
to be cleared by an effective immune response after only several
days of viremia. Accordingly, this relatively delayed progression
of symptoms is more likely to reflect secondary injury from the
downstream cascade of excitotoxic events and a secondary wave
of inflammation. In cases where the temporal course suggests that
indirect immune-mediated mechanisms may be contributing to
neuronal injury, a trial of high-dose corticosteroids seems justified.
There also has been great interest in passive immunization with
IVIg for the treatment of patients with acute WNV infection.
Immune serum frequently was used in the pre-antibiotic era to
treat infectious diseases, and animal data indicate an important
role for humoral immunity in controlling WNV infection. Given
the endemic nature of WNV in the Middle East, IVIg obtained
from Israeli blood donors that contains WNV-specific antibodies
provides clear-cut protection to animals treated before or shortly
after infectious challenge with WNV. In contrast, IVIg obtained
from blood donors from the United States without WNV-specific
antibodies has no similar protective effect. Hence, neutralizing
antibody therapeutics show promise in inhibiting WNV infection
and preventing acute flaccid paralysis in vivo, which justifies
phase I and II studies using humanized or human monoclonal
antibodies.
The author’s observations and literature review suggest that
patients with WNV infection who have muscle weakness or other
neuromuscular signs and symptoms often are given erroneous
diagnoses and may receive inappropriate, potentially injurious
treatments. Among patients referred to the author’s rehabilitation
center with WNV neuroinvasive disease, initial diagnoses that
ultimately proved to be erroneous included evolving stroke,
GBS, myopathy, food poisoning, endocarditis, sepsis, heat
stroke, malingering, gastroenteritis, drug reaction, spinal cord
compression, diabetic amyotrophy, and myocardial infarction.
Diagnostic studies and therapies directed at these erroneous
diagnoses are typically ineffective and can produce significant
morbidity. Hence, physicians should consider a diagnosis of WNV
infection in any patient who presents with a febrile illness that
progresses over several days associated with neurological signs or
symptoms, especially during the summer months (i.e., “summer
flu” plus neurological symptoms). Healthcare providers also need
to be aware that the spectrum of neuromuscular manifestations
may range from a poliomyelitis syndrome in the absence of
overt fever or meningoencephalitis to subjective weakness and
disabling fatigue. This awareness will help to avoid less tenable
diagnoses and inappropriate treatment.
DIFFERENTIAL DIAGNOSIS OF
NEUROINVASIVE WEST NILE INFECTION
The differential diagnoses of WNV infection include other
arbovirus encephalitides (e.g., St. Louis encephalitis virus;
Japanese encephalitis virus; Eastern, Western, and Venezuelan
equine encephalitis viruses; tick borne encephalitis virus), other
viral meningoencephalitides (La Crosse virus, Murray Valley
virus, coxsackievirus, echovirus, enterovirus), bacterial meningitis
or encephalitis (including Lyme disease and Leptospirosis),
tick paralysis, and noninfectious conditions that affect brain
or spinal cord (e.g., stroke, brain or spinal cord tumors, spinal
cord compression). Guillian-Barré syndrome and other immunemediated neuropathies are also diagnostic considerations, since
in some cases WNV poliomyelitis may mimic these disorders
12
CONCLUSION
Although anterior horns are the major site of spinal cord
pathology in WNV infection, inflammatory changes may also
involve muscle fibers, peripheral nerves, spinal roots, and spinal
sympathetic neurons and ganglia, contributing to the wide
spectrum of neuromuscular manifestations of WNV infection.
Although there is no specific treatment or vaccine approved for
human WNV infection, several drugs that can alter the cascade
of immunobiochemical events leading to neuronal death may
be potentially useful. Treatment of PPS is also supportive and
includes physical, occupational, and speech therapy, and
medications to control pain and lessen fatigue.
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
REFERENCES
1. Campbell GL, Marfin AA, Lanciotti RS, Gubler DJ. West Nile virus.
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Poliomyelitis World Health Organization Fact Sheet, <http://www.
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Post-Polio Syndrome Fact Sheet, <http://www.ninds.nih.gov/
factsheets>, 2012.
Nash D, Mostashari F, Fine A, Miller J, et al. West Nile Outbreak
Response Working Group. The outbreak of West Nile virus infection
in the New York City area in 1999. N Engl J Med 1999;344:1807-1814.
West Nile Virus World Health Organization Fact Sheet, <http://
www.who.int/mediacentre/factsheets>, 2012.
Tyler, KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters
BK. CSF findings in 250 patients with serologically confirmed West
Nile virus meningitis and encephalitis. Neurology 2006;66:361-365.
Jeha LE, Sila CA, Lederman RJ, Prayson RA, et al. West Nile virus
infection. A new acute paralytic illness. Neurology 2003;61:55-59.
Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. The
West Nile virus outbreak of 1999 in New York City: the Flushing
Hospital experience. Clin Infect Dis 2000;30:413-418.
Leis AA, Stokic D, Polk JL, Dostrow V, et. al. Acute flaccid paralysis
syndrome associated with West Nile virus infection, Mississippi and
Louisiana, 2002. MMWR Morbidity and Mortality Weekly Report,
Centers for Disease Control 2002;51:825-828.
Leis AA, Stokic D, Polk JL, Dostrow V, Winkelmann M.
Poliomyelitis-like syndrome from West Nile virus infection. N Engl
J Med 2002;347:1279-1280.
Glass JD, Samuels O, Rich MM. Poliomyelitis due to West Nile
virus. N Engl J Med 2002;347:1280-1281.
12. Li J, Loeb JA, Shy ME, Shah AK, et al. Asymmetric flaccid paralysis:
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a neuro muscular presentation of West Nile virus infection. Ann
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Fratkin JD, Leis AA, Stokic DS, Slavinski SA, Geiss RW. Spinal
cord neuropathology in human West Nile virus infection. Arch
Pathol Lab Med 2004;128:533-537.
Emig M, Apple DJ. Severe West Nile virus disease in healthy adults.
Clin Infect Dis 2004;38:289-292.
Pepperell C, Rau N, Krajden S, Kern R, et al. West Nile virus
infection in 2002: Morbidity and mortality among patients admitted
to hospital in southcentral Ontario. CMAJ 2003;168: 1399-1405.
Leis AA, Stokic DS. Neuromuscular manifestations of West Nile
virus infection. Front Neurol 2012;3:37.
Leis AA, Szatmary G, Ross MA, Stokic DS. West Nile virus
infection and myasthenia gravis. New York Academy of Science,
12th International Conference on Myasthenia Gravis and Related
Disorders, May 21-23, 2012.
Montgomery SP, Chow CC, Smith SW, Marfin AA, et al.
Rhabdomyolysis in patients with West Nile encephalitis and
meningitis. Vector Borne Zoonotic Dis 2005;5:252-257.
Hassin-Baer S, Kirson ED, Shulman L, Buchman AS, et al.
Stiff-person syndrome following West Nile fever. Arch Neurol
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Paul JR. A history of poliomyelitis. New Haven: Yale University
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Diamond MS. Progress on the development of therapeutics against
West Nile virus. Antiviral Res 2009;83:214-227.
13
14
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Peripheral Nervous System
Complications of Neuroborreliosis
John J. Halperin, MD
Chair, Department of Neurosciences
Overlook Medical Center
Summit, New Jersey
INTRODUCTION
On September 26, 1922, almost precisely 90 years ago, two French
physicians, Charles Garin, an intern at the time, and A. Bujadoux,
about whom we know nothing more, evaluated a 56-year-old sheep
farmer1 with an illness dating to June 14 when he had removed an
attached tick from his left buttock. Three weeks following the bite
he developed a painful red ring the size of a “5 franc coin” around
the bite site, with severe local pain and left sided sciatica. The
ring then enlarged to involve both buttocks, the abdomen, and
the left thigh to the knee. He also developed excruciating pain
unresponsive to morphine involving both lower extremities and
the right brachial plexus and arm. When first seen by the authors
in September, he had right deltoid paralysis and atrophy but an
otherwise normal neurologic examination. Cerebrospinal fluid
(CSF) showed a polymorphonuclear-predominant pleocytosis
(75 cells); a Wassermann test was slightly positive. The authors
concluded he had non-syphilis spirochetosis and treated him with
neoarsphenamine. His pain disappeared almost immediately.
They argued that this was a case of tick bite paralysis, noting that
false-positive Wassermann tests were seen in tick borne relapsing
fever and Rocky Mountain spotted fever (RMSF).
This initial description is fascinating and informative in many
ways. The clinical observations were very astute. The conclusion
that this was a spirochetosis was inspired. At the same time the
authors clearly were unaware of descriptions of the same tick
bite-associated rash published a dozen years earlier.2 They also
conflated a number of unrelated disorders (assuming this was
a case of tick bite paralysis, something now known to be toxinmediated) but even then were recognized as nonpainful disorders
associated with neither inflammatory spinal fluid nor muscle atrophy.
This discussion will consider how this vignette relates to a
pediatric rheumatologic disorder first characterized in Lyme,
Connecticut,3 and how vivid imaginations have led some to argue
for pathophysiologic linkages even more misguided than that
initial presumption of tick bite paralysis.
HISTORY
The disorder now referred to as Lyme disease has two distinct
historical threads, joined in the early 1980s with the recognition
that both were caused by a closely related family of tick-transmitted
spirochetes, known collectively as Borrelia burgdorferi sensu lato.
In the mid-1970s, parents in Lyme and Old Lyme, Connecticut,
became concerned that a surprising number of children in a
very small area were being diagnosed with juvenile rheumatoid
arthritis. This resulted in a series of detailed studies3 culminating in
the observations that many of the affected children had preceding
tick bites and an unusual rash. More specifically, the disease was
linked exclusively to bites of small hard-shelled Ixodes ticks.
The rash was noted to begin with some latency following the
tick bite, be relatively asymptomatic, and gradually (over days
to a number of weeks) enlarge to at least 5 cm in diameter but
often many times that size. As physicians dealing with what
was originally termed Lyme arthritis became more cognizant of
these dermatologic presentations they realized that the rash was
identical to that described in the U.S. literature in 1970,4 and in
the European literature in the early 20th century.2
15
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF NEUROBORRELIOSIS
With the assessment of ever more patients with Lyme disease, it
became clear that this was in fact a multisystem disease, with a
number of specific organotropisms. Skin is clearly involved most
frequently. Although the site of inoculation in all patients, an
observed rash is estimated to occur in about 50% of adults but 90%
of children5 (presumably as children’s skin is more likely to be
monitored by concerned outside observers). During its prolonged
feeding the tick ingests blood which triggers proliferation of
spirochetes in the tick’s gut. Spirochetes then circulate throughout
the tick, ultimately invading its salivary glands, from which
they are injected into the host—a process that typically requires
up to about 48 hours6—making it highly unlikely that bites of
shorter duration will result in infection. Infection initially remains
localized to the skin. Spirochetes slowly multiply locally and
migrate centrifugally from the inoculation site. The advancing
edge of migration triggers an inflammatory reaction, causing the
expanding ring-like erythroderm, known as erythema migrans
(EM; previously erythema chronicum migrans).
Ultimately, spirochetes may disseminate systemically, causing the
expected inflammatory response to a bacteremia—a febrile illness,
often with nonspecific widespread achiness, headache, fatigue,
and loss of mental agility—comparable to that seen in virtually
any systemic inflammatory disorder. Although termed flu-like,
patients do not develop upper respiratory or gastrointestinal
symptoms.
With systemic dissemination, other organ systems can become
targets of involvement. With the strain of B. burgdorferi responsible
for all U.S. cases of Lyme disease (known as B. burgdorferi sensu
stricto) the most common secondary site is again the skin. Up
to a quarter of infected individuals develop multifocal EM,5 with
each new EM representing a nidus of metastatic infection, and
each recapitulating the slowly expanding pattern. In Europe,
infection is caused primarily by this strain plus two closely related
borrelias: B. garinii and B. afzelii. Presumably because of strain
differences, multifocal EM is reported in a far smaller percentage
of European patients. Conversely, two of the earliest reported
European cutaneous manifestations, acrodermatitis chronica
atrophica and borrelia lymphocytoma, are rarely if ever reported
in the United States.
In early series, approximately 5% of patients first presented with
unexplained heart block, on occasion third degree, requiring a
temporary pacemaker. An additional 15% presented with various
neurologic manifestations.7 An usual form of arthritis, affecting
single large joints in a relapsing fashion (termed a relapsing
large joint oligoarthritis), was the manifestation of systemic
involvement that led to the initial identification of the disease.
Notably, small joints (fingers and toes) and the spine are not
typically involved. Individual joints spontaneously become
inflamed, swollen, and painful for days to weeks, and then subside
spontaneously or with either anti-inflammatory or antimicrobial
therapy. Joint involvement is usually considered one of the later
manifestations, occurring months or years after initial infection,
although on occasion it can occur soon after initial dissemination.
Importantly, the face of this disease has changed over the decades
since its earliest descriptions. Many of the originally described
phenomena occurred in individuals who had experienced early
manifestations, were not diagnosed or treated with antimicrobials,
16
and then went on to develop signs and symptoms of disseminated
infection. With widespread recognition of the signs of early
infection, and even more widespread early treatment, the
frequency of many of these phenomena has likely decreased
substantially.
The European thread of the story is somewhat different. Again,
EM and other cutaneous manifestations were the first described.2
However, the first appreciation of systemic involvement was the
report by Garin and Bujadoux.8 Hence, systemic involvement has
been viewed as a primarily neurologic disorder from the outset. The
neurologic triad described early on—meningitis, radiculoneuritis,
and cranial neuritis—was for many years the sine qua non for
diagnosing this disease. From the time of Garin and Bujadoux
going forward, this was always viewed as a nervous system
infection and treated accordingly, including using penicillin as
early as the 1950s.9 Perhaps as a result of these divergent histories
there has long been an emphasis on the differences between
European and U.S. Lyme disease, emphasizing the prominent
nervous system involvement in Europe and joint involvement in
the United States. However, current epidemiologic studies suggest
that about 15% of infected individuals have nervous system
involvement on both continents, with forms of involvement that
are qualitatively remarkably similar.10 Although joint involvement
may be more prominent in the United States there is a significant
ascertainment bias, with the seminal U.S. literature on Lyme
disease written by rheumatologists. Regardless, it is likely safe to
assume that nervous system involvement is sufficiently similar so
that insights into neurologic disease gained in Europe and North
America should be generally applicable in both regions.
Given that this disorder has been known for over a century, that
the basic neurologic manifestations were characterized 9 decades
ago, that treatment with penicillin was shown to be effective 6
decades ago, and that the causative organism was identified 30
years ago, it is perhaps surprising that so much controversy still
surrounds this illness. The controversy has centered on several key
misunderstandings regarding diagnosis in general, diagnosis of
nervous system disease in particular, and the efficacy of standard
antimicrobial therapy. In all three areas, the scientific data are
quite clear, yet some continue to insist on alternative hypotheses
based not on fact but on pseudoscientific misconceptions.
DIAGNOSIS
Diagnosis of infectious diseases typically relies on isolation of the
responsible organism from affected patients. In Lyme disease, this
can be easily performed in patients with EM, a lesion that, much
like the analogous chancre in syphilis, contains innumerable
spirochetes that are clearly demonstrable on biopsy. However, EM
is such a characteristic lesion that, in the appropriate setting, the
diagnosis should be made presumptively based on its appearance,
with treatment instituted.11 In all other circumstances, laboratory
confirmation of the diagnosis is required.
Microbiological confirmation is often difficult for a number
of reasons. The organism will only grow in specific media,
something not available in most microbiology laboratories.
Incubation must be at a lower temperature than for most human
pathogens and, given the slow dividing time, cultures must be
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
maintained for weeks before judged positive or negative. Likely
most significant though is that the number of organisms present
in readily available samples (serum, CSF, etc.) is so low that even
using polymerase chain reaction type technologies has very low
diagnostic sensitivity; there often simply are no organisms present
in the tested sample.12
As a result, as in many other infections, diagnosis has relied
primarily on demonstration of the host antibody response to
the causative organism. While early serologic assays had a
number of technical limitations, those available today have as
good sensitivity and specificity as those available for most other
infections. However, the way in which they are used rather than
how they perform has been frequently misinterpreted as evidence
of their inadequacy. With virtually all other serologic tests, one
measures both acute and convalescent titers, using the evolution
in the antibody response as evidence of acute infection. In Lyme
disease (perhaps by analogy to the Venereal Disease Research
Laboratory [VDRL] and related assays in syphilis) it has been
customary to use just a one-time titer. However, the VDRL is a
measure of nonspecific anticardiolipin antibodies arising as part
of a broader and misdirected immune response, not as a targeted
response to the causative organism. Use of a one-time measure
of specific antibody concentration has two important limitations.
Very early in any infection, the amount of specific antibody in
serum is minimal and undetectable. The patient is said to be
seronegative, not because the infection is not present, but because
the antibody response is not yet measurable against background
seroreactivity. In Lyme disease, this initial seronegativity typically
last up to 4-6 weeks (as opposed to as long as 6 months in human
immunodeficiency virus). Serologies in this setting, which
includes many patients with EM, will often be negative. This is
not because the test is inadequate but because normal biology
dictates that there is not yet a measurable response. Conversely, a
single positive titer could be cross-reactive, could be due to past
infection, or could be due to current disease.
Although the best approach would still be to obtain acute and
convalescent titers, two recommendations serve to limit the impact
of these issues. First, in patients with pathognomonic early disease
(i.e., EM) treatment should be initiated without even drawing a
serologic test and certainly regardless of its result.11 Second, to
minimize the likelihood of a false-positive result due to crossreactive epitopes, testing should use a two-tier assay.11,13 Sera
should be screened with a quantitative assay such as an enzymelinked immunosorbent assay (ELISA), which measures total
reactive antibody. If, and only if, this produces results interpreted
as positive or borderline, a second test, a Western blot, should be
performed to determine if the antibodies detected in the ELISA are
relevant or cross-reactive. Western blot criteria were developed in,
and applicable to, patients with positive and borderline serologies
only, and are based on statistical observations.
In acute disease (< 1-2 months duration), the response is typically
primarily immunoglobulin M (IgM). Three IgM bands were
identified as informative; individuals with acute Lyme disease
usually have at least two of these (Table 1). Importantly though,
by the end of the first or at most second month of infection,
the immune system converts the predominant response to
immunoglobulin
Table 1. Western blots criteria in Lyme disease.
IgM
IgG
18, 23, 28, 31, 39,
Bands
23, 39, 41 kD
41, 45, 58, 66, 93
kD
Positive if: Two of three
Five of 10
Disease > 4-6 weeks
Role:
Early disease only
duration
These are to be used as the second step in two-tier testing and
are applicable only if enzyme-linked immunosorbent assay is positive
or borderline
__________________________________________________________
G (IgG). If a patient with more than a month’s symptoms only
has IgM bands on Western blot, this almost certainly is a falsepositive result. Similarly, in patients with disease of more than
a month or two duration, 10 IgG bands have been identified as
informative, such that patients who have any five of the 10 almost
certainly have, or have had, Lyme disease (Table 1). These bands
are not selected because any of them are unique to Lyme disease
(none are) but rather to maximize positive and negative predictive
values. A patient with fewer than five of these bands is highly
unlikely to have infection. Although some laboratories have
established their own lists of interpretive criteria, none of these
are based on any systematic analysis of data; such alternatives
that do not have demonstrated accuracy should not be used.
Unfortunately, some early studies described patients with presumed
Lyme disease of long duration who appeared to be seronegative.14
Looking back, there are many potential explanations for these
observations but the simplest is that the diagnostic technology
then available was inadequate. However, observations such as
these, as well as the literature prior to the identification of the
organism and development of serologic techniques, led to the
notion that “Lyme disease is a clinical diagnosis.” While this
assertion still has validity, it cannot be interpreted to mean that
any clinician can simply assert that something is Lyme disease
because (s)he thinks that is what it is. Rather, as in any analogous
context, clinical diagnosis requires an appropriate synthesis of
clinical observations with laboratory, epidemiological, and other
scientifically-validated data to come to an appropriate conclusion.
Finally, as the evidence in support of standard diagnostic
technologies has become more compelling, some have started to
invoke “coinfections”—the notion that patients’ symptoms relate
to infection with other tick-borne pathogens—most commonly
babesia, ehrlichia, and anaplasma, and occasionally bartonella.
All cause acute febrile illnesses, some with potentially serious
consequences. None cause prolonged more indolent symptoms
and none have been associated with prolonged nervous system
involvement.
One other laboratory technique that can be useful in central (but
not peripheral) nervous system infection with B. burgdorferi
is the demonstration of intrathecal production of specific
antibody.15-18 Because the central nervous system (CNS) acts
as an independent immunologic compartment, and since
17
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF NEUROBORRELIOSIS
infection with B. burgdorferi (as in other infections) leads to
migration of targeted B cells into the CNS with subsequent local
proliferation, measuring concentrations of specific antibodies
in CSF, comparing this to serum antibodies after correcting
for blood brain barrier function, can produce a relative index
indicative of local production of antibodies in the CNS. When
positive, this allows the inference that at some time there was
active B. burgdorferi infection in the CNS. Unfortunately, just
as with serum antibodies, this measure can remain elevated
long after active infection has resolved. Fortunately, active
infection is almost always accompanied by a CSF pleocytosis,
elevated protein, and often other evidence of antibody production
such as oligoclonal bands or increased IgG synthesis rate.
Neurologic Manifestations
Although the focus of this discussion is on peripheral nervous
system (PNS) manifestations, a brief mention of concerns about
CNS symptoms in Lyme disease is essential to understand the
purported controversy. The single most egregious misconception
is that individuals who perceive difficulties with memory and
cognition should be assumed to have nervous system Lyme
disease. As every practicing neuromuscular medicine specialist
knows, virtually any state with a systemic inflammatory response
(urinary or respiratory tract infections in older individuals, sepsis,
flu, active rheumatoid arthritis to name a few) can induce a toxic
metabolic encephalopathy.19 Somewhat similar symptoms occur
in individuals who are sleep deprived, stressed, depressed, or
have other neurobehavioral disorders. Without minimizing the
impact or importance of these symptoms, it is critical to recognize
that they are not indicative of CNS disease and have no more
specificity for Lyme disease than for depression, systemic lupus,
or the flu. The notion that the diagnosis of Lyme disease can be
made based primarily on such symptoms is not only illogical but
actually harmful, particularly when coupled with the incorrect
notion that it reflects a purportedly difficult to treat infection of the
brain, as the diagnosis of any brain infection is rightly terrifying
to most rational people.
Actual parenchymal brain infection with B. burgdorferi is
remarkably rare, estimates years ago were of about 1 case per
million population at risk per year. Current incidence, with more
widespread early treatment, is undoubtedly even lower. When
this does occur, it is typically a form of meningoencephalitis
with inflammatory CSF and focal abnormalities on neurologic
examination and magnetic resonance imaging (MRI) of the
appropriate part of the neuraxis. Affected individuals almost
always have intrathecal antibody production. Single photon
emission computed tomography scans have been suggested to
assess neuroborreliosis; they are generally uninformative. In
instances in which the MRI demonstrates focal inflammation,
positron emission tomography scans demonstrate locallyincreased metabolic activity.20
How then does Lyme disease affect the PNS? The most common
form of nervous system involvement, occurring in up to 15% of
infected individuals, consists of one or more of three elements:
meningitis, cranial neuritis, and radiculoneuritis.21,22 All most
commonly occur in the early disseminated phase of infection,
typically within one or a few months of infection onset. Often,
18
Table 2. Range of peripheral nervous system manifestations associated
with Lyme disease
Clinical presentation
Radiculopathy
Plexopathy
Mononeuropathy
Mononeuropathy
multiplex
Details
Motor, sensory, mixed
Lumbosacral, brachial
One or several
Large or small nerves,
and confluent
VII, III-VI, occasionally
Cranial neuropathies
VIII; rarely IX-XII
Diffuse: acute, subacute
Diffuse polyneuropathies or indolent
Rarely demyelinating
Entrapment
Carpal tunnel
Motor neuron disease
????
patients with more severe symptoms present earlier, those with
more subtle or indolent symptoms later, suggesting a doseresponse effect related either to inoculum size or the nature of the
individual’s inflammatory response to the particular spirochete
substrain.
Meningitis, which often co-occurs with PNS manifestations but is
likely not responsible for them, presents with typical headaches,
photosensitivity, neck stiffness, and systemic symptoms. Symptom
severity is highly variable and bears only a weak relationship to
degree of the pleocytosis. Compared to enteroviral meningitis,23
onset tends to be over days (rather than a few hours or less with
enterovirus) and less severe overall. Cerebrospinal fluid usually
demonstrates a lymphocytic pleocytosis, mildly elevated protein,
and often intrathecal antibody production or other evidence of
heightened antibody production such as oligoclonal bands.
As in the case described by Garin and Bujadoux, PNS symptoms
can be pleomorphic. Cranial neuropathies likely are the most
common presentation, particularly with seventh nerve palsies,
which represent about 80% of Lyme disease associated cranial
neuropathies. Facial palsy can be bilateral in up to 20%. Other
commonly affected nerves include those to the extraocular muscles,
and occasionally either the trigeminal or the vestibuloacoustic.
Although involvement of the lowest cranial nerves has been
reported in rare anecdotes, this is truly unusual. Involvement of
the optic nerve is as rare as is involvement of other parts of the
parenchymal CNS. A range of PNS manifestation associated with
Lyme disease are presented in Table 2.
The patient described by Garin and Bujadoux was quite typical
of individuals with Lyme radiculoneuritis. Pain is radicular in
character, and is often confused with a mechanical radiculopathy.
It tends to involve the limb that was the site of the tick bite, is
quite severe, and though somewhat dermatomal, typically spreads
beyond a single dermatome. It likely is the most frequently
misdiagnosed form of nervous system Lyme disease. Clues often
include the absence of relevant abnormalities on spine imaging,
the involvement of multiple dermatomes clinically and on
neurophysiologic testing, and a CSF pleocytosis.
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Table 3. Recommended antibiotic regimens for patients with peripheral
nervous system Lyme disease
• All regimens for 2-4 weeks.
• All regimens oral unless otherwise stated.
• Pediatric weight-based doses not to exceed adult doses.
• Doxycycline is not to be used in children under 8 years of age
due to effect on bones and teeth
Setting
Regimen
Radiculoneuritis, cranial
Doxycycline
neuritis, other PNS diseases
Alternatives, reasonable but
not proven in nervous system Amoxicillin
disease
Cefuroxime
or
axetil
Parenchymal CNS, severe
disease, or after oral treatment Ceftriaxone
fails
Cefotaxime
or Penicillin G
Adult dose
Pediatric dose
100 mg orally, two 4 mg/kg/day in two
times/day
divided doses
500 mg, three
times/day
50 mg/kg/day in
three divided doses
500 mg, two
times/day
30 mg/kg/day in two
divided doses
2 gm IV/day
50-75 mg/kg/day IV,
single dose
2 gm IV every 8
hours
3-4 million units
IV, every 4 hours
150-200 mg/kg/day
IV in three divided
doses
200,000-400,000
U/kg/day IV in six
divided doses
CNS = central nervous system, PNS = peripheral nervous system
__________________________________________________________
It appears likely that both the cranial neuropathies and the
radiculoneuritis are manifestations of a Lyme disease-related
mononeuropathy multiplex.24 Patients can present with more
typical mononeuropathies, or with lumbosacral or brachial
plexopathies. Some patients, particularly those with more
longstanding infection, can present with more of a stocking
glove-type picture. Neurophysiologically, these patients appear
to have a confluent mononeuropathy multiplex. In fact, looking
neurophysiologically at a broad cross section of patients with
Lyme disease-related PNS involvement, it appears that all
represent various presentations of the same pathophysiologic
process.
The few available neuropathologic studies25,26 demonstrate
perivascular inflammatory infiltrates (without true vasculitis) and
patchy nerve damage. Although there have been rare case reports
and small series of Guillain-Barré syndrome-like patients27 with
apparent Lyme disease, this must be considered either very rare or
coincidental, given the low frequency with which it is observed.
Pathophysiology is unclear. In the only animal model of
neuroborreliosis, the experimentally infected rhesus macaque
monkey,28 neurophysiologic and histopatholgic findings are
identical to those described above. In no animal or human material
has there ever been evidence of intact spirochetes, immune
complex deposition, vasculitis, or other compelling evidence of
a specific mechanism. In both humans and experimental animals,
PNS changes resolve fairly rapidly after antimicrobial therapy.
Finally, particularly in light of the preceding discussion, a
consideration of motor neuron disease, a subject of controversy
for 2 decades, is useful. Several anecdotes described patients who
appeared to have motor neuron disease,29,30 were treated for Lyme
disease, and recovered. One epidemiologic study in an endemic
area raised the possibility of an association between motor neuron
disease and positive Lyme serologies, but showed no compelling
response to treatment.31 Most data suggest that an association is
unlikely. That said, it is important to recognize that B. burgdorferi
infection is associated with a polyradiculopathy, that occasionally
motor symptoms can be more prominent than sensory, and
that, in some patients with radiculoneuropathy, there can be
associated involvement of the spinal cord at the affected level,
potentially resulting in upper motor neuron signs. Consequently,
in individuals with potential exposure and a predominantly lower
motor neuron picture, perhaps with mild myelopathic features,
the diagnosis should be considered, just as one considers cervical
compressive myelopathies and other alternative diagnoses in the
appropriate setting.
TREATMENT
In vitro, B. burgdorferi is highly sensitive to a broad range of
simple antimicrobials. Although not studied systematically in the
United States, the European literature is quite clear that meningitis,
radiculoneuritis, and cranial neuritis are equally effectively
treated (cured in 90-95%) by oral doxycycline and intravenous
cephalosporins such as ceftriaxone or cefotaxime.32 Common
practice is to treat patients with PNS Lyme disease with 3-4 weeks
of oral doxycycline. If they do not start to show improvement
within 2-3 months (or if they worsen significantly after treatment)
retreatment with 2-4 weeks of intravenous ceftriaxone is usually
curative (Table 3).
The role of a CSF examination is unclear. Given that meningitis is
typically cured by oral antibiotics, one can make a strong case for
simply treating orally, regardless of the CSF findings, rendering
the CSF information irrelevant. On the other hand, one might
argue that in a patient who fails to respond, CSF examination may
be informative, and in this setting knowledge of the pre-treatment
findings would be helpful. However, given the small number of
patients who require retreatment, the role of pretreatment CSF
assessment remains highly unclear.
SUMMARY
Peripheral nervous system involvement occurs in up to 10-15% of
patients with Lyme disease, most commonly manifesting as facial
nerve palsy, but occasionally involving other cranial nerve roots
or peripheral nerves. Most often missed is the originally-described
syndrome of acute, severely painful, mono- or oligoradicular
involvement. Virtually all manifestations appear to be attributable
to a mononeuropathy multiplex. Although immune mechanisms
may play a role in the pathophysiology of PNS involvement,
antimicrobial therapy is generally highly effective in rapidly
ending progression of disease, indicating a required role of active
infection. Currently available serologic testing is highly accurate
in nervous system Lyme disease, with the single exception that
occasionally symptoms may occur so early in infection that
serologic responses may not yet be demonstrable. In this setting,
a followup titer in several weeks will usually be diagnostic. Two
to 4 week courses of simple antibiotics such as oral doxycycline,
or occasionally parenteral cephalosporins, are highly effective.
19
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF NEUROBORRELIOSIS
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Henriksson A, Link H, Cruz M, Stiernstedt G. Immunoglobulin
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R. Evaluation of the intrathecal antibody response to Borrelia
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20. Kalina P, Decker A, Kornel E, Halperin JJ. Lyme disease of the
brainstem. Neuroradiology 2005;47:903-907.
21. Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE.
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24. Halperin JJ, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme
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treatable cause of peripheral neuropathy. Neurology 1987;37:1700-1706.
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28. England JD, Bohm RP, Roberts ED, Philipp MT. Mononeuropathy
multiplex in rhesus monkeys with chronic Lyme disease. Ann
Neurol 1997;41:375-384.
29. Waisbren B, Cashman N, Schell R, Johnson R. Borrelia burgdorferi
antibodies and amyotrophic lateral sclerosis. Lancet 1987;2:332-333.
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PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Polyneuropathies Associated
With Infectious Disease
Taylor B. Harrison, MD
Assistant Professor, Neuromuscular Division
Department of Neurology
Grady Memorial Hospital
Atlanta, Georgia
An estimated 7% of the adult population is afflicted by
polyneuropathy (PN).1 In approximately 75% of cases a detailed
history and focused laboratory evaluation will identify a proximate
cause.2 Although not routinely considered in the initial differential
diagnosis of PN, infectious diseases are important contributors to
multiple PN syndromes and, conversely, PN may be associated
with many infectious diseases. Infection-related PNs are, in most
cases, indirect consequences of immune activation rather than
a direct result of peripheral nerve infection or toxin production.
Polyneuropathies may present with prototypical sensorimotor
axonal PN, acquired demyelinating PN, or mononeuritis
multiplex. This discussion will provide a general overview of the
presentation, diagnosis, and management of the more common PN
syndromes associated with selected infectious diseases: human
immunodeficiency virus (HIV) and viral hepatitis (hepatitis B
virus [HBV] and hepatitis C virus [HCV]). The bacterial and viral
infections associated with Guillain-Barré syndrome (GBS) will be
reviewed. Diphtheria and leprosy, although rare in industrialized
countries, will also be discussed given that these conditions
remain relevant for the neuromuscular practitioner given the ease
of international travel and migration.
HUMAN IMMUNODEFICIENCY VIRUS
More than 34 million people currently live with HIV/acquired
immune deficiency syndrome(AIDS), with approximately 7,000
new infections per day in 2010.3 In North America, approximately
1.3 million are infected. The most common neurological
complication of HIV infection is PN. Polyneuropathy in this
clinical population is generally related to chronic HIV infection
with moderate-to-severe immunodeficiency, HIV-associated
distal sensory PN (HIV-PN), or a treatment-related toxicity
related to select antiretroviral drugs, known as antiretroviral
toxic neuropathy (ATN). Less common PN syndromes include
autonomic neuropathy, PN associated with diffuse infiltrative
lymphomatosis syndrome (DILS), peripheral nervous system
(PNS) vasculitis, and inflammatory demyelinating PNs.
Human immunodeficiency virus-associated distal sensory PN
and ATN are the most common PN syndromes and are clinically
important primarily due to neuropathic pain and measurable impact
on quality of life, function, and disability.4-6 Early in the era of
combination antiretroviral therapy (cART) approximately 35% of
patients with moderate-to-severe immunodeficiency (CD4 T cell
count < 300) had symptomatic PN.7-10 Asymptomatic neuropathy
signs may be observed in another 20% and, morphological
data from autopsy specimens suggest that neuropathy is nearly
ubiquitous with severe end-stage AIDS. The most consistent risk
factor for HIV-PN across multiple studies is age. Recent data
suggest symptomatic PN impacts a smaller percentage (10%) of
the HIV-infected population than previously described.11 Trends
in earlier HIV diagnosis and earlier initiation of effective nonneurotoxic cART likely contribute to these observations. While
the pathophysiology is not precisely known, HIV-PN is likely a
consequence of chronic immune activation as opposed to direct
viral infection of peripheral nerves, dorsal root ganglia (DRG), or
Schwann cells.
The dideoxynucloside nucleoside reverse transcriptase inhibitors
(NRTIs) didanosine (ddI), zalcitabine (ddC), and stavudine
(d4T)—the so-called “d-drugs”—have all been associated with
the development of ATN.12-15 While the frequency of ATN has
21
POLYNEUROPATHIES ASSOCIATED WITH INFECTIOUS DISEASE
decreased markedly with increased availability of non-neurotoxic
cART options, ATN remains important in resource-limited
regions where d4T in particular is a common cART component.
D-drug neurotoxicity stems from inhibition of the mitochondrial
DNA (mtDNA) gamma polymerase, a key enzyme for mtDNA
replication and repair.16 Typically, ATN occurs within 1 year
of treatment initiation and most commonly within the first
3 months.17,18
Human immunodeficiency virus-associated PN typically presents
with stocking-distribution sensory symptoms, numbness, and
neuropathic pain being most frequent. Examination reveals
minimal distal extensor weakness with decreased or absent ankle
reflexes.19 Polyneuropathy may also be symptom-predominant
with a normal examination, consistent with small fiber pathology.
Nerve conduction studies (NCSs) typically show generalized
length-dependent sensorimotor axonal PN, but may be normal.
Needle electromyography (EMG) may show distal-to-proximal
gradient of chronic reinnervation changes, though it is typically
normal if NCSs show no large myelinated fiber involvement.
Classic pathological findings of HIV-PN include distal axonal
degeneration with reduced unmyelinated fiber density and lesser
reductions in small and large myelinated fiber densities.20 Skin
biopsy is more sensitive than NCSs, showing reduced epidermal
nerve fiber density.21-23 Antiretroviral toxic neuropathy shares
similar clinical and electrophysiological features with HIV-PN,
the clinical distinction based on the timing of symptom onset or
worsening related to drug exposure and the patient’s response to
dosage reduction or drug withdrawal.12 At times the neuropathic
symptoms of ATN may continue to progress for weeks after drug
withdrawal, a phenomenon commonly referred to as “coasting.”
Attention to the prevailing state of immunodeficiency during
the onset and evolution of PN symptoms is paramount when
approaching the diagnostic workup. When PN onset coincides
with severe immunodeficiency in a cART-naïve patient, the
high prevalence of HIV-PN makes alternative causes unlikely.
Conversely, if PN symptoms commence with only mild
immunodeficiency (e.g., CD4 > 500), HIV-PN is unlikely
and other etiologies should be investigated, with testing as
recommended by American Association of Neuromuscular
and Electrodiagnostic Medicine-endorsed laboratory testing
guidelines.2 Worsening neuropathic pain in the setting of stable
HIV disease (suppressed viral load, only mildly or moderately
immunosuppressed) on non-neurotoxic cART with suppressed
viral load should also prompt thorough evaluation. Commonly
used medications which may contribute to PN include dapsone,
metronidazole, trimethoprim/sulfamethoxazole, and isoniazid.
Alcohol or intravenous drug (e.g., heroin) abuse, malnutrition,
vitamin (e.g., thiamine, B12) deficiency, renal insufficiency, and
disorders of glucose metabolism may all significantly contribute
to PN risk in the setting of HIV.
Efficacy for neuroregenerative therapy has not been established.24-28
Though limited data suggest cART initiation may improve HIVPN, no large scale trial documents significant improvement.29,30
Management has therefore focused on symptomatic pain relief.
Unfortunately, trials evaluating multiple agents from different
drug classes have failed to show clinically meaningful efficacy:
amitriptyline,31,32 gabapentinoids,33,34 mexiletine,31,35 topical
lidocaine gel,36 low-dose topical capsaicin,37 and Peptide T
22
(an in vivo gp120 inhibitor).38 There is no evidence in support
of acupuncture.32 Improvement in neuropathic pain has been
described with lamotrigine (specifically in ATN), high-dose (8%)
topical capsacin, recombinant nerve growth factor, and smoked
marijuana.39-42
Autonomic Neuropathy
The prevalence of HIV-associated autonomic neuropathy is
not known; autonomic symptoms, however, are frequent and
particularly so with severe immunodeficiency.43-45 Autonomic
neuropathy is important due to its association with cardiac
morbidity.46 Resting tachycardia, orthostatic hypotension,
impotence and urinary dysfunction, early satiety, constipation
and/or diarrhea, and disorders of sweating may be present. Study
of sympathetic ganglia shows neuronal degeneration coupled
with perivascular mononuclear cell infiltration with T cells and
macrophages.47
Bedside evaluation may reveal a > 20 mmHg drop in systolic or
> 10 mmHg drop in diastolic blood pressure without an adequate
increase in heart rate. In the absence of a dedicated autonomic
laboratory or quantitative sensory testing, electrophysiological
evaluation of suspected autonomic neuropathy is unfortunately
limited. Sympathetic skin response, which evaluates small fiber
sudomotor function, and may be available on standard needle
EMG equipment but is insensitive. Heart rate variability with the
Valsalva maneuver or deep breathing may also be evaluated with
some standard needle EMG equipment. Important considerations
with suspected autonomic dysfunction are the contributions of
anemia, hypovolemia, cardiomyopathy, and adrenal insufficiency,
the latter which may be suggested by orthostatic hypotension with
generalized fatigue, myalgia, weakness, and hyponatremia and/
or hyperkalemia. Adrenal insufficiency may be diagnosed with
a random cortisol or a cosyntropin stimulation test. Treatment
of orthostatic hypotension with autonomic dysfunction may
include salt (sodium chloride, NaCl) supplementation, thigh-high
compression stockings, the mineralocorticoid fludrocortisones,
midodrine, or erythropoietin.
Diffuse Infiltrative Lymphomatosis Syndrome
Diffuse infiltrative lymphomatosis syndrome is rare, estimated
in 3-4%, and characterized by multisystem CD8 lymphocytic
visceral infiltration involving primarily salivary glands and
lungs.48 Peripheral nerve, kidney, and gastrointestinal involvement
are also seen. Clinical presentation is of parotid enlargement,
sicca symptoms and CD8 hyperlymphocytosis (generally defined
as CD8 counts > 1,500). Diagnosis is based on the presence of
xerostomia, chronic (> 6 months) submandibular enlargement,
and lymphocytic infiltration on either salivary biopsy or gallium
scintigraphy.
Patients with peripheral nerve involvement typically present
with acute or subacute painful sensorimotor axonal PN.49 The
pathological hallmark consists of angiocentric peripheral nerve
infiltration of T lymphocytes, mimicking that seen with T-cell
lymphoma.50 It is important to recognize this PN syndrome
as management includes initiation of cART with or without
low-to-moderate doses of systemic corticosteroids. Analgesic
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
management may be considered contingent upon pain severity
and its impact on function.
Inflammatory Demyelinating Polyneuropathies
Acute and chronic inflammatory demyelinating PNs (AIDP
and CIDP, respectively) are relatively rare conditions in the
setting of HIV infection, with descriptions limited to small case
series, and are classically associated with mild-to-moderate
immunosuppression.51,52 Early published reports emphasized
these syndromes as neurological presentations prompting to the
diagnosis of HIV infection: AIDP in particular has been described
with the HIV seroconversion syndrome, which may occur
between 3-9 weeks after initial virus exposure. The symptoms
of an HIV seroconversion syndrome, which is estimated to occur
subsequent to one-third to one-half of acute HIV infection, are
typically indistinct “viral” complaints of fever, headache, myalgia,
arthralgia, rash, or diarrhea. However, AIDP may also occur with
severe immunodeficiency, though CD4 counts are rarely < 50.
Clinical, electrophysiological, and pathological findings do
not differ from that observed in non-HIV infected patients. An
important unique clinical feature of AIDPs in the setting of HIV
infection is the presence of a mild lymphocytic pleocytosis in
cerebrospinal fluid (CSF), which contrasts with the traditional CSF
profile of the relatively acellular albuminocytologic dissociation.
Differential diagnosis of HIV-associated AIDP may include
cytomegalovirus (CMV) polyradiculopathy or HIV-associated
neuromuscular weakness syndrome (HANWS). While
CMV has been associated with AIDP in the setting of severe
immunodeficiency, it is more commonly associated with ascending
weakness due to polyradiculopathy. Early bladder (urinary
retention) or bowel (obstipation) involvement are important
clinical signs that help distinguish this syndrome from AIDP.
Cerebrospinal fluid reveals a polymorphonuclear pleocytosis
(average cell count of 500-600/ml) with elevated protein and
decreased glucose, although may be normal.53-57 A positive
CMV polymerase chain reaction in CSF confirms the diagnosis.
Preferred therapy of CMV polyradiculopathy is a combination of
gancyclovir with initiation of cART.57 Without antiviral therapy,
survival is on the order of weeks.53
Human immunodeficiency virus-associated neuromuscular
weakness syndrome is an acute (1-2 weeks) or subacute (> 2
weeks) syndrome of rapidly progressive neuromuscular weakness
associated with lactic acidosis and possibly hepatic steatosis.58
Most patients with HANWS present with nausea, vomiting,
abdominal pain, and a sensorimotor axonal PN, though some
patients have been noted to have mixed features of demyelination
and/or concomitant myopathy. While the cause is not clear,
mitochondrial dysfunction is the leading hypothesis. This
condition has been linked mostly to stavudine (d4T) and there
exist little evidence-based management options outside of NRTI
withdrawal and supportive care.
Management consists of plasma exchange (PE) or intravenous
immunoglobulin (IVIg) for AIDP and oral immunosuppressants
with or without IVIg or PE for CIDP, essentially unchanged from
that recommended for non-HIV infected patients. There exist few
data describing outcomes of acquired inflammatory demyelinating
PNs in the setting of HIV outside of one small study documenting
that intensive care unit length of stay and number of days on
ventilation does not differ between HIV and non-HIV infected
patients.59
Peripheral Nervous System Vasculitis
Peripheral nervous system vasculitis has a low incidence in HIV (<
1%), but it is important to recognize as it is a severe condition that
is treatable. Peripheral nervous system vasculitis may be observed
at any stage of infection, though generally observed early after
initial infection or late in the setting of severe immunodeficiency.
Whereas an underlying state of immune activation may be at play
early in the infection, CMV reactivation or another infectious
phenomenon is the major consideration in late stages of infection.
A painful mononeuropathy multiplex (MM) is the classic
presentation with asymmetrical non-length–dependent signs and
symptoms. Nerve conduction studies document an asymmetric
sensorimotor axonal PN; overlapping mononeuropathies,
however, may at times obscure the multifocal nature and
the condition presents as a prototypical length-dependent
sensorimotor axonal PN. Needle EMG shows non-length–
dependent and/or asymmetric active denervation coupled with
variable acute, subacute, or chronic reinnervation changes. In
some cases concomitant irritably myopathy is noted. When
nerve biopsy is performed (generally sural, superficial peroneal,
or radial), concomitant muscle biopsy (gastrocnemius, peroneus
brevis, or deltoid) may increase diagnostic sensitivity. The
pathological hallmark is necrotizing thrombosis or inflammatory
infiltration of vessels on nerve biopsy. Small, medium, and large
vessel vasculitis have all been reported.
When vasculitis occurs relatively early in HIV with mildto-moderate immunosuppression, it may be associated with
immune complex deposition or infiltrating CD8 T cells. These
inflammatory processes may reflect a reaction to HIV infection
of endothelial cells or, in some cases, neoplasm. Other potential
causes for a similar clinical picture are related to HBV or HCV
co-infection, cryoglobulinemia, immune complex disease, or drug
reaction. Serum autoantibodies must be interpreted with caution
in HIV/AIDS due to the high frequency of polyclonal B-cell
activation in the setting of abnormal T cell regulation. With severe
immunodeficiency, CMV is the classic pathogen and particularly
so with a history of prior or current CMV infection (e.g, retinitis,
gastroenteritis, or pneumonia). Vasculitis has also been reported
with mycobacterium tuberculosis, and pneumocystis jirovecii.
Management depends mostly on the severity of prevailing
immunodeficiency: early HIV-associated vasculitis may be treated
with ARVs whereas in later stages therapy is directed towards
the underlying co-infection. For those with advanced disease
and evidence of CMV, gancyclovir with or without foscarnet is
preferred.
POLYNEUROPATHY ASSOCIATED
WITH VIRAL HEPATITIS
Hepatitis B
Hepatitis B causes chronic infection in approximately 10%
of infected patients, and the global burden of chronic HBV is
considerable given that approximately 350 million people are
23
POLYNEUROPATHIES ASSOCIATED WITH INFECTIOUS DISEASE
infected worldwide and, as of 2009, and estimated 30 million
chronically infected in the United States.60 Rates of acute infection
in the United States have dropped dramatically after introduction
of immunization programs in 1991.
Of those with chronic HBV infection, approximately 20% develop
extrahepatic disease. While in unselected chronic HBV carriers
the reported frequency of neuropathy does not appear to be higher
than in the general population, PN is very common in the setting of
HBV-associated polyarteritis nodosa (PAN).61 Hepatitis B virusassociated PAN is a vasculitis affecting medium-sized muscular
arteries and is the most serious presentation of HBV-associated
extrahepatic disease. The pathogenesis of PAN is likely due to the
deposition of immune complexes containing hepatitis B surface
antigen (HBSAg) or “e” antigen (HBeAg, a protein that circulates
with actively replicating virus) which triggers activation of the
complement cascade and activation of neutrophils. Polyarteritis
nodosa generally occurs within 6 months of viral infection.
Polyneuropathy is the most frequent finding in PAN, seen
between half to three quarters of patients, and may be the earliest
manifestation in approximately 25%.62
Clinical presentation of PAN includes PN, new-onset hypertension
from renal involvement, skin nodules, orchitis, as well as
abdominal pain and bleeding.63 Mononeuropathy multiplex is the
most common PN presentation, predominately affecting fibular,
tibial, ulnar, and radial nerves. Hepatitis B can be diagnosed
by the presence of HBSAg and antigen to soluble nucleocapsid
protein, hepatitis B core antigen (HBcAg).
Multiple antiviral regimens are currently available for the
treatment of HBV including tenofovir, entecavir, as well as
pegylated interferon in the absence of cirrhosis. Combined
antiviral and immunosuppressive treatment with steroids, PE
(to remove immune complexes), or cyclophosphamide are
recommended with severe disease.
Hepatitis C
An estimated 130-170 million people worldwide are infected
with hepatitis C, approximately 4 million in the United States.64
Natural history studies suggest that 55-85% of acutely infected
patients will become chronically infected. Chronic HCV infection
is related to a number of extrahepatic syndromes, including
mixed cryoglobulinemia, renal impairment, polyarthralgia, and
sicca symptoms. Polyneuropathy is considered the most common
neurological complication of chronic HCV infection, with clinical
PN estimated to affect approximately 10%.65,66
Hepatitis C virus-associated PN is primarily associated with
cryoglobulinemia, with an observed frequency of up to 50% in
chronic infection.65 Cryoglobulins are immunoglobulins (Igs)
which precipitate in vitro at temperatures ≤ 37°C, generated by
clonal B cell expansion associated with the persistent immune
stimulation of chronic infection. Cryoglobulinemia is classified
by clonality and immunoglobulin type: type I, monoclonal
immunoglobulins only; type II, a combination of monoclonal
and polyclonal immunoglobulins; and type III, characterized
by only polyclonal immunoglobulins. Hepatitis C virus-related
cryoglobulinemia is generally “mixed” cryoglobulinemia,
consisting of either monoclonal IgM with polyclonal IgG (type
II) or polyclonal IgM and IgG (type III). After identification
24
of HCV virus in the late 1980s, it was realized that > 80% of
mixed cryoglobulinemia could be ascribed to HCV infection. The
pathogenic IgM generally feature rheumatoid factor (RF) activity.
Hepatitis C virus PN may present as a generalized sensorimotor
PN or MM. Pathologically, cryoglobulinemia may be associated
with vasculitis affecting small arteries, arterioles, capillaries, and
venules. Nerve tissue shows axonal loss with fascicular variability,
demyelination, and perivascular mononuclear infiltrates. Palpable
purpura with underlying leukocytoclastic vasculitis is common,
as are Raynaud’s disease, glomerulonephritis, and gastrointestinal
pain. Strict attention to collection and laboratory processing
are paramount when assessing for cryoglobulins (reviewed in
Ramos-Casals and collegues67). Additional laboratory findings
which may support a diagnosis of cryoglobulinemia included low
complement (C4 and CH50, with C3 levels typically normal) and
presence of rheumatoid factor activity.
Treatment of HCV-associated PN is based on therapy directed
towards the underlying infection, which currently includes
ribavirin and pegylated interferon-α. Antiviral therapy combined
with high-dose corticosteroids have been used with severe
vasculitis in spite of negative trials, as the effect of antiretroviral
therapy is relatively delayed.68,69 Severe cryoglobulinemic
vasculitis may also be treated with rituximab, a monoclonal
antibody against the CD20 antigen expressed on B cells.70
INFECTIONS ASSOCIATED WITH
GUILLAIN-BARRÉ SYNDROME
Guillain-Barré syndrome is the most common cause of
neuromuscular paralysis in nonpolio afflicted industrialized
countries, with a incidence of 0.62-2.66/100,000 person
years.71 A detailed description of the clinical presentation,
electrophysiologic and clinical variants, as well as therapeutic
options are beyond the scope of this discussion, the details of
which are reviewed elsewhere (see Hughes and Cornblath72).
While there is little doubt that GBS is immune mediated, is
atypical for an autoimmune disease given that it is monophasic,
demonstrates male predominance, and incidence increases with
older age. Guillain-Barré syndrome is commonly considered to be
a postinfectious neurological syndrome given that up to two-thirds
of patients report an illness in the preceding 6 weeks (generally
the previous 1-4 weeks) before neurological symptoms. In most
cases, the antecedent infectious cause cannot be definitively
identified. Respiratory and gastrointestinal syndromes are most
frequently reported.
The infectious pathogen most commonly associated with GBS
is Campylobacter jejuni, a gram negative rod which is the most
common cause of bacterial gastroenteritis in developed countries.
C. jejuni has been implicated in up to 32% of GBS cases in
prospective series.73,74 Gastroenteritis from C. jejuni is generally
a febrile illness with abdominal pain and non-bloody diarrhea.
Epidemics of acute motor axonal neuropathy (AMAN) related to
C. jejuni have been reported in Northern China, while seasonal
gastroenteritis associated with AMAN has been described in
Mexico.75,76 Such has also been described in Japan. C. jejuni
infection may portend more severe GBS, typically in setting
of AMAN and acute motor and sensory axonal neuropathy
(AMSAN), and a poorer prognosis.73,77 The vast majority of
patients with C. jejuni gastroenteritis, however, do not develop
GBS, and GBS with asymptomatic C. jejuni infection have also
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
been reported; these findings suggest important host determinants
exist which contribute to the GBS development. Apart from
AMAN, C. jejuni has also been associated with AIDP, AMSAN,
and the Miller-Fisher variant of GBS.
C. jejuni triggers GBS through a mechanism coined “molecular
mimicry,” wherein cross-reactivity between bacterial cell wall
epitopes and nonprotein gangliosides of human peripheral nerve
leads to immune-mediated nerve damage. C. jejuni polymorphisms
of the gene involved in production of ganglioside epitopes (cstII) is associated with both host antibody production and clinical
phenotypes (e.g., Miller-Fisher variant, with gangliosides GQ1b,
GM1, and GD1a, with weakness).78 C. jejuni gastroenteritis is
associated with generation of IgG against the GM1 ganglioside,
the presence of which may predict a more severe case for GBS
with worse recovery. Although other ganglioside antibodies have
also been identified against GD1a, GM1b, and GalNac-GD1a
in the setting of C. jejuni, these antibodies are not consistently
associated with neither a particular infectious agent nor a
particular electrophysiological GBS phenotype.
The second most common bacterial infection preceding GBS
is mycoplasma pneumonia, associated with up to 5% of GBS,
typically in younger patients.79,80 The most common presentation
of M. pneumoniae infection, which causes an atypical or walking
pneumonia, is low grade fever, dry or nonproductive cough,
diffuse arthralgia, and headache. Sputum gram stain and cultures
are negative. Diagnosis is made by presence of cold agglutinins
or though collection of acute and convalescent antibody titers.
M. pneuomiae may be associated with glactocerebroside (Gal-C)
antibodies.81
The most common virus associated with GBS is CMV, followed
by Epstein-Barr virus (EBV).73,74 Both of these viruses may be
more common in younger GBS patients. Although transaminase
elevations have been believed to suggest potential CMV or EBV
infection in GBS, the majority of transaminase elevations with
GBS are idiopathic.82 Atypical lymphocytes in peripheral blood,
cold agglutinins, or the presence of polymorphonuclear cells
in spinal fluid may suggest CMV infection. Cytomegalovirus
has been estimated to precede neurological symptoms in
approximately 17% of GBS.73 Clinically, CMV infection is
associated with a nonspecific upper respiratory viral syndrome
with lymphadenopathy and diagnosis can be made through
collection of acute and convalescent sera. Cytomegalovirus is
associated with generation of IgM targeting the ganglioside
GM2. Cytomegalovirus has been reported to cause more sensory
symptoms, cranial nerve involvement, and may be associated with
delayed recovery. Epstein-Barr virus also causes a nonspecific
viral syndrome with fever, pharyngitis, lymphadenopathy, and
atypical lymphocytes lasting 1-4 weeks. Rarely, it may involve
splenic enlargement of liver involvement. Epstein-Barr virus
may be diagnosed with either a Monospot test (Paul-Bunnell
heterophile IgM) or acute and convalescent antibody titres. It has
been suggested that EBV infection may be associated with less
milder form of GBS (e.g., capable of ambulating at nadir).80
At this time neither the identification of a specific pathogen nor a
particular autoantibody influences GBS treatment decisions.
Diptheria
Corynebacterium diphtheria is a toxogenic gram positive bacterium
that causes local infection of the upper respiratory tract or skin.
Diphtheria is currently rare given longstanding immunization
programs, with the last confirmed U.S. case in 2003.83
C. diptheria persists in resource-poor settings, which in the
Americas includes Haiti and the Dominican Republic and in
nonimmunized individuals and, when associated with neurological
symptoms, is an important consideration in the differential
diagnosis of GBS.
Diphtheria typically begins as an exudative pharyngitis, with a
greyish-while membranous exudate. In severe cases a “bull neck”
due to cervical lymphadenopathy and local tissue swelling may be
observed. Neurological symptoms begin after acute infection in
up to 20% of patients, typically in a biphasic pattern.84 In classic
diphtheric PN, bulbar symptoms develop between 3-6 weeks after
pharyngitis. Common symptoms and signs include weakness of
the soft palate, impaired pharyngeal sensation, and paralysis of
pupillary accommodation (which causes blurring of near vision).
A more generalized demyelinating sensorimotor PN, which when
severe may cause diaphragmatic weakness, may follow after 8
weeks. Cardiovascular complications may be observed, with
loss of vagal tone and tachycardia secondary to involvement of
large myelinated parasympathetic fibers. Cutaneous infection,
which is less common than the classic pharyngitis, may cause
local neuropathic symptoms and signs, the distribution of which
is dependent upon the proximity of selected nerves to the skin
lesion(s).
C. diphtheria produces a protein exotoxin which causes segmental
demyelination of nerve roots and peripheral nerves. Most
pathologic changes are seen at the level of the roots and DRG,
due to the presence of fenestrated capillaries which produce an
ineffective blood-nerve barrier. While bulbar symptoms are
believed to reflect local effects of exotoxin, the generalized
sensorimotor PN follows hematogenous dissemination of
exotoxin. Electrophysiology and CSF findings are similar to that
observed with AIDP.
Management includes intravenous penicillin and early treatment
with diphtheritic horse serum antitoxin.84 Antitoxin may prevent
or lessen the PN severity, but treatment decisions are necessary
generally prior to confirmation of diagnosis for antitoxin to be
effective. Administration of antitoxin may be associated with
serum sickness, which has been reported in up to 10% of those
receiving treatment. Cultures from the pharynx or skin swabs are
confirmatory, but specific culture conditions are required. Acute
and convalescent serum titres can also be supportive for infection.
Treatment of the subsequent neurological complications is
supportive and, given the cardiac morbidity, cardiac monitoring
is warranted.
LEPROSY
Mycobacterium leprae was first identified as the pathogen
responsible for chronic granulomatous infection of skin and
peripheral nerve in the late 1800s by Dr. Gerhard Hansen, hence
the moniker Hansen’s disease, but recognition of the syndrome
dates back over 2,000 years. Generally considered in the current
25
POLYNEUROPATHIES ASSOCIATED WITH INFECTIOUS DISEASE
era as a disease of poverty, leprosy remains an important cause
of PN worldwide and is the leading infectious cause of disability.
Overall, an estimated 2-3 million people are currently living with
leprosy-related disability and, although prevalence has dropped
substantially due to global eradication efforts, approximately
250,000 new cases are reported annually.85 The disease is
predominately found in tropic and subtropic regions, with the
most cases currently reported in Brazil, India, and Indonesia. The
recorded prevalence and incidence of leprosy are considered low
given the stigma associated with the condition contributing to
reluctance of patients to seek care. Pockets of endemism in the
United States occur in Texas, Louisiana, Hawaii, and California
with most cases being identified in immigrant populations.
Humans are the principle reservoir, though some primates carry
M. leparae and in the Americas armadillo-derived strains account
for up to two-thirds of isolates. Infection is intracellular, involving
macrophages in skin and Schwann cells in nerve. Transmission is
belived to be via respiratory or nasal droplets, though cutaneous
transmission cannot be entirely excluded. M. leprae is slow
growing, and there is a long interval between infection and
clinical symptoms, spanning around 5-7 years. The majority of
M. leprae-infected individuals do not develop clinical disease;
the exact proportion, however, is not known as no diagnostic test
reliably identifies subclinical infection.
Familiarity with the signs of leprosy is important as there exists no
confirmatory point-of-care diagnostic test and prompt treatment
prevents the development of disability. Clinical diagnosis is made
by the presence of typical skin lesions, enlarged nerves, and skin
smear or biopsy documenting acid-fast bacilli. Skin lesions include
macules (< 10 mm) or plaques (> 10 mm) located over the trunk
or abdomen, but may occur anywhere. Skin lesions are generally
hypopigmented, have a raised edge, and are accompanied by
sensory loss. Based on skin lesions, the disease may be classified
as paucibacillary (up to five skin lesions) or multibacillary
(over five skin lesions), a schema which helps guide treatment
decisions (discussed later). In an estimated 10% of patients, rash
may be absent and with PN being the only symptom. Leprosy
is further classified as being either tuberculoid or lepromatous,
with the type of disease determined by the host’s cell-mediated
immune response: tuberculoid leprosy is characterized by a
good cell-mediated immune response with few skin lesions and
no detectable myocobacteria; lepromatous leprosy, by contrast,
features a poor immune response (anergy) with multiple skin
lesions and high mycobacterial burden. Tuberculoid leprosy is
generally paucibacillary while lepromatous disease is typically
multibacillary. Many patients lie in the middle of these extremes, a
condition referred to as borderline leprosy. Infectivity is generally
limited to lepromatous leprosy.
Leprosy-related PN stems from either M. leprae’s direct infection
of Schwann cells or may be a consequence of the immune response
to myocbacterial antigens. On average, approximately 20-30% of
leprosy patients have PN signs and symptoms at time of diagnosis,
though estimates vary significantly amongst different studies.
In patients with PN, sensory symptoms are more common than
motor symptoms, and “negative symptoms” or loss of function
predominates. Loss of autonomic function results in anhydrosis in
the distribution of involved nerves with cool, dry skin. Pain, when
26
present, usually occurs with nerve inflammation and edema. An
asymmetrical, non-length dependent MM is the most common PN
pattern. Generalized PN, however, may also be seen.
In tuberculoid leprosy nerve involvement is typically in close
proximity to skin lesions. Common nerves involved in disease
include the sural, fibular, posterior tibial, median, ulnar, posterior
auricular, and superficial radial sensory nerves. Nerve swelling
is typically proximal to the skin lesion. In lepromatous disease
PN is more prominent, with more diffusely enlarged nerves,
and pathology frequently involves cooler regions of the body,
including the nose, ears, and the tips of fingers and toes, reflecting
both diffuse disease and M. leprae’s predilection for replicating in
cooler temperatures.
The host immune response is an important mediator of nerve
damage. Generally speaking there exist two types of immune
responses, or reactions: (1) a type I, or reversal reaction (RR);
and (2) a type II reaction, or erythema nodosum leprosum (EHL).
These reactions can occur before, during, or after introduction of
multidrug therapy and may lead to the patient’s initial neurologic
presentation. Type I RRs represent an increase in cell-mediated
immunity and is recognized clinically by erythematous skin
lesions and peripheral nerve swelling (particularly the ulnar nerve
at the elbow and tibial nerve behind the malleolus). Type I RR
reactions generally occur with borderline leprosy and during the
first year of therapy. Type II EHL reactions present with painful
erythematous skin nodules (pannicultis), acute mononeuropathies,
as well as orchitis, arthritis, and fevers. Type II EHL reactions are
typically seen with lepromatous leprosy though may also occur
with borderline disease.
The World Health Organization currently recommends 6
months of multidrug therapy with dapsone and rifampicin for
paucibacillary disease or 12 months of dapsone, rifampicin, and
clofazimine for multibacillary disease. Steroids are a mainstay
of therapy to improve neurologic outcome of RR s, with current
recommendations endorsing prednisolone 40 mg daily, generally
for about 12 weeks.86 Recognizing that patients with pre-existing
neuropathy are at higher risk for worsened neuropathy after
treatment initiation, however, there is no conclusive evidence that
steroids can prevent neuropathy.87 Shorter courses of steroids are
generally used for EHL, but for severe and/or recurrent reactions
thalidomide may be considered.
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29
30
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Varicella Zoster Virus and Postherpetic
Neuralgia: A New Era?
Dianna Quan, MD
Associate Professor of Neurology
University of Colorado Denver
Aurora, Colorado
INTRODUCTION
Varicella zoster virus (VZV) is a stable, highly neurotropic,
human alpha herpesvirus that causes chickenpox (varicella).
After primary infection, VZV becomes latent in cranial nerve,
dorsal root, and autonomic ganglia along the entire neuraxis.1,2
Decades later, viral reactivation produces herpes zoster (shingles),
characterized by dermatomal pain and rash.3,4 Pain usually lasts
4-6 weeks but may persist for months or years, a condition
known as postherpetic neuralgia (PHN). Postherpetic neuralgia
is the most common neurological complication of zoster, and
most clinicians agree to define it as pain lasting 3 months or
longer after resolution of rash. In addition to PHN, zoster may
also be complicated by sensorimotor deficits due to associated
meningoradiculitis, unilateral segmental motor neuronitis, and
degeneration of related motor and sensory spinal roots. These
neuromuscular sequelae of VZV infection are challenging to treat
and have important implications for quality of life and utilization
of healthcare resources.
ZOSTER AND ITS COMPLICATIONS
Herpes zoster has the highest incidence of all neurological
diseases, affecting about 1 million people each year in the United
States,5 with millions more worldwide. Zoster skin lesions
typically resolve within 7-10 days, but pain during this period
may be intense. In cases with more severe inflammatory damage
to structures beyond sensory ganglia, numbness and weakness
in corresponding dermatomes and myotomes cause lasting
functional impairments. In some cases, the diagnosis of zosterinduced neurological dysfunction is confounded by the absence
of rash, a condition known as zoster sine herpete.6
Zoster results from latent VZV reactivation and transport to
basal epidermis of skin. Initially, infected cells down-regulate
interferon-α and lymphocyte adhesion molecules, favoring
virus spread.7 As infected cells die, interferon-α is induced in
neighboring cells, slowing the spread of VZV and enhancing
T-cell clearance of the infection.8,9 The frequency of zoster is
proportionally related to the incidence of chickenpox, which is
independent of socioeconomic status, population density, gender,
or ethnic origin.10 No genetic predisposition has been identified.11
Most cases of zoster resolve without incident, but a minority of
patients go on to develop PHN, the most common neurological
complication of zoster. Pain is usually aching, burning, or
lancinating. Other features include allodynia (pain with normally
innocuous tactile stimuli) and hyperalgesia (hypersensitivity to
mildly painful stimuli). Estimates of the incidence and prevalence
of PHN vary depending on the definition used and the age and
immune system function of the population under study. Older
age, presence of prodromal pain, greater rash severity, and greater
acute pain severity are all clear risk factors.12-15
Older individuals are especially vulnerable to zoster and PHN
because of decreased cell-mediated immunity.16 A retrospective
review of 916 zoster patients found that nearly 40% of those over
age 60 continued to have pain for months or years after resolution
of rash compared to 4.2% in those younger than age 20.17 In a
prospective study of patients older than 60, a similar PHN
prevalence of 35% was observed 6 months after zoster onset.18
Using a more stringent criterion of pain ≥ 3 on a 0 (“no pain”)
to 10 (“pain as bad as you can imagine”) scale, a large herpes
zoster vaccine trial in individuals over age 60 demonstrated a
31
VARICELLA ZOSTER VIRUS AND POSTHERPETIC NEURALGIA: A NEW ERA?
lower PHN prevalence of 12.5% among placebo-treated patients
who developed zoster.5 Overall, zoster and PHN may be viewed
in the context of a continuum of immunodeficiency, ranging from
a natural decline in VZV-specific cell mediated immunity (CMI)
with age to more serious immune deficits seen in cancer patients
and transplant recipients, and ultimately in patients with acquired
immune deficiency syndrome.19
The exact cause of PHN is uncertain, but data suggest several
possible mechanisms. One is that decreased VZV-specific
cellular immunity in elderly patients may contribute to lowlevel ganglionitis, which in turn may sustain pain and even
contribute to alteration of neural circuitry involved in pain
perception. The hypothesis that viral ganglionitis contributes to
PHN is compatible with other concepts of pain generation in this
condition. Rowbotham and Fields have suggested that PHN is
not a homogeneous disorder and that multiple pathophysiological
mechanisms are likely responsible for pain.20 These include
abnormal sensitivity of damaged cutaneous afferents to stimuli,
destruction of sensory nerves or cell bodies resulting in altered
central nervous system processing of normally innocuous tactile
stimuli, and deafferentation due to destruction of large and small
diameter sensory fibers and accompanying sensitization of
central pain transmitting neurons. Ongoing nerve or ganglionic
inflammation due to persistent viral activity may further amplify
pain by increasing input along these central and peripheral
pathways.21-25
The impact of PHN on quality of life may be severe and longlasting.
Due to unrelenting pain, patients can develop a wide array of
disturbances in psychosocial and physical functioning, including
depression, impaired sleep and appetite, diminished energy, as
well as physical, occupational, and social disability.26-28 Changes
in mood, personality, activity level, and social interactions are
common.29 The cost of incompletely effective drugs and increased
utilization of primary care physicians, specialists, and other
services are a significant public health problem that may consume
substantial healthcare resources.30,31
VARICELLA ZOSTER VIRUS VACCINES
The chickenpox vaccine was developed by passaging VZV
isolated from a 3-year-old boy 11 times in human embryonic lung
cells, six to seven times in guinea pig embryo (GPE) cells, and two
to six times in human diploid WI-38 cells.32 Merck laboratories
further passaged the virus though different cell lines to produce
the commercial varicella vaccine (Varivax®) which contains
1,350 plaque-forming units (PFUs) in 0.5 ml of sterile water.33
Like wild-type virus, Oka/Merck vaccine virus becomes latent in
ganglia and can reactivate to produce zoster.34,35 To date, the rate
of zoster in vaccinated children is comparable to that in healthy
children after natural varicella (http://www.varivax.com/).
The attenuated Oka/Merck-VZV vaccine containing 18,70060,000 PFUs of virus was tested in a large-scale double-blind,
placebo-controlled, multi-center Shingles Prevention Study (SPS)
to determine the effect of VZV vaccination in preventing zoster.5
More than 38,000 recipients of the zoster vaccine were followed
closely for 3 years. The incidence of zoster in the placebo group
was 11.1 per 1,000-person years. This figure approximates the
32
results of an epidemiological survey performed a decade ago,
which revealed zoster exceeding 10 cases per 1,000-person years
among individuals older than 75 years.36 Overall, the vaccine
reduced zoster incidence by about 50% but did not prevent the
disease in everyone.5 The incidence of PHN was reduced by 66%.
The zoster vaccine was introduced in 2006, and vaccination is
now recommended for immunocompetent adults aged 60 or older.
Studies are ongoing to evaluate the use of vaccine in younger
adults and immunocompromised individuals.
IMPACT OF VACCINATION
While the varicella and shingles vaccines represent impressive
steps in the prevention of VZV-related disease, they will not
eliminate chickenpox, zoster, or PHN, because not all individuals
who would benefit get vaccinated, and not all vaccinated
individuals develop adequate immunity. Even if all older adults
in the United States were vaccinated in the next few years,
many would still develop zoster, PHN, or other complications.
Furthermore, childhood varicella vaccine will not eliminate PHN.
The precise longterm effect of childhood immunization on the
incidence of zoster and PHN is unknown. While VZV vaccination
protects most children from chickenpox, less exposure of adults to
infected children may reduce periodic immune boosts, resulting
in lower cell-mediated immunity to VZV.37 Thus, vaccination of
children may actually place today’s adults at higher risk for zoster
and PHN later in life.38,39
By the year 2050, 20.2% of Americans (88.5 million people) will
be 65 years or older. The population over 85 will increase by more
than 100% to 19 million (http://www.census.gov/population/
www/projections/summarytables.html), greatly increasing the
number of people at risk for zoster and PHN. There are also likely
to be more patients with cancer, human immunodeficiency virus
infection, organ transplants, and other sources of pharmacological
immunosuppression who will be susceptible to the serious
complications of VZV reactivation. Despite recent progress in
disease prevention, zoster and PHN will continue to be important
clinical problems for many decades to come.
COST EFFECTIVENESS OF ZOSTER
VACCINATION
Numerous analyses have examined the cost effectiveness of
zoster vaccination in different countries, and most have found
the vaccine to be cost effective. Data from the United States
predicts a similar favorable outcome for society and payers. In
a 2007 analysis, Pellisier and colleagues modeled the effect that
vaccination would have on a cohort of 1 million people older than
age 60 compared to an unvaccinated group.40 The age-specific
incidence, health-care resource use, costs, and quality-adjusted
life years (QALYs) were examined. Costs and outcomes were
presented over the lifetime of vaccinees.
The analysis assumed a vaccine cost of $150, and healthcare
resource utilization and costs associated with the diagnosis
of herpes zoster and PHN were calculated from the Medstat
database. The cost calculation included inpatient admissions,
outpatients doctors’ visits, emergency visits, diagnostic
procedures, and outpatient pharmacy prescription. Using PHN
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
data derived from the SPS, vaccination of 1 million Americans
over age 60 is expected to prevent 75,548-88,928 cases of zoster
and 20,000 cases of PHN. The model predicts that over 300,000
outpatient visits, 375,000 prescriptions, 9,000 emergency room
visits, and 10,000 hospitalizations could be avoided. The cost
savings would be $82-100 million, with cost effectiveness ratios
between $16,229-27,609 per QALY gained. This is well below
most accepted thresholds for cost effectiveness.40
CURRENT TREATMENT OF ZOSTER AND ITS
COMPLICATIONS
Oral antiviral medication for 7-10 days is standard treatment for
herpes zoster that is within 72 hours of onset. Early aggressive
treatment of pain may also be beneficial to reduce the chances of
developing PHN. The Federal Drug Administration has approved
lidoderm, gabapentin, and pregabalin for treatment of PHN. A
new long acting 8% capsaicin patch was also recently approved
for this indication.41 Other generic medications including oral
narcotics, tricyclic antidepressants, and numerous other antiepileptic medications are also routinely used off-label in clinical
care. American Academy of Neurology practice guidelines
give a level A recommendation (class I and II evidence) for
tricyclic antidepressants, gabapentin, pregabalin, opioids, topical
lidocaine, capsaicin cream, and preservative-free intrathecal
methylprednisolone. Other modalities have less evidence to
support their use.42 Unfortunately, most treatments are associated
with significant potential side effects, especially in the elderly
population that suffers the most from PHN.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
SUMMARY
Varicella zoster virus causing zoster and its related complications
is a common cause of neuromuscular dysfunction. Postherpetic
neuralgia is the most common problem but meningoradiculitis,
segmental motor neuronitis, and ganglionitis may also occur.
Varicella and herpes zoster vaccination are major steps toward
the reduction of these complications, but the vaccines do not
provide complete protection. The socioeconomic impact of
zoster complications remains substantial and will remain so in
the decades to come due to increases in the populations at risk.
Antiviral treatment reduces the length and severity of acute zoster
symptoms and may help prevent PHN. Data also suggest acute
pain management may reduce the risk of PHN.18,43 However,
current treatments are incompletely effective and better options
are needed.
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PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
Peripheral Nervous System Complications
of Infectious Diseases
CME Questions:
1.
Electrodiagnostic (EDX) studies in patients with West Nile
virus (WNV) poliomyelitis show which of the following?
1. Markedly decreased or absent motor responses in the paretic limbs
2. Preserved sensory responses
3. Widespread asymmetric muscle denervation
4. No evidence of demyelination or myopathy
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
4. All of the following statements regarding poliovirus
infection are correct EXCEPT:
A. Poliovirus continues to infect millions of people and paralyze or kill over half a million people worldwide every year.
B. There are still 1 million polio survivors in the United States and hundreds of thousands of cases of postpolio syndrome.
C. Poliovirus cases have decreased by over 99% since the late 1980s.
D. Previously polio-free countries are reinfected due to imports of the virus.
2. Clinical and laboratory features of poliomyelitis, which help
physicians discern it from Guillian-Barré syndrome (GBS),
include which of the following?
1. Fever and leukocytosis
2. Sensory loss and painful distal paresthesias
3. Asymmetric distribution of weakness
4. Lack of pleocytosis in cerebrospinal fluid with
elevated protein (albuminocytologic dissociation)
5. The Centers for Disease Control now classifies WNV
infection into WNV fever and neuroinvasive disease, with
further subdivision of the latter group into which of the
following?
1. Meningitis
2. Poliomyelitis
3. Encephalitis
4. Myositis
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
3. Common neuromuscular manifestations of WNV infection
include each of the following EXCEPT:
A. Disabling fatigue.
B. Poliomyelitis.
C. Demyelinating polyneuropathy.
D. Involvement of brainstem motor neurons.
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
6. Perceptions
of
the
predominant
extracutaneous
manifestations of Lyme disease have been important in the
development of the understanding of this infection. Which
of the following statements are TRUE?
1. In Europe, the major emphasis has been on nervous
system involvement
2. In Europe, the major emphasis has been on
rheumatologic involvement
3. In the United States, the major emphasis has been on
rheumatologic involvement
4. In the United States, the major emphasis has been on
nervous system involvement
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
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CME QUESTIONS
7. Which of the following disorders might be seen in a patient
with peripheral nervous system (PNS) Lyme disease?
1. Unilateral facial nerve palsy
2. Brachial plexitis
3. Radial nerve palsy
4. Acute painful L4 radiculopathy
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
8. A patient presents in summer in an area endemic for Lyme
disease and recalls a tick bite 6 weeks previously. Which
of the following would be compelling evidence of Lyme
disease?
1. History of a 3 cm diameter target shaped rash that
began within hours of the tick bite, attained its full
diameter in 2 hours, and faded over the next 2 days
2. History of a 3 cm diameter target shaped rash that
began 3 days after the tick bite, enlarged to 20 cm in
diameter over the course of 14 days, then gradually
faded
3. New onset of right facial nerve palsy this morning,
negative serum Lyme enzyme-linked immunosorbent
assay (ELISA) and Western blot
4. New onset of right facial nerve palsy this morning,
strongly positive Lyme ELISA and Western blot
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
9. In a patient with likely exposure to Lyme disease 5 years
ago and a positive Lyme ELISA and immunoglobulin G
Western blot currently, which of the following disorders
would MOST LIKELY be causally related to Lyme disease?
1. History of bilateral facial nerve palsy 4½ years ago
2. History of spontaneous onset of severe radicular-type
pain in the right arm 4½ years ago, resolving over 6
months, with residual deltoid atrophy
3. History of aseptic meningitis 4½ years ago
4. History of typical amyotrophic lateral sclerosis
beginning 4½ years ago, with the patient now on a
ventilator
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A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
10. Which one of the following test results would be indicative
of Lyme disease in a patient with symptoms of 3 months
duration?
A. Negative ELISA; Western blot with two IgM bands, two IgG bands.
B. Negative ELISA; Western blot with two IgM bands, five IgG bands.
C. Positive ELISA; Western blot with two IgM bands, two IgG bands.
D. Positive ELISA; Western blot with one IgM band, five IgG bands.
11. GBS has been associated with infections related to which of
the following?
1. Campylobacter jejuni
2. Mycoplasma pneumoniae
3. Cytomegalovirus
4. Salmonella enteritidis
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
12. PNS vasculitides related to hepatitis infection:
1. Are always associated with mixed cryoglobulins
2. Are generally associated with systemic symptoms
3. Are generally only seen with chronic active hepatitis
4. May be treated with combination antiviral and
immunosuppressant medication
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
13. Clinical features of diphtheric polyneuropathy include
which of the following?
1. Autonomic dysfunction
2. A progressive, monophasic clinical course
3. Impairment in near vision
4. Early onset of areflexia
A. Only 1, 2, and 3 are correct.
B. Only 1 and 3 are correct.
C. Only 2 and 4 are correct.
D. All are correct.
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF INFECTIOUS DISEASES
14. An human immunodeficiency virus (HIV)-positive female is
referred to the clinic for bilateral stocking-distribution lower
extremity dysesthesia and allodynia, which have evolved
over the past 6 months. Her CD4 count is currently 400 cells/
mm3 with a nadir CD4 of 273 2 years prior. Current CD8
count is 900 cells/mm3. Her antiretroviral regimen includes
emtricitabine and tenofovir coupled with atazanavir boosted
with ritonavir, which she has been on for 2 years. What is the
MOST LIKLEY cause of this neuropathic pain syndrome in
this patient?
A. Diffuse interstitial lymphomatosis syndrome.
B. Antiretroviral toxic neuropathy.
C. HIV-associated distal sensory polyneuropathy.
D. It is likely related to alternative causes and further workup is necessary.
15. All of the following statements regarding leprosy are correct
EXCEPT:
A. Duration and type of therapy can be determined by skin findings.
B. Reversal reactions are important mechanisms of peripheral nerve injury.
C. Hypopigmented skin lesions with a raised edge and sensory loss are prototypical clinical findings.
D. Mycobacterium leprae infects skin macrophages, schwann cells, and dorsal root ganglia.
16. Pick the TRUE statement.
A. Postherpetic neuralgia is an uncommon neurological condition.
B. Varicella zoster virus is a zoonotic infection.
C. Varicella zoster virus is a herpes virus.
D. Zoster only affects sensory nerves.
17. Which of the following is the MOST important risk factor
for developing postherpetic neuralgia?
A. Sex.
B. Age at time of zoster outbreak.
C. Age at time of chicken pox infection.
D. Severity of chicken pox rash.
18. Which statement is TRUE regarding commercially-available
zoster vaccine?
A. It works in 90% of people who receive it.
B. It comes in killed and live attenuated forms.
C. The virus used in zoster vaccine is different from the virus used in chicken pox vaccine.
D. It works better in younger people.
19. Which of the following medications is considered first line
treatment for postherpetic neuralgia?
A. Mexilitine.
B. Serotonin-norepinephrine reuptake inhibitors.
C. Carbamazepine.
D. Opioids.
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