brizzi - peripheral nerve in infectious diseases

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http://nho.sagepub.com/ The Neurohospitalist

http://nho.sagepub.com/content/early/2014/06/19/1941874414535215The online version of this article can be found at:

DOI: 10.1177/1941874414535215

published online 20 June 2014The Neurohospitalist

Kate T. Brizzi and Jennifer L. LyonsPeripheral Nervous System Manifestations of Infectious Diseases

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Review

Peripheral Nervous SystemManifestations of Infectious Diseases

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

Abstract

Infectious causes of peripheral nervous system (PNS) disease are underrecognized but potentially treatable. Heightenedawareness educed by advanced understanding of the presentations and management of these infections can aid diagnosisand 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.

Keywordsperipheral nervous system, neuropathy, radiculopathy, infectious disease, antibiotics, antivirals

Introduction

Although relatively rare compared to vascular and primary

inflammatory or autoimmune causes, infection can be an

unrecognized cause for peripheral nervous system (PNS) dis-

ease. 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 radi-

culopathies, peripheral neuropathies, and neuromuscular junc-

tion disorders by causative organism in an attempt to aid in

clinical decision making in PNS disease.

Viruses With Clinical Implications in the

PNS

Retroviruses

Human immunodeficiency virus. Any discussion of the PNScomplications of infectious disease would be incomplete with-

out comment about human immunodeficiency virus (HIV),

arguably the most well-described viral etiology of PNS dys-

function. 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 Organi-

zation (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 infec-

tion.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 pre-

valence of this syndrome is still high despite combination anti-

retroviral 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 anti-

retrovirals 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.

1 Massachusetts General Hospital, Brigham and Women’s Hospital, and

Harvard Medical School, Boston, MA, USA2 Brigham and Women’s Hospital and Harvard Medical School, Boston,

MA, USA

Corresponding Author:

Jennifer L. Lyons, Department of Neurology, Division of Neurological

Infections, Brigham and Women’s Hospital, 45 Francis Street, Boston, MA

02115, USA.

Email: [email protected]

The Neurohospitalist

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ª The Author(s) 2014

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Inflammatory demyelinating polyneuropathy, mononeuro-

pathy 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 suppor-tive 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 possi-

ble 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 patho-

logic 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 myelopa-

thy/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 implica-

tions in other aspects of the nervous system. Associations with

polymyositis and inclusion body myositis as well as poly-

neuropathies in a stocking and glove distribution with auto-

nomic 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 ante-rior horn cells.9 Isolated cases of myasthenia gravis-like syn-

drome 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

Table 1. Summary of the Most Common Peripheral Nervous SystemPresentations for Selected Organisms.

Organism Clinical Presentation

Viruses

HIV

Early disease Acute inflammatory demyelinatingpolyneuropathy

Mononeuropathy multiplexCranial neuropathy

Advanced disease Distal symmetric polyneuropathyHuman T-cell lympho-

tropic virusHTLV-l-associated myelopathy/tropical

spastic paraparesisPolyneuropathies with autonomic

disturbancesMotor neuron diseaseMyasthenia gravis-like syndrome

Herpes simplex virus Sacral radiculitisVaricella-zoster virus Acute inflammatory demyelinating

polyneuropathy

Postherpetic neuralgiaMotor neuropathyCranial neuropathyMyeloradiculitis

Cytomegalovirus Acute inflammatory demyelinatingpolyneuropathy

MyeloradiculopathyMononeuritis multiplexDistal peripheral neuropathy

Epstein-Barr virus Acute inflammatory demyelinatingpolyneuropathy

MyeloradiculitisEncephalomyeloradiculitis

West Nile Virus Flaccid paralysisDemyelinatine polyneuropathy

Hepatitis C virus Axonal sensory polyneuropathyRabies virus Acute flaccid paralysis of

affected limb

Bacteria and mycobacteria

Borrelia burgdorferi RadiculopathyCranial neuropathyMononeuropathyPolyneuropathy

Corynebacterium

diphtheriae

Neuropathy of the soft palateCranial neuropathyDistal sensorimotor polyneuropathy

Campylobacter jejuni Acute inflammatorydemyelinatingpolyneuropathy

Mycobacterium

tuberculosis

Cranial neuropathyCompressive radiculopathy

Mycobacterium leprae MononeuropathyDistal symmetric polyneuropathy

Brucella spp. Cranial neuropathyRadiculopathyPeripheral neuropathy

Clostridium botulinum Symmetric descending paralysis

Abbreviation: HIV, human immunodeficiency virus.

2 The Neurohospitalist


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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), areneurotropic 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 reacti-

vation 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 symp-toms. Sexually active women are preferentially affected. Cere-

brospinal 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 sympto-matic period.16 Recurrence of symptoms has been reported.17

Varicella-zoster virus. Varicella-zoster virus is the cause of var-

icella and herpes zoster. Primary infection with VZV typically

occurs in childhood and is characterized by a viral exanthem.

Guillain-Barré syndrome (GBS) is a rare complication of pri-

mary 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 postherpe-

tic neuralgia, which is a dermatomal distribution pain follow-

ing 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 thecervical 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 antidepres-

sants, 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 rec-

ommended for children and for adults older than 60 years of

age and is the best preventive strategy for postherpetic neur-

algia in the latter population, but it remains unclear how long

the immunity from the zoster vaccine lasts. In immunocom-

petent individuals, early treatment of VZV infection is recom-

mended with antiviral agents such as acyclovir, valacyclovir,

and famciclovir for 7 days. In immunocompromised individ-

uals 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 CMV-

GBS, 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 multiplexand a painful distal neuropathy.12 The myelomeningoradiculi-

tis 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 How-

ever, pathology shows cytomegalic inclusions in Schwann

cells and invasion of the cauda equina nerve roots by endo-

neurial 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,

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

A 65-year-old right-handed man with a history of non-Hodgkinlymphoma on salvage chemotherapy developed a vesicular rashin the V1 dermatome on the right. The eye was initially swollenshut, but after several days improved, at which point the patientnoted binocular diplopia and a right eyelid ptosis. On neurological

consultation four weeks later, his exam demonstrated weaknessin 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 proteinto 50 mg/dL, normal glucose at 56 mg/dL. No varicella DNA wasdetected. Gadolinium-enhanced MRI of the brain and MRA of thecerebral vasculature were normal. The rash and diplopiaultimately resolved but the ptosis did not.

Figure 1.

Brizzi and Lyons 3




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with CSF pleocytosis ranging from the hundreds to thousands

with a polymorphonuclear (PMN) predominance, elevated

protein, and positive CMV PCR (sensitivity 92% and specifi-

city 94%).1 Treatment is with intravenous (IV) ganciclovir

and immune reconstitution, although efficacy remains uncer-

tain and prognosis is often poor regardless. In an analysis of

13 patients with advanced HIV and presumed CMV-GBS whowere treated with ganciclovir, only 1 patient regained inde-

pendent 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 mul-

tifocal necrotizing vasculitis of the epineural arteries with

intranuclear and intracytoplasmic inclusion bodies, but the

sensitivity of biopsy remains poor.23 Treatment is with ganci-

clovir 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 lympho-tropic herpes virus. Infection of the PNS is rare but has been

associated with GBS, acute myeloradiculitis, and encephalo-

myeloradiculitis. 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 pleo-

cytosis, 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 inflam-

matory 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.

Flaviviridae

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 com-

mon symptoms being headache, low-grade fevers, and a mor-

billiform 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 progres-

sive asymmetric flaccid paralysis involving the upper extremi-

ties 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 ampli-

tudes, reduced conduction velocities, conduction block, and

increased F-wave latencies, consistent with a demyelinating

neuropathy with secondary axonal degeneration. Cerebrosp-

inal fluid analysis in patients with WNV shows a PMN or

mononuclear pleocytosis (mean 200 cells/µL), elevated pro-

tein, and normal glucose.11 Diagnosis is typically made by ser-

ologic 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, viralRNA in the CSF is diagnostic of acute WNV, and CSF serol-

ogies are also specific; viral RNA clears rapidly, although, and

intrathecal antibodies take weeks to develop, creating a win-

dow of absence in terms of evidence of WNV infection. Treat-

ment is supportive, as none of the treatments that have been

tried, including WNV IV Ig and ribavirin, have proved

effective.

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 extrahe-

patic 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 symp-

toms including arthralgias, palpable purpura, and peripheral

neuropathy.32 In patients with mixed cryoglobulinemia, per-

ipheral neuropathy is usually a moderate axonal sensory poly-

neuropathy. In a study of 51 patients with HCV in Italy,

evidence of cryoglobulinemia was found in 78%. Electrophy-

siologic and histologic studies were performed in these

patients, which showed that peripheral neuropathy was found

in both cryoglobulinemia-positive and -negative patients, butthe severity of disease, both clinically and electrophysiologi-

cally, 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 neu-

ropathy could be at play.33 Others have postulated that

a cytopathic or immunologic process may contribute to

the peripheral neuropathy.34 Treatment of symptomatic





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hepatitis C wastraditionally with steroids andrecombinantinter-

feron 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

lookedat the impactof the older regimen, which utilized steroids

and recombinant interferona2b, in patients with peripheral neu-

ropathy. In these studies, although analysis of patients soonafter 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 cryoglobu-

lin levels. It remains unclear whether the worsening of the neu-

ropathy is due to the disease process itself or whether this may be

an effect of treatment.35,36

Rhabdovirdiae

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 nico-

tinic 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 paralysiswith 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 detec-

tion from skin biopsy at the nape of the neck. Postexposure

prophylaxis with human rabies immune globulin and vaccina-

tion are recommended to prevent disease,37 but once neurolo-

gical 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 Hamp-

shire, Maine, and Connecticut.

41

In Europe, at least 5 differentstrains 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 devel-

opment of the erythema migrans rash, a ‘‘bull’s 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.41Within the PNS, Lyme has been reported to cause radicu-

lopathies, cranial neuropathies, mononeuropathies, and dif-

fuse 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 dis-

ease.46 Bannwarth syndrome, a painful lymphocytic menin-

goradiculitis, 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 pre-

sentation. 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 atthe 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, begin-

ning with a Lyme ELISA, which, if positive, should prompt

testing for Lyme IgG and IgM in the serum 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

Brizzi and Lyons 5




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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 dox-

ycycline, amoxicillin, or cefuroxime axetil for 14 days. How-

ever, 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 alterna-

tives. 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 haslong 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-Barré range from 20% to

40%;54,55 however, the risk of developing GBS after Campy-

lobacter is quite low, estimated at only 1:1000.56 The

mechanism by which C jejuni leads to Guillain-Barré is

hypothesized to involve molecular mimicry as well as a

Figure 2. Polyradiculitis in acute neurological Lyme disease. Axial T1 magnetic resonance imaging of the thoracolumbar spine at the level of L1before (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 fromWestern Massachusetts developed right-sided upper back painthat radiated down the right arm in the setting of fever, myalgias,generalized fatigue, and erythema migrans just under the rightclavicle. Shewas given a course of doxycyclinefor presumed Lymebut discontinued it after 3 days. Her pain worsened, and althoughshe did have a pulsatile headache and meningismus, the back pain

was much more prominent, progressing to mild weakness in aC6 distribution. She also developed a left-sided cranial nerve VIIpalsy. She received 4 weeks of IV ceftriaxone for presumed CNSLyme. Her pain regimen included fentanyl transdermal patch 25mcg every 72 hours, hydromorphone 2mg three times daily, tra-madol 50mg threetimes daily,and gabapentin 600mg TID. Lumbarpuncture was not performed at the time. One month later, herpain was not controlled but her arm weakness had resolved. Lum-bar puncturewas acellular withnormal protein,and LymeIgM titerfrom blood by antibody capture enzyme immunoassay was 7.1(normal


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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 vac-cination 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 suscepti-

ble to diphtheria, given waning immunity in adulthood in

many individuals.1 Spread is primarily via respiratory dro-

plets, and the bacteria typically infect the pharynx and tonsils.

The bacteria produce an exotoxin, which, while unable to

cross the blood–brain barrier, can have deleterious effects

on the PNS in up to 75% of cases, with the severity of presen-

tation 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 sen-

sorimotor polyneuropathy can also occur secondary to parano-dal and segmental myelin degeneration with late axonal

degeneration.59 Diagnosis by culture is difficult, but serologi-

cal 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 thrombocytope-

nia, anemia, hepatitis, and endocarditis.60 Neurologic mani-

festations 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 periph-

eral neuropathies. In 1 review of 154 patients with neurobru-

cellosis, 19% had CN involvement, with involvement of CN

VIII most common, followed by CN VI and VII. Cerebrosp-

inal fluid culture was positive in only 14% of patients, and

thus serologic tests remain the most clinically useful evalua-

tion.60 Typically, diagnosis is made clinically in patients

with systemic brucellosis and neurologic symptoms. Optimal

treatment of neurobrucellosis is unclear, although most regi-

mens recommend prolonged treatment for >2 months withtriple antibiotic therapy, typically ceftriaxone, rifampin, and

doxycycline.61

Clostridium botulinum

Clostridium botulinum is a spore-forming anaerobic, gram-

positive 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 pre-

synaptic 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 bioterror-

ism agent. Symptoms represent cholinergic blockade, with

nausea, constipation, dry mouth, and diplopia. If untreated,

this can then be followed by a symmetric descending paraly-

sis, starting with the CNs, then affecting the upper extremities,

respiratory muscles, and lower extremities. Sensory systemsare unaffected. Cerebrospinal fluid is normal, helping to dif-

ferentiate 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 leptomenin-

gitis, pachymeningitis, tuberculomas, and myelitis.11,65 Cra-

nial 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 moreCNs.66 Aside from CN dysfunction, TB involvement of the

spinal cord in Potts disease can lead to myelitis and to radi-

cular 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 fol-

lowed 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 trans-

mission 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

Brizzi and Lyons 7




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response.70 Typical presentation is with a mononeuropathy or

a symmetric polyneuropathy. The disease is classified on a

spectrum of the patient’s immune response, ranging from

tuberculoid leprosy (paucibacillary), in which the patient

mounts a strong cell-mediated immune response to the dis-

ease, to lepromatous (multibacillary), in which the patients are

only able to mount a low cell-mediated immune response tothe disease. Lepromatous leprosy tends to have late presenta-

tion of neural lesions, at which point patients develop bilateral

symmetrical distal neuropathies. Histology shows relative pre-

servation of nerve architecture with foamy cells in the peri-

neum 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 cell-

mediated immune response (type 1 reaction) or flares in

systemic inflammatory response to large amounts of antibody–antigen complexes (type 2 reaction).1 Diagnosis of

leprosy is primarily by the presence of 1 of the 3 factors: anes-

thetic 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 dis-

tal 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 Serolo-

gic 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, ofloxa-

cin, 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 PNSChagas 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 asympto-

matic, 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 associ-

ated 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 recep-

tor and others have suggested a direct effect of the parasite-

mia.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

unclear.74

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 aremostly associated with length-dependent small fiber neuropa-

thies, 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, sym-

metric, 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 pre-

vent 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 fluoroqui-

nolones 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 sec-

ondary 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 neuromus-

cular 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 toxi-

city 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





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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 relation-

ship of the symptoms with beginning treatment. Stavudine is

also associated with a Guillain-Barré-like syndrome deemed

HIV-associated neuromuscular weakness syndrome, which

typically presents with lactic acidosis.2

Finally, linezolid has garnered significant attention for neu-

ropathy 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 inthe 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 dis-

continuation of the drug.79

Conclusion

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 inde- pendently and as such a high index of suspicion and early

initiation of definitive treatment may preempt long-term

sequelae. Additionally, adjunctive use of immune modula-

tion may, in select cases, improve outcomes. However, for

most diseases, further clinical studies are warranted to opti-

mize outcomes of infectious PNS disease. Finally, a cau-

tionary point is that use of some antimicrobial agents

may actually prompt similar PNS diseases, and early cessa-

tion 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.

Funding

The authors received no financial support for the research, author-

ship, and/or publication of this article.

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A 41-year-old right-handed man was treated with oral linezolidfor infected hardware after polymicrobial bacteremia. Afterabout 14 weeks on the linezolid, he developed burning pain in thesoles of his feet that progressed to the point of limiting his abilityto walk, at which point he sought medical care. Linezolid was

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brizzi - peripheral nerve in infectious diseases

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