Anda di halaman 1dari 12

The Neurohospitalist

Peripheral Nervous System Manifestations of Infectious Diseases

Kate T. Brizzi and Jennifer L. Lyons
The Neurohospitalist published online 20 June 2014
DOI: 10.1177/1941874414535215
The online version of this article can be found at:

Published by:

Additional services and information for The Neurohospitalist can be found at:
Email Alerts:

>> OnlineFirst Version of Record - Jun 20, 2014

What is This?

Downloaded from at East Carolina University on June 22, 2014


Peripheral Nervous System

Manifestations of Infectious Diseases

The Neurohospitalist
The Author(s) 2014
Reprints and permission:
DOI: 10.1177/1941874414535215

Kate T. Brizzi, MD1, and Jennifer L. Lyons, MD2

Infectious causes of peripheral nervous system (PNS) disease are underrecognized but potentially treatable. Heightened
awareness educed by advanced understanding of the presentations and management of these infections can aid diagnosis
and facilitate treatment. In this review, we discuss the clinical manifestations, diagnosis, and treatment of common bacterial, viral,
and parasitic infections that affect the PNS. We additionally detail PNS side effects of some frequently used antimicrobial agents.
peripheral nervous system, neuropathy, radiculopathy, infectious disease, antibiotics, antivirals

Although relatively rare compared to vascular and primary
inflammatory or autoimmune causes, infection can be an
unrecognized cause for peripheral nervous system (PNS) disease. However, PNS disease related to infection can
cause severe neurological injury, either due to direct effects
of the microbe or due to secondary immune overactivation
(Table 1). Distinguishing infectious neurologic etiologies
from noninfectious ones and understanding the differences
between various pathogens can help guide treatment and in
some cases cure or at least prevent ongoing injury to the
patient. Herein, we approach major infectious causes of radiculopathies, peripheral neuropathies, and neuromuscular junction disorders by causative organism in an attempt to aid in
clinical decision making in PNS disease.

Viruses With Clinical Implications in the

Human immunodeficiency virus. Any discussion of the PNS
complications of infectious disease would be incomplete without comment about human immunodeficiency virus (HIV),
arguably the most well-described viral etiology of PNS dysfunction. Human immunodeficiency virus is a retrovirus that
is transmitted primarily by sexual contact and contaminated
blood. In the most recent reports by the World Health Organization (WHO), an estimated 34 million people were living
with HIV in 2011, with significant geographic variability in
the prevalence of the disease. Human immunodeficiency virus
commonly affects both the central nervous system (CNS) and

the PNS (Table 1). Distal symmetric polyneuropathy (DSP)

associated with HIV is the most common PNS complaint,
affecting up to 30% to 50% of patients with advanced infection.1,2 Typical symptoms of the DSP include paresthesias
or numbness in a stocking-glove distribution, though up to
71% of patients may be asymptomatic.1 Diagnosis is clinical,
as electromyography (EMG) is frequently unremarkable or
too difficult for the patient even to tolerate. Although the prevalence of this syndrome is still high despite combination antiretroviral therapy (cART), the mainstay of treatment is control
of underlying HIV infection. However, several antiretroviral
medications are also implicated in the development of similar
conditions and should be avoided. Commonly implicated antiretrovirals include didanosine, zalcitabine, and stavudine (also
known as d drugs for their 3-letter acronyms: ddI, ddC, and
d4T), but others have been associated, as well. Treatment is
otherwise largely identical to that of other neuropathic pain
syndromes, although in severe cases, medications commonly
used for neuropathic pain may not offer sufficient pain relief,
requiring a multidisciplinary approach.

Massachusetts General Hospital, Brigham and Womens Hospital, and

Harvard Medical School, Boston, MA, USA
Brigham and Womens Hospital and Harvard Medical School, Boston,
Corresponding Author:
Jennifer L. Lyons, Department of Neurology, Division of Neurological
Infections, Brigham and Womens Hospital, 45 Francis Street, Boston, MA
02115, USA.

Downloaded from at East Carolina University on June 22, 2014

The Neurohospitalist

Table 1. Summary of the Most Common Peripheral Nervous System

Presentations for Selected Organisms.

Clinical Presentation

Early disease

Acute inflammatory demyelinating

Mononeuropathy multiplex
Cranial neuropathy
Distal symmetric polyneuropathy
HTLV-l-associated myelopathy/tropical
spastic paraparesis
Polyneuropathies with autonomic
Motor neuron disease
Myasthenia gravis-like syndrome
Sacral radiculitis
Acute inflammatory demyelinating
Postherpetic neuralgia
Motor neuropathy
Cranial neuropathy
Acute inflammatory demyelinating
Mononeuritis multiplex
Distal peripheral neuropathy
Acute inflammatory demyelinating
Flaccid paralysis
Demyelinatine polyneuropathy
Axonal sensory polyneuropathy
Acute flaccid paralysis of
affected limb

Advanced disease
Human T-cell lymphotropic virus

Herpes simplex virus

Varicella-zoster virus


Epstein-Barr virus

West Nile Virus

Hepatitis C virus
Rabies virus
Bacteria and mycobacteria
Borrelia burgdorferi

Campylobacter jejuni

Mycobacterium leprae
Brucella spp.

Clostridium botulinum

Cranial neuropathy
Neuropathy of the soft palate
Cranial neuropathy
Distal sensorimotor polyneuropathy
Acute inflammatory
Cranial neuropathy
Compressive radiculopathy
Distal symmetric polyneuropathy
Cranial neuropathy
Peripheral neuropathy
Symmetric descending paralysis

Abbreviation: HIV, human immunodeficiency virus.

Inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, and polyradiculopathies have also been
described in patients with HIV having varying degrees of
immune suppression but more commonly early in infection.1
Diagnosis is typically made clinically in patients with known
HIV and appropriate symptoms not attributable to other causes
of peripheral neuropathy, although EMG can provide supportive data by demonstrating distal axonal type degeneration.
Aside from distal peripheral neuropathies, HIV has also
been associated with cranial neuropathies, particularly facial
palsies, including facial diplegia. Although bilateral facial
weakness is rare, its presence should raise suspicion for possible presenting HIV infection.3
Although rare and controversial, motor neuron disease has
additionally been described as a complication of HIV, even as
the initial manifestation of HIV infection. Although no pathologic evidence exists for virus or viral proteins being the cause
of this entity, reports of cure with initiation of cART make
attention to the occurrence in HIV of this otherwise fatal
disease warranted.4
Human T-cell lymphotropic virus. Human T-cell lymphotropic
virus (HTLV) is a human retrovirus transmitted by bodily
fluids that infects T lymphocytes and is the causative agent
in adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the
number of individuals estimated to be infected with the virus
is approximately 20 million, less than 5% of individuals have
symptomatic neurologic disease.5 Human T-cell lymphotropic
virus 1-associated myelopathy/TSP typically presents as a
slowly progressive paraparesis with bladder dysfunction and
sensory abnormalities. Patients have spastic weakness in
lower extremities and hyperreflexia. Disease progression is
faster in women for unclear reasons, particularly prior to
menopause, and in patients who are immunocompromised.
Diagnosis remains challenging, as up to 40% to 65% of
patients in endemic regions who are suspected to have
HAM/TSP are HTLV-1 seronegative.6 In addition to HAM/
TSP, HTLV-1 has more recently been noted to have implications in other aspects of the nervous system. Associations with
polymyositis and inclusion body myositis as well as polyneuropathies in a stocking and glove distribution with autonomic disturbances have been described.7,8 Rare reports of
HTLV-1 motor neuron disease have also been reported, with
lymphocytic infiltrates throughout the CNS and loss of anterior horn cells.9 Isolated cases of myasthenia gravis-like syndrome associated with HTLV-1 have also been reported in the
literature.10 Treatment is supportive.

Herpes Viruses
The herpes viruses are double-stranded DNA viruses that can
produce symptoms after years of lying dormant. The ability of
these viruses to cause CNS disease and transverse myelitis is
well documented,11 but they also impact the PNS and have

Downloaded from at East Carolina University on June 22, 2014

Brizzi and Lyons

Case vignette #1: Varicella zoster virus reactivation in CN V1

A 65-year-old right-handed man with a history of non-Hodgkin
lymphoma on salvage chemotherapy developed a vesicular rash
in the V1 dermatome on the right. The eye was initially swollen
shut, but after several days improved, at which point the patient
noted binocular diplopia and a right eyelid ptosis. On neurological
consultation four weeks later, his exam demonstrated weakness
in the muscles innervated by the superior division of CN III.
Lumbar puncture revealed 14 white blood cells/cm3(100%
lymphocytes), 14 red blood cells/cm3, slightly elevated protein
to 50 mg/dL, normal glucose at 56 mg/dL. No varicella DNA was
detected. Gadolinium-enhanced MRI of the brain and MRA of the
cerebral vasculature were normal. The rash and diplopia
ultimately resolved but the ptosis did not.
Figure 1.

been implicated in radiculopathies and cranial neuropathies.

Three of these viruses, varicella-zoster virus (VZV), and
herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), are
neurotropic and reside in neural ganglia.
Herpes simplex virus. Herpes simplex virus 1 and HSV-2 are
acquired via contact with mucosal surfaces. Herpes simplex
virus 1 is primarily acquired in childhood, and HSV-2 causes
most cases of genital herpes, although incidence of HSV-1
causing genital herpes is rising.12 Peripheral nervous system
manifestations of primary HSV infection are rare, but reactivation of the infection can lead to both CNS and PNS diseases.
Herpes simplex virus 2 has a propensity to lie dormant in
sacral root ganglia and can cause a sacral radiculitis known
as Elsberg syndrome.13,14 Typical presentation includes acute
urinary retention, constipation, and sensory lumbosacral symptoms. Sexually active women are preferentially affected. Cerebrospinal fluid (CSF) shows a lymphocytic pleocytosis and
elevated CSF protein, and HSV-2 polymerase chain reaction
(PCR) from the CSF is often positive. The syndrome may be
a result of reactivation of the dormant virus, as the positive
HSV-2 immunoglobulin (Ig) M antibodies in the serum are not
thought to indicate primary infection in this setting.14 Magnetic
resonance imaging (MRI) can be normal, but in some cases
may show lower spinal cord edema and hyperintensity on
T2-weighted images with contrast enhancement of the sacral
radicular fibers.15 Symptoms usually remit within several
weeks, although antiviral treatment may shorten the symptomatic period.16 Recurrence of symptoms has been reported.17
Varicella-zoster virus. Varicella-zoster virus is the cause of varicella and herpes zoster. Primary infection with VZV typically
occurs in childhood and is characterized by a viral exanthem.
Guillain-Barre syndrome (GBS) is a rare complication of primary infection18 and even more rarely reported in association
with herpes zoster. Reactivation of VZV occurs primarily in
the elderly patients and immunosuppressed, manifesting as the
dermatomal rash of shingles; rarely, the manifestation is as

dermatomal pain without rash or zoster sine herpete. In the

PNS, the most commonly reported complication is postherpetic neuralgia, which is a dermatomal distribution pain following shingles. It is unclear whether this syndrome is due to the
persistence of the viral infection or due to damage caused to
sensory ganglia. Motor neuropathy in the extremities is rare
but has been reported, particularly when reactivation is in the
cervical or lumbar nerve root ganglia. Weakness and sensory
changes in the cranial nerves (CNs) can occur, such as
weakness of the facial muscles associated with zoster otitis
in the Ramsay-Hunt syndrome, sensory changes associated
with CN V, or ophthalmoplegia of CN III.12 An illustration
of this presentation is provided in the vignette subsequently
(Figure 1). Pain may be refractory to treatment, but options
for symptom relief include pregabalin, tricyclic antidepressants, gabapentin, topical lidocaine, anticonvulsants, and/or
capsaicin, just as in other neuropathic pain syndromes.
Diagnosis of VZV neuropathy is primarily clinical,
although in challenging cases, titers of VZV IgG and IgM
in the serum and CSF can be compared to assess intrathecal
production of the virus.1 Varicella-zoster virus DNA in the
CSF can also be tested but has low sensitivity. Vaccine is recommended for children and for adults older than 60 years of
age and is the best preventive strategy for postherpetic neuralgia in the latter population, but it remains unclear how long
the immunity from the zoster vaccine lasts. In immunocompetent individuals, early treatment of VZV infection is recommended with antiviral agents such as acyclovir, valacyclovir,
and famciclovir for 7 days. In immunocompromised individuals or patients older than 60 years of age, therapy should be
continued until all lesions have resolved. Glucocorticoids as
adjunctive treatment remain controversial, with some studies
showing accelerated early healing. Corticosteroid use has not
been shown to reduce the incidence of postherpetic neuralgia
and given the possible side effects of steroid use, it should be
instituted with caution.19
Cytomegalovirus. Unlike VZV and HSV, cytomegalovirus
(CMV) is a lymphotrophic herpes virus. In immunocompetent
patients, CMV has been associated with GBS. In an analysis
of 506 patients with GBS, 12.4% were felt to have CMVGBS, and the incidence of CMV-GBS was estimated to be
2.2 cases per 1000 cases of primary CMV infection.20 In
immunosuppressed patients, CMV has been implicated in
causing a myelomeningoradiculitis, mononeuritis multiplex
and a painful distal neuropathy.12 The myelomeningoradiculitis is characterized by progressive lower extremity numbness
and weakness as well as sphincter dysfunction, closely
mimicking GBS. Indeed, EMG studies in these patients show
acute denervation and abnormal spontaneous activity.21 However, pathology shows cytomegalic inclusions in Schwann
cells and invasion of the cauda equina nerve roots by endoneurial fibroblasts.22 Magnetic resonance imaging may be
normal but may also show enhancement of the lower spinal
cord leptomeninges.21 Cerebrospinal fluid analysis is variable,

Downloaded from at East Carolina University on June 22, 2014

The Neurohospitalist

with CSF pleocytosis ranging from the hundreds to thousands

with a polymorphonuclear (PMN) predominance, elevated
protein, and positive CMV PCR (sensitivity 92% and specificity 94%).1 Treatment is with intravenous (IV) ganciclovir
and immune reconstitution, although efficacy remains uncertain and prognosis is often poor regardless. In an analysis of
13 patients with advanced HIV and presumed CMV-GBS who
were treated with ganciclovir, only 1 patient regained independent ambulation and median survival was 2.7 months.21
Another syndrome associated with immunocompromise
and CMV infection is mononeuritis multiplex, characterized
by multifocal asymmetric sensorimotor deficits.12 This is
often seen in advanced HIV infection. Biopsy may show multifocal necrotizing vasculitis of the epineural arteries with
intranuclear and intracytoplasmic inclusion bodies, but the
sensitivity of biopsy remains poor.23 Treatment is with ganciclovir and/or foscarnet, and some have argued for indefinite
therapy in patients who are immunocompromised.24
Epstein-Barr virus. Epstein-Barr virus (EBV) is also a lymphotropic herpes virus. Infection of the PNS is rare but has been
associated with GBS, acute myeloradiculitis, and encephalomyeloradiculitis. In a serologic study of 100 patients with
GBS, 8 had EBV-specific IgM.25 Rare case reports of more
systemic neurologic involvement of EBV in the form of a
myeloradiculitis or an encephalomyeloradiculitis are also
documented in the literature. Majid et al reported on 4 such
cases, all of which had a CSF mononuclear predominant pleocytosis, elevated CSF protein, and EBV DNA in the CSF.26
All 4 cases received antiviral treatment with either acyclovir
or ganciclovir, and 2 of the 4 cases received steroids.
Overall, it is unclear whether the neurologic manifestations
of EBV are from the virus itself or from parainfectious inflammatory mechanisms. There is no definitive treatment for EBV
myeloradiculitis, and antivirals have not been demonstrated to
impact disease course, but the utility of immune modulation
with corticosteroids and IVIg is not clear.

West Nile virus. West Nile virus (WNV) belongs to a group of
RNA viruses called Flaviviruses and in the PNS, WNV has
been associated with a flaccid paralysis syndrome similar to
poliomyelitis. West Nile virus is transmitted by a mosquito
vector and has been reported in all 48 contiguous States and
Canada, with 91% of neurologic infections occurring between
July and September.27 Approximately 25% of patients
infected with WNV will be symptomatic, with the most common symptoms being headache, low-grade fevers, and a morbilliform or maculopapular rash. Approximately 1% of the
symptomatic patients will have neuroinvasive disease, and the
majority of patients with neuroinvasive disease present with
encephalitis.28 Acute flaccid paralysis makes up only 3% of
neuroinvasive WNV cases, but mortality is as high as 12%
in these cases.27 Burton et al reviewed 26 cases of WNV in

Canada and found 11 had neuromuscular disease. Of these

patients, 7 had acute flaccid paralysis, with EMG showing
absence of compound muscle action potentials and motor
units but with fibrillation potentials, consistent with anterior
horn cell involvement.29 Other patients had a rapidly progressive asymmetric flaccid paralysis involving the upper extremities and face or lower extremities, and EMG showed reduced
motor amplitudes in multiple nerves, denervation, and
increased F-wave latencies with normal sensory studies. Of
the 11 patients, 3 had reduced motor and sensory nerve amplitudes, reduced conduction velocities, conduction block, and
increased F-wave latencies, consistent with a demyelinating
neuropathy with secondary axonal degeneration. Cerebrospinal fluid analysis in patients with WNV shows a PMN or
mononuclear pleocytosis (mean 200 cells/L), elevated protein, and normal glucose.11 Diagnosis is typically made by serologic testing, although serum IgG persists for many years and
as such may be indicative only of prior infection. However,
repeat serologies several weeks apart demonstrating at least
a 4-fold increase indicate acute infection. Additionally, viral
RNA in the CSF is diagnostic of acute WNV, and CSF serologies are also specific; viral RNA clears rapidly, although, and
intrathecal antibodies take weeks to develop, creating a window of absence in terms of evidence of WNV infection. Treatment is supportive, as none of the treatments that have been
tried, including WNV IV Ig and ribavirin, have proved
Hepatitis C virus. Hepatitis C virus (HCV) is an RNA virus with
a predilection for the liver and lymphocytes, although HCV
has also been implicated in nervous system disease, as well.
Approximately 170 million people are estimated to have
HCV, and up to 50% develop cryoglobulinemia as an extrahepatic manifestation of the disease.30,31 Cryoglobulinemia
refers to the presence of circulating Igs that below a certain
temperature can precipitate in small blood vessels. Although
some patients are asymptomatic, others may develop symptoms including arthralgias, palpable purpura, and peripheral
neuropathy.32 In patients with mixed cryoglobulinemia, peripheral neuropathy is usually a moderate axonal sensory polyneuropathy. In a study of 51 patients with HCV in Italy,
evidence of cryoglobulinemia was found in 78%. Electrophysiologic and histologic studies were performed in these
patients, which showed that peripheral neuropathy was found
in both cryoglobulinemia-positive and -negative patients, but
the severity of disease, both clinically and electrophysiologically, was greater in the group with cryoglobulinemia, and
polyneuropathy, as opposed to mononeuropathy, was more
prevalent in the group with cryoglobulinemia. In this study,
histology was consistent with a vasculitic process in both
cryoglobulinemia positive and negative patients, and authors
postulated that an ischemic etiology for the peripheral neuropathy could be at play.33 Others have postulated that
a cytopathic or immunologic process may contribute to
the peripheral neuropathy.34 Treatment of symptomatic

Downloaded from at East Carolina University on June 22, 2014

Brizzi and Lyons

hepatitis C was traditionally with steroids and recombinant interferon a2b; however, newer treatments have been developed and
are being used in some countries. The impact of these newer
medications on the PNS is still unclear, but several studies have
looked at the impact of the older regimen, which utilized steroids
and recombinant interferon a2b, in patients with peripheral neuropathy. In these studies, although analysis of patients soon after
treatment did not show worsening of neuropathy, retrospective
analysis of patients treated with this regimen at 3 and 8 years
showed progression of the neuropathy despite stable cryoglobulin levels. It remains unclear whether the worsening of the neuropathy is due to the disease process itself or whether this may be
an effect of treatment.35,36

Rabies virus. Rabies is caused by a RNA virus that is typically
transmitted by the bite of an infected animal. In the United
States, human rabies is rare, with only 2 cases reported in
2010. However, worldwide, according to the US Centers for
Disease Control (CDC) and the WHO, there are an estimated
55 000 deaths from rabies per year, with 95% occurring in
Africa and Asia. The virus has an incubation period usually
lasting from 20 to 90 days during which the virus replicates
within muscle at the site of inoculation. It then binds to nicotinic acetylcholine receptors at the neuromuscular junction
and travels retrograde along the peripheral nerves to dorsal
root ganglia, where further replication occurs followed by
rapid spread to the CNS.37 For approximately 67% of patients,
presentation will be with focal weakness and pain followed by
psychosis, hydrophobia, and aerophobia, with autonomic
instability. The other 33% of patients will have paralytic
rabies in which they present with an acute flaccid paralysis
with rapidly progressive encephalopathy.38 Diagnosis is by
PCR of the virus using samples from the saliva, hair, or nuchal
skin containing hair follicles or by rabies virus antigen detection from skin biopsy at the nape of the neck. Postexposure
prophylaxis with human rabies immune globulin and vaccination are recommended to prevent disease,37 but once neurological symptoms develop there is no proven therapy, and
prognosis is almost invariably poor. There has been 1 reported
survival after neurological symptomatology manifested,
and this patient was treated with a strategy of induced coma
and antivirals until natural immunity waxed, known as the
Milwaukee protocol.39 This has been attempted in subsequent
patients, albeit without success.

Spirochetes With Clinical Implications

in the PNS
Borrelia burgdorferi
Borrelia burgdorferi, the causative agent in Lyme disease in
the United States, is a spirochete transmitted by Ixodes ticks.
Transmission occurs by attachment of the nymph stage tick to

its host for a prolonged period, typically greater than

36 hours.40 Lyme disease is predominantly seen in Northern
latitudes, with cases reported in the Eastern, Midwestern, and
Western United States, as well as throughout Europe and
Russia. In 2011, the CDC reported the highest incidence of
Lyme in Delaware, closely followed by Vermont, New Hampshire, Maine, and Connecticut.41 In Europe, at least 5 different
strains of the Borrelia bacterium are present, which cause a
slightly variable disease profile.40 Infection tends to occur in
the late spring and summer when ticks are in the nymph stage
and more actively feeding.
The classic presentation of Lyme disease is the early development of the erythema migrans rash, a bulls eye-shaped
erythematous rash with central clearing, approximately 7 to
14 days after tick detachment. Arthralgias, neck pain, and
headache are common features, and fevers may be present.
Early reports suggested that approximately 10% of patients
develop a neurologic manifestation of the infection,42
although more recent reports suggest that neurologic sequelae
are less frequent.41
Within the PNS, Lyme has been reported to cause radiculopathies, cranial neuropathies, mononeuropathies, and diffuse polyneuropathies (Figure 2). Cranial neuropathies and
painful radiculopathies are by far the most common and are
typically seen within the first 1 to 2 months of infection,43
as described in the case vignette (Figure 3). Involvement of
almost every CN has been described in case reports, with the
most prevalent being CN VII.43,44 In a prospective analysis by
Halperin of 74 patients with Lyme borreliosis, 3% had Bell
palsy and 6% had radicular pain.45 In a study of 102 patients
in Sweden with facial palsy, 34 were found to have Lyme disease.46 Bannwarth syndrome, a painful lymphocytic meningoradiculitis, has been associated with Lyme disease and is
more frequently seen in Europe.43,47
Lyme neuroborreliosis should be suspected in patients with
meningitic symptoms or multiple CN palsies in endemic areas
who have had a preceding rash. Serologic tests with an
enzyme-linked immunosorbent assay (ELISA) and a Western
blot for confirmation are typically positive at the time of presentation. In patients with peripheral neuropathy as their only
symptom, routine screening for Lyme is not helpful given that
testing will be positive if the patient was previously exposed to
Lyme and does not indicate causality. In differentiating Lyme
from aseptic meningitis, factors that have been associated with
a higher likelihood of Lyme infection include lower fevers at
the time of presentation, longer duration of symptoms prior to
presentation, cranial neuropathy, preceding rash, and higher
CSF protein.48-50 The Infectious Disease Society of America
(IDSA) recommends a 2-tiered approach at diagnosis, beginning with a Lyme ELISA, which, if positive, should prompt
testing for Lyme IgG and IgM in the serum if <30 days from
symptom onset or Lyme IgG alone if >30 days from symptom
onset. There is a high rate of false positives with Lyme IgM.
Lyme PCR in the CSF has variable sensitivity and is currently
not approved by the Food and Drug Administration (FDA) for

Downloaded from at East Carolina University on June 22, 2014

The Neurohospitalist

Figure 2. Polyradiculitis in acute neurological Lyme disease. Axial T1 magnetic resonance imaging of the thoracolumbar spine at the level of L1
before (left) and after (right) the administration of gadolinium demonstrate diffuse, abnormal enhancement of the lumbosacral nerve roots
(arrow heads).

Case vignette #2: Lyme radiculitis

In early summer, an 82-year-old right-handed woman from
Western Massachusetts developed right-sided upper back pain
that radiated down the right arm in the setting of fever, myalgias,
generalized fatigue, and erythema migrans just under the right
clavicle. She was given a course of doxycycline for presumed Lyme
but discontinued it after 3 days. Her pain worsened, and although
she did have a pulsatile headache and meningismus, the back pain
was much more prominent, progressing to mild weakness in a
C6 distribution. She also developed a left-sided cranial nerve VII
palsy. She received 4 weeks of IV ceftriaxone for presumed CNS
Lyme. Her pain regimen included fentanyl transdermal patch 25
mcg every 72 hours, hydromorphone 2mg three times daily, tramadol 50 mg three times daily, and gabapentin 600 mg TID. Lumbar
puncture was not performed at the time. One month later, her
pain was not controlled but her arm weakness had resolved. Lumbar puncture was acellular with normal protein, and Lyme IgM titer
from blood by antibody capture enzyme immunoassay was 7.1
(normal <1). Anaplasma and babesia PCRs were negative. She was
given a methylprednisolone five-day taper and gabapentin was
increased to 900mg three to four times daily; all narcotics and tramadol were weaned. After the steroid taper her symptoms markedly improved, and at follow up two months later all pain had
resolved and her medications were weaned.
Figure 3.

diagnosis. There appears to be little evidence for relapse of

Lyme disease in patients who have been infected. In a study
by Nadelman et al of 22 paired consecutive episodes of
erythema migrans, none of the paired episodes showed the
same strain of B burgdorferi on culture, suggesting reinfection
as opposed to relapse.51

According to the IDSA guidelines, treatment of localized

or early, disseminated Lyme disease in the United States in the
absence of neurologic manifestations can be treated with doxycycline, amoxicillin, or cefuroxime axetil for 14 days. However, in the cases of Lyme meningitis or other manifestations
of early neurologic Lyme disease, recommended treatment is
with IV antibiotics with ceftriaxone (2 g once/d for 14-28
days), with cefotaxime or penicillin being acceptable alternatives. For patients who are intolerant of b-lactam antibiotics,
doxycycline (200-400 mg/d in 2 divided doses orally for
10-28 days) may be adequate, but evidence is insufficient.
Retreatment is not recommended unless relapse is proven by
objective measures, and at this time, there is no convincing
evidence to support the use of long-term antibiotic therapy
in patients with post-Lyme syndromes.52

Bacteria With Clinical Implications in

the PNS
Campylobactor jejuni
Campylobacter jejuni is a gram-negative bacteria that has
long been described to have an antecedent association with
GBS, with certain subtypes, such as O:19 in the United
States, carrying increased risk.53 There are multiple case
control studies that have examined the prevalence of C jejuni
as an antecedent infection in patients with GBS. Estimates of
C jejuni in patients with Guillain-Barre range from 20% to
40%;54,55 however, the risk of developing GBS after Campylobacter is quite low, estimated at only 1:1000.56 The
mechanism by which C jejuni leads to Guillain-Barre is
hypothesized to involve molecular mimicry as well as a

Downloaded from at East Carolina University on June 22, 2014

Brizzi and Lyons

cross-reactive immune response.53 Treatment of GBS is with

IV Ig or plasmapheresis.57

Corynebacterium diphtheriae
Diphtheria, caused by the gram positive Corynebacterium
diphtheriae, has been largely eliminated in countries with vaccination schedules but remains a global threat. In 2012,
according to the WHO, there were 4489 reported cases of
diphtheria, with 2500 deaths. Adults are particularly susceptible to diphtheria, given waning immunity in adulthood in
many individuals.1 Spread is primarily via respiratory droplets, and the bacteria typically infect the pharynx and tonsils.
The bacteria produce an exotoxin, which, while unable to
cross the bloodbrain barrier, can have deleterious effects
on the PNS in up to 75% of cases, with the severity of presentation correlating with the severity of respiratory symptoms.58
Neuropathies of the CNs, particularly of the soft palate, can
develop and lead to aspiration and regurgitation. Distal sensorimotor polyneuropathy can also occur secondary to paranodal and segmental myelin degeneration with late axonal
degeneration.59 Diagnosis by culture is difficult, but serological tests are available. Therapy is with diphtheria antitoxin,
and early treatment is critical.

Brucella spp.
Brucellosis is infection caused by Brucella bacteria, which are
small, gram-negative coccobacilli. Typically, this infection is
acquired via consumption of unpasteurized milk or by contact
with infected animal products. Symptoms include fevers,
myalgias, and arthralgias but can also include thrombocytopenia, anemia, hepatitis, and endocarditis.60 Neurologic manifestations are rare, but when they do occur can affect
virtually any part of the nervous system. In the PNS, patients
can develop cranial neuropathies, radiculopathies, and peripheral neuropathies. In 1 review of 154 patients with neurobrucellosis, 19% had CN involvement, with involvement of CN
VIII most common, followed by CN VI and VII. Cerebrospinal fluid culture was positive in only 14% of patients, and
thus serologic tests remain the most clinically useful evaluation.60 Typically, diagnosis is made clinically in patients
with systemic brucellosis and neurologic symptoms. Optimal
treatment of neurobrucellosis is unclear, although most regimens recommend prolonged treatment for >2 months with
triple antibiotic therapy, typically ceftriaxone, rifampin, and

Clostridium botulinum
Clostridium botulinum is a spore-forming anaerobic, grampositive bacterium with an ability to produce neurotoxins.
Although there are 7 different types of neurotoxins produced,
all act under a similar mechanism, binding irreversibly to presynaptic nerve endings in the PNS and thus inhibiting release

of acetylcholine.62 Botulism can occur as foodborne botulism,

wound botulism, infant botulism, and as a potential bioterrorism agent. Symptoms represent cholinergic blockade, with
nausea, constipation, dry mouth, and diplopia. If untreated,
this can then be followed by a symmetric descending paralysis, starting with the CNs, then affecting the upper extremities,
respiratory muscles, and lower extremities. Sensory systems
are unaffected. Cerebrospinal fluid is normal, helping to differentiate botulism from GBS, and the edrophonium chloride
test, used in myasthenia gravis, is also negative.63 If there is a
high suspicion for botulism, confirmatory tests include mouse
inoculation and stool culture through the CDC. Treatment is
with mechanical ventilation and antitoxin.

Mycobacteria With Clinical Implications in

the PNS
Mycobacterium tuberculosis
Tuberculosis (TB) is caused by Mycobacterium tuberculosis,
a bacillus that typically infects the lungs but can spread to the
nervous system. According to the WHO 2012 report, there
were almost 9 million new cases of TB in 2011. Estimates
of nervous system involvement of TB range from 1% to
10% of cases with TB.64,65
Tuberculosis has been associated with basilar leptomeningitis, pachymeningitis, tuberculomas, and myelitis.11,65 Cranial nerve palsies are a common complication of tuberculous
meningitis, with CN VI being the most frequently involved,
although involvement of multiple CNs can occur. In a study
done on 158 patients with TB meningitis in India, 38% had
CN involvement and 10% had involvement of 2 or more
CNs.66 Aside from CN dysfunction, TB involvement of the
spinal cord in Potts disease can lead to myelitis and to radicular symptoms.67 Diagnosis of TB in the nervous system
remains challenging, as yield from acid-fast bacilli (AFB)
stain or culture from the CSF is low.68 Treatment of TB
including CNS TB involves a 4-drug regimen with rifampin,
isoniazid, pyrazinamide, and ethambutol for 2 months followed by 7 to 10 months of isoniazid and rifampin. Data
on steroids remain uncertain, with most studies indicating
that patients who are not infected with HIV should be given
a regimen that includes dexamethasone.68

Mycobacterium leprae
Leprosy has long been known to have effects on the PNS. It is
caused by the AFB Mycobacterium leprae. In the United
States, few cases of endemic leprosy have been reported, but
cases in Texas and Louisiana have occurred, with possible
transmission from infected armadillos. Typical route of transmission of the disease is thought to be through nasal droplet
infection, although this has not been definitively proven.69
The bacillus has a predilection for Schwann cells, but damage
to the PNS can also occur through an immune-mediated

Downloaded from at East Carolina University on June 22, 2014

The Neurohospitalist

response.70 Typical presentation is with a mononeuropathy or

a symmetric polyneuropathy. The disease is classified on a
spectrum of the patients immune response, ranging from
tuberculoid leprosy (paucibacillary), in which the patient
mounts a strong cell-mediated immune response to the disease, to lepromatous (multibacillary), in which the patients are
only able to mount a low cell-mediated immune response to
the disease. Lepromatous leprosy tends to have late presentation of neural lesions, at which point patients develop bilateral
symmetrical distal neuropathies. Histology shows relative preservation of nerve architecture with foamy cells in the perineum of nerves and numerous bacilli. Borderline leprosy
can have multiple nerves involved, with more rapid nerve
involvement than in lepromatous leprosy. Tuberculoid leprosy
tends to present with asymmetrical nerve enlargement, usually
proximal to the skin lesions, and histology shows destruction
of nerve architecture with granulomas in nerves.70,71 Reaction
syndromes can occur wherein patients have flares in cellmediated immune response (type 1 reaction) or flares in
systemic inflammatory response to large amounts of antibodyantigen complexes (type 2 reaction).1 Diagnosis of
leprosy is primarily by the presence of 1 of the 3 factors: anesthetic skin lesions, enlarged peripheral nerves, and AFB on
biopsy. Approximately 10% of patients have pure neural
leprosy, in which peripheral neuropathy occurs in the absence
of skin lesions. Electromyography shows prolongation of distal latencies and segmental slowing of conduction velocities
early in the disease, and later disease can show increased
insertional activity and polyphasic, large-amplitude, and
long-duration motor units with reduced recruitment.70 Serologic tests with phenolic glycolipid 1 have low sensitivity in
some forms of leprosy and thus use remains limited to certain
situations. Gold standard is with histological diagnosis.72
Treatment depends on the number of lesions and whether or
not presentation is paucibacillary or multibacillary and
includes a multidrug regimen with dapsone, rifampin, ofloxacin, minocycline, or clofazimine depending on classification.
Steroids have been shown to aid in neural recovery, although
optimal dose and duration remain under study.73 Additionally,
immunosuppressants may be needed in type 1 reactions, and
thalidomide may be needed for type 2 reactions.

Parasites With Clinical Implications in

the PNS
Chagas Disease
Chagas disease is caused by the parasite Trypanosoma cruzi
and is transmitted by insects that feed off the blood of humans.
It is found in South America, Central America, and southern
parts of North America. Acute infection is typically asymptomatic, but at 20 to 40 days after infection, fever, enlargement
of the liver and lymph nodes, and subcutaneous edema can
develop. The chronic infection is associated with degeneration
of the ganglia of the autonomic nervous system, leading to

megacolon, megaesophagus, and cardiac abnormalities, all

of which can develop 10 to 30 years after initial infection.74
Additionally, sensory peripheral neuropathy may be associated with the disease, as demonstrated by a study of patients
with trypanosomiasis by Genovese et al.75 The mechanism
by which Chagas disease causes autonomic nervous system
pathology is debated, although some studies have suggested
binding of autoantibodies to the nicotinic acetylcholine receptor and others have suggested a direct effect of the parasitemia.74,76 Diagnosis of chronic Chagas disease is based on
detection of IgG antibodies to T cruzi antigens. Treatment of
acute infection is with benznidazole and nifurtimox, but the
benefit of treatment in patients with chronic Chagas remains

Complications of Treatment With

Antibiotics and Antivirals
Unfortunately, numerous agents used to treat infections may
have untoward side effects that manifest in the PNS. These are
mostly associated with length-dependent small fiber neuropathies, and many medications have been implicated.
An FDA warning was published in 2013 to warn against the
development of peripheral neuropathy with fluoroquinolone
antibiotics. It is not clear how often this occurs or which
patients are at risk.77 Symptoms are typically of a distal, symmetric, burning pain starting in the soles of the feet and
ascending in a length-dependent fashion. The medication
should be substituted with another suitable antibiotic to prevent further damage. Treatment is otherwise supportive with
neuropathic pain medication often as first-line therapy, but
pain control can be difficult.
Although the risk of peripheral neuropathy from fluoroquinolones is newly recognized, isoniazid, used in the treatment
and prevention of TB, has long been known to be associated
with a peripheral neuropathy. The neuropathy develops secondary to isoniazid-related antagonism of pyridoxine (vitamin
B6), leading to axonal degeneration. One large study of 24 221
patients in South Africa found that 0.21% of patients treated
with isoniazid developed a peripheral neuropathy, but other
studies suggested rates of 2% to 10% depended on the dose
given.78 Rapid removal of the drug or preventive treatment
with vitamin B6 can help to reduce the chance of long-term
impairment. Aside from isoniazid, other anti-TB medications
have effects on the PNS. Optic neuropathy has been associated
with ethambutol, and aminoglycosides can induce neuromuscular blockade in select patients and thus should particularly
be avoided in patients with myasthenia gravis.
Treatment of HIV requires use of multiple antiretroviral
agents, some of which have side effects on the PNS. The toxicity of these agents is mostly related to mitochondrial toxicity.
As such, the dideoxynucleoside agents such as didanosine,
zalcitabine, and stavudine are considered the most toxic to the
nervous system among HIV treatment modalities. Zidovudine
has been implicated quite commonly, as well. The neuropathy

Downloaded from at East Carolina University on June 22, 2014

Brizzi and Lyons

Case vignette #3: Linezolid-induced neuropathy

A 41-year-old right-handed man was treated with oral linezolid
for infected hardware after polymicrobial bacteremia. After
about 14 weeks on the linezolid, he developed burning pain in the
soles of his feet that progressed to the point of limiting his ability
to walk, at which point he sought medical care. Linezolid was
immediately switched to doxycycline. Exam demonstrated allodynia on the soles of the feet and dropped deep tendon reflexes in
the ankles along with subungual discoloration in the hands. Work
up for other causes of peripheral neuropathy, including infectious
causes, metabolic deficiency, and heavy metal toxicity were unremarkable. He was initially treated with gabapentin up to a dose of
600mg in the morning and afternoon and 1200 mg at night, along
with lidocaine transdermal patches, but these medications did not
control his pain. His regimen was then cross tapered to pregabalin and the dose titrated to 75 mg three times daily only, which
provided excellent long-term relief.
Figure 4.

usually begins several months after antiretroviral therapy

begun, and treatment is with substitution of the offending
medication and supportive care. Distinguishing this syndrome
from the distal symmetric neuropathy associated with HIV can
be challenging and is usually based on the temporal relationship of the symptoms with beginning treatment. Stavudine is
also associated with a Guillain-Barre-like syndrome deemed
HIV-associated neuromuscular weakness syndrome, which
typically presents with lactic acidosis.2
Finally, linezolid has garnered significant attention for neuropathy associated with its use. This also typically presents as
burning pain in the soles of the feet that spreads proximally
with continued exposure. The majority of cases described in
the literature have been in patients who were treated for
greater than 28 days with the antibiotic, as demonstrated in the
vignette (Figure 4). The frequency of this side effect is not
known, and symptoms may improve or at least arrest after discontinuation of the drug.79

Despite their relative rarity, affectations of the PNS by
infectious diseases represent a potentially treatable group
of diseases. Although commonly associated with other
manifestations of infection, these entities may occur independently and as such a high index of suspicion and early
initiation of definitive treatment may preempt long-term
sequelae. Additionally, adjunctive use of immune modulation may, in select cases, improve outcomes. However, for
most diseases, further clinical studies are warranted to optimize outcomes of infectious PNS disease. Finally, a cautionary point is that use of some antimicrobial agents
may actually prompt similar PNS diseases, and early cessation of offending medications is the best intervention to
arrest nervous system damage.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

The authors received no financial support for the research, authorship, and/or publication of this article.

1. Estanislao L, Hart P, Simpson D. HIV neuropathy and selected
infectious neuropathies. Continuum. 2003;9(6):118-145.
2. Kranick SM, Nath A. Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy. Contin
Lifelong Learn Neurol. 2012;18(6):1319-1337.
3. Abboud O, Saliba I. Isolated bilateral facial paralysis revealing AIDS: a unique presentation. Laryngoscope. 2008;118(4):
4. Lyons J, Venna N, Cho T. A typical nervous system manifestations of HIV. Semin Neurol. 2011;31(3):254-265.
5. Goncalves DU, Proietti FA, Ribas JGR, et al. Epidemiology,
treatment, and prevention of human T-cell leukemia virus type
1-associated diseases. Clin Microbiol Rev. 2010;23(3):577-589.
6. Araujo AQ, Silva MTT. The HTLV-1 neurological complex.
Lancet Neurol. 2006;5(12):1068-1076.
7. Nascimento O, Marques W. Human T-cell leukemia virus
(HTLV)-associated neuropathy. Handb Clin Neurol. 2013;115:
8. Gabbai AA, Wiley CA, Oliveira AS, et al. Skeletal muscle involvement in tropical spastic paraparesis/HTLV-1-associated myelopathy. Muscle Nerve. 1994;17(8):923-930.
9. Silva MTT, Leite ACC, Alamy AH, Chimelli L, Andrada-Serpa
MJ, Araujo AQC. ALS syndrome in HTLV-I infection. Neurology. 2005;65(8):1332-1333.
10. Lalive PH, Allali G, Truffert A. Myasthenia gravis associated
with HTLV-I infection and atypical brain lesions. Muscle Nerve.
11. Cho T, Vaitkevicius H. Infectious myelopathies. Contin Lifelong
Learn Neurol. 2012;18(6):1392-1416.
12. Steiner I. Herpes virus infection of the peripheral nervous
system. Peripheral Nerve Disorders. 2013;115:543-558.
13. Elsberg CA. Experiences in spinal surgery: observation upon 60
laminectomies for spinal disease. Surg Gynecol Obstet. 1931;16:
14. Eberhardt O, Kuker W, Dichgans J, Weller M. HSV-2 sacral
radiculitis (Elsberg syndrome). Neurology. 2004;63(4):758-759.
15. Ellie E, Rozenberg F, Dousset V, Beylot-Barry M. Herpes simplex virus type 2 ascending myeloradiculitis: MRI findings and
rapid diagnosis by the polymerase chain method. J Neurol
Neurosurg Psychiatry. 1994;57(7):869-870.
16. Krishna A, Devulapally P, Ghobrial I. Meningitis retention syndrome. J Community Hosp Intern Med Perspect. 2012;2(1):1-3.
17. Aurelius E, Forsgren M, Gille E, Skoldenberg B. Neurologic
morbidity after herpes simplex type 2 meningitis: a retrospective
study of 40 patients. Scand J Infect Dis. 2002;34:278-283.

Downloaded from at East Carolina University on June 22, 2014


The Neurohospitalist

18. Cresswell F, Eadie J, Longley N, Macallan D. Severe GuillainBarre syndrome following primary infection with varicella zoster virus in an adult. Int J Infect Dis. 2010;14(2):
19. Solomon CG, Cohen JI. Herpes zoster. N Engl J Med. 2013;
20. Orlikowski D, Porcher R, Sivadon-Tardy V, et al. Guillain-Barre
syndrome following primary cytomegalovirus infection: a prospective cohort study. Clin Infect Dis. 2011;52(7):837-844.
21. So YT, Olney RK. Acute lumbosacral polyradiculopathy in
acquired immunodeficiency syndrome: experience in 23
patients. Ann Neurol. 1994;35(1):53-58.
22. Behar R, Wiley C, McCutchan J. Cytomegalovirus polyradiculoneuropathy in acquired immune deficiency syndrome. Neurology. 1987;37(4):557-561.
23. Roullet E, Assuerus V, Gozlan J, et al. Cytomegalovirus multifocal neuropathy in AIDS analysis of 15 consecutive cases. Neurology. 1994;44(11):2174-2174.
24. Kim Y, Hollander H. Polyradiculopathy due to cytomegalovirus:
report of two cases in which improvement occurred after prolonged therapy and review of the literature. Clin Infect Dis.
25. Dowling PC, Cook SD. Role of infection in Guillain-Barre syndrome: laboratory confirmation of herpes viruses in 41 cases.
Ann Neurol. 1981;9(suppl):44-55.
26. Majid A, Galetta S, Sweeney C, et al. Epstein-Barr virus myeloradiculitis and encephalomyeloradiculitis. Brain. 2002;125(pt 1):
27. Lindsey NP, Staples JE, Lehman JA, Fischer M. Surveillance for
human west Nile virus diseaseUnited States, 1999-2008.
MMWR Surveill Summ. 2010;59(2):1-17.
28. Petersen LR. West Nile virus: review of the literature. JAMA.
29. Burton JM, Kern RZ, Halliday W, et al. Neurological manifestations of West Nile virus infection. Can J Neurol Sci. 2003;31(2):
30. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S.
HCV-related nervous system disorders. Clin Dev Immunol.
31. Cacoub P, Saadoun D, Limal N, Leger JM, Maisonobe T.
Hep C virus infection and mixed cryoglobulinaemia vasculitis: a review of neurological complications. AIDS. 2005;
19(suppl 3):S128-S134.
32. Mayo MJ, Kaplan NM, Palmer BF. Extrahepatic manifestations
of hepatitis C infection. Am J Med Sci. 2003;325(3):135-148.
33. Nemni R, Sanvito L, Quattrini A, Santuccio G, Camerlingo M,
Canal N. Peripheral neuropathy in hepatitis C virus infection
with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 2003;74(9):1267-1271.
34. Bonetti B, Scardoni M, Monaco S, Rizzuto N, Scarpa A. Hepatitis C virus infection of peripheral nerves in type II cryoglobulinaemia. Virchows Arch. 1999;434(6):533-535.
35. Briani C, Chemello L, Zara G, et al. Peripheral neurotoxicity of
pegylated interferon alpha: a prospective study in patients with
HCV. Neurology. 2006;67(5):781-785.

36. Ammendola A, Sampaolo S, Ambrosone L, et al. Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle Nerve. 2005;31(3):382-385.
37. Jackson AC. Rabies. Neurol Clin. 2008;26(3):717-726.
38. Hemachudha T, Ugolini G, Wacharapluesadee S, Sungkarat W,
Shuangshoti S, Laothamatas J. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol. 2013;12(5):
39. Willoughby RE Jr, , Tieves KS, Hoffman GM, et al. Survival
after treatment of rabies with induction of coma. N Engl J Med.
40. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis.
Lancet. 2012;379(9814):461-473.
41. Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL. Lyme
disease in children in southeastern Connecticut. N Engl J Med.
42. Steere A. Lyme disease. N Engl J Med. 1989;321(9):586-596.
43. Halperin JJ. Lyme disease and the peripheral nervous system.
Muscle Nerve. 2003;28(2):133-143.
44. Clark J, Carlson RD, Sasaki CT, Pachner AR, Steere AC. Facial
paralysis in Lyme disease. Laryngoscope. 1985;95(11):1341-1345.
45. Halperin J.Lyme neuroborreliosis. Peripheral nervous system
manifestations. Brain. 1990;113(4):1207-1221.
46. Bremell D, Hagberg L. Clinical characteristics and cerebrospinal
fluid parameters in patients with peripheral facial palsy caused by
Lyme neuroborreliosis compared with facial palsy of unknown
origin (Bells palsy). BMC Infect Dis. 2011;11(1):1-6.
47. Pfister HW, Einhaupl K, Preac-Mursic V, Wilske B, Schierz G.
The spirochetal etiology of lymphocytic meningoradiculitis of
Bannwarth (Bannwarths syndrome). J Neurol. 1984;231(3):
48. Eppes SC, Nelson DK, Lewis LL, Klein JD. Characterization of
Lyme meningitis and comparison with viral meningitis in children. Pediatrics. 1999;103(5):957-960.
49. Tuerlinckx D, Bodart E, Jamart J, Glupczynski Y. Prediction of
Lyme meningitis based on a logistic regression model using clinical and cerebrospinal fluid analysis: a European study. Pediatr
Infect Dis J. 2009;28(5):394-397.
50. Shah SS, Zaoutis TE, Turnquist J, Hodinka RL, Coffin SE. Early
differentiation of Lyme from enteroviral meningitis. Pediatr
Infect Dis J. 2005;24(6):542-545.
51. Nadelman RB, Hanincova K, Mukherjee P, et al. Differentiation
of reinfection from relapse in recurrent Lyme disease. N Engl J
Med. 2012;367(20):1883-1890.
52. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical
assessment, treatment, and prevention of Lyme disease, human
granulocytic anaplasmosis, and babesiosis: clinical practice
guidelines by the infectious diseases society of America. Clin
Infect Dis. 2006;43(9):1089-1134.
53. Nyati KK, Nyati R. Role of Campylobacter jejuni infection in
the pathogenesis of Guillain-Barre syndrome: an update. Biomed
Res Int. 2013;2013:1-13.
54. Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter
jejuni infection and GuillainBarre syndrome. N Engl J Med.

Downloaded from at East Carolina University on June 22, 2014

Brizzi and Lyons


55. Mishu B, Ilyas AA, Koski CL, et al. Serologic evidence of previous Campylobacter jejuni infection in patients with the Guillain-Barre syndrome. Ann Intern Med. 1993;118(12):947-953.
56. Van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barre syndrome. Lancet Neurol.
57. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre syndrome. In: The Cochrane Collaboration, Hughes RA, eds. Cochrane Database of Systematic
Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2012;7.
58. Hadfield TL, McEvoy P, Polotsky Y, Tzinserling VA, Yakovlev
AA. The pathology of diphtheria. J Infect Dis. 2000;181(suppl
59. Cleange A, Meyrignac C, Roualdes B, Degos JD, Gherardi
RK. Diphtheritic neuropathy. Muscle Nerve. 1995;18(12):
60. Gul HC, Erdem H, Bek S. Overview of neurobrucellosis: a
pooled analysis of 187 cases. Int J Infect Dis. 2009;13(6):
61. Guven T, Ugurlu K, Ergonul O, et al. Neurobrucellosis: clinical
and diagnostic features. Clin Infect Dis. 2013;56(10):1407-1412.
62. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United
States: a clinical and epidemiologic review. Ann Intern Med.
63. Sobel J. Botulism. Clin Infect Dis. 2005;41(8):1167-1173.
64. Dye C. Global burden of tuberculosis: estimated incidence,
prevalence, and mortality by country. JAMA. 1999;282(7):
65. Phypers M, Harris T, Power C. CNS tuberculosis: a longitudinal
analysis of epidemiological and clinical features. Int J Tuberc
Lung Dis. 2006;10(1):99-103.
66. Sharma P, Garg RK, Verma R, Singh MK, Shukla R. Incidence,
predictors and prognostic value of cranial nerve involvement in
patients with tuberculous meningitis: a retrospective evaluation.
Eur J Intern Med. 2011;22(3):289-295.

67. Le Page L, Feydy A, Rillardon L, et al. Spinal tuberculosis: a

longitudinal study with clinical, laboratory, and imaging outcomes. Semin Arthritis Rheum. 2006;36(2):124-129.
68. Thwaites GE, Hien TT. Tuberculous meningitis: many questions, too few answers. Lancet Neurol. 2005;4(3):160-170.
69. Rodrigues LC, Lockwood DN. Leprosy now: epidemiology,
progress, challenges, and research gaps. Lancet Infect Dis.
70. Ooi W, Shrinivasan J. Leprosy and the peripheral nervous system. Muscle Nerve. 2004;30(4):393-409.
71. Agrawal A, Pandit L, Dalal M, Shetty JP. Neurological manifestations of Hansens disease and their management. Clin Neurol
Neurosurg. 2005;107(6):445-454.
72. Britton WJ, Lockwood D. Leprosy. Lancet. 2004;363(9416):
73. Wagenaar I, Brandsma W, Post E, et al. Two randomized controlled
clinical trials to study the effectiveness of prednisolone treatment in
preventing and restoring clinical nerve function loss in leprosy: the
TENLEP study protocols. BMC Neurol. 2012;12(1):159.
74. Rassi A, Rassi A, Marcondes de Rezende J. American trypanosomiasis (Chagas disease). Infect Dis Clin North Am. 2012;
75. Genovese O, Ballario C, Storino R, Segura E, Sica RE. Clinical
manifestations of peripheral nervous system involvement in human
chronic Chagas disease. Arq Neuropsiquiatr. 1996;54(2):190-196.
76. Goin JC, Venera G, Bonino M, Sterin-Borda L. Circulating antibodies against nicotinic acetylcholine receptors in chagasic
patients. Clin Exp Immunol. 1997;110(2):219-225.
77. Kuehn B. FDA warning and study highlight fluoroquinolone
risks. JAMA. 2013;310(10):1014.
78. Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs. 2010;24(8):655-667.
79. Rho J, Sia I, Crum B, Dekutoski M, Trousdale R. Linezolidassociated peripheral neuropathy. Mayo Clin Proc. 2004;79(7):

Downloaded from at East Carolina University on June 22, 2014