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Review
The Neurohospitalist
1-11
The Author(s) 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1941874414535215
nhos.sagepub.com
Abstract
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.
Keywords
peripheral 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) 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.
The Neurohospitalist
Clinical Presentation
Viruses
HIV
Early disease
Advanced disease
Human T-cell lymphotropic virus
Cytomegalovirus
Epstein-Barr virus
Corynebacterium
diphtheriae
Campylobacter jejuni
Mycobacterium
tuberculosis
Mycobacterium leprae
Brucella spp.
Clostridium botulinum
Radiculopathy
Cranial neuropathy
Mononeuropathy
Polyneuropathy
Neuropathy of the soft palate
Cranial neuropathy
Distal sensorimotor polyneuropathy
Acute inflammatory
demyelinating
polyneuropathy
Cranial neuropathy
Compressive radiculopathy
Mononeuropathy
Distal symmetric polyneuropathy
Cranial neuropathy
Radiculopathy
Peripheral neuropathy
Symmetric descending paralysis
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
The Neurohospitalist
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 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
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
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 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.
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).
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
doxycycline.61
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
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
The Neurohospitalist
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 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.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
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