UNIVERSITY OF PERPETUAL HELP-DJGTMU

College of Medicine
Sto. Nino, Binan City, Laguna

VIRAL DISEASES

GROUP 2
Copo, Nico
Cuartel, Wilson
De Guzman, Carlo
De Silva, Melchor
Del Pilar, Dexter
Del Rosario, Lijean
Dela Cruz, Janine
Diagsay, Deborah
Dizon, Jerome
Escobido, Aiko
Eusores, Warren
Formaran, Phaen

Dr. Arman F. Oronce

OUTLINE

VIRAL INFECTION
I.
Acute Aseptic Meningitis
II.
Chronic Persistent and Recurrent Meningitis
III.
Acute encephalitis
A.
Arboviral encephalitis
B.
Herpes Simplex encephalitis
C.
HHV-6 encephalitis in Stem cell tansplant
D.
Rabies
E.
Acute Cerebellitis (Acute Ataxia of childhood)
IV.
Syndromes of Herpes Zoster
V.
Neurologic Diseases induced by Retroviruses including HIV and
Secondary Opportunistic Infections
VI.
Viral infection of the Developing Nervous System
VII. Acute Anterior Poliomyelitis
VIII. Subacute and Chronic Viral Infection

INTRODUCTION

Viral infection usually begins in peripheral tissues and can invade the
nervous system. It spreads into the peripheral and more rarely the central
nervous systems. The CNS is protected from most virus infections by
effective immune responses and multi-layer barriers. Still, some viruses
enter the nervous system with high efficiency via the bloodstream or by
directly infecting nerves that innervate peripheral tissues, resulting in
debilitating direct and immune-mediated pathology. Most viruses in the
nervous system are opportunistic or accidental pathogens, but a few, most
notably the alpha herpesviruses and rabies virus, have evolved to enter the
nervous system efficiently and exploit neuronal cell biology. The alpha
herpesviruses can establish quiescent infections in the PNS, with rare but
often fatal CNS pathology.
Some virus that affect the nervous system includes group of HIV, herpes
simplex, herpes zoster or varicella zoster, Epstein Barr, cytomegalovirus,
polio viruses, rabies and other arthropod-borne.

PATHWAYS OF INFECTION
1.

Respiratory passages: mumps, measles and varicella

2.

Oral-intestinal route: poliovirus, enteroviruses

3.

Oral-genital route: herpes simplex virus

4.

Inoculation (animal bites): rabies or mosquitoes (arboviruses)

5.

Transplacentally: Rubella, CMV, HIV

6.

Viremia: Seeding to brain or CSF

7.
Peripheral nerves: (Herpes simplex, varicella zoster, rabies
viruse)
8.

Trigeminal nerve and gasserian ganglion

9.

Hematogenous spread is by far the most important

MECHANISM OF VIRAL INFECTION

1.The host cell must have specific receptor sites on its cytoplasm to
which the virus attaches.
2. Some infections are confined to meningeal cells (viral meningitis):
enteroviruses
3. Others will involve particular classes of neurons of the brain
(encephalitis) or spinal cord (poliomyelitis)

4. The virus or its nucleocapsid penetrates the cell mainly by

endocytosis
5. For virus reproduction to occur, the cell must have the metabolic
capacity to transcribe and translate virus-coated proteins, replicate
viral nucleic acid and under the direction of the viruss genome, to
assemble viruses
Viral Infection
I. Acute Aseptic Meningitis
The term aseptic meningitis was first introduced to designate what was
thought to be a specific diseaseaseptic because bacterial cultures were
negative. The term is now applied to a symptom complex that is produced by
any one of numerous infective agents, the majority of which are viral (but a
few of which are bacterialmycoplasma, Q fever, other rickettsial infections,
etc.). Since aseptic meningitis is rarely fatal, the precise pathologic changes
are uncertain but are presumably limited to the meninges. Conceivably,
there may be some minor changes in the brain itself, but these are of
insufficient severity to cause neurologic symptoms and signs or to alter the
results of computed tomography (CT)or magnetic resonance imaging (MRI).
In outline, the clinical syndrome of aseptic meningitis consists of fever,
headache, signs of meningeal irritation, and a predominantly lymphocytic
pleocytosis with normal cerebrospinal fluid (CSF)glucose. Usually the onset is
acute and the temperature is elevated, from 38 to 40_C (100.4 to 104_F).
Headache, perhaps more severe than that associated with other febrile
states, is the most frequent symptom. A variable degree of lethargy,
irritability, and drowsiness may occur; confusion, stupor, and coma mark the
case as an encephalitis rather than a meningitis. Photophobia and pain on
movement of the eyes are common additional complaints. Stiffness of the
neck and spine on forward bending attests to the presence of meningeal
irritation (meningismus), but at first it may be so slight as to pass unnoticed.
Here the Kernig and Brudzinski signs help very little, for they are often
absent in the presence of manifest viral meningitis. When there are
accompanying neurologic signs, they too tend to be mild or fleeting:
paresthesias in an extremity, isolated strabismus and diplopia, a slight
inequality of reflexes, or wavering Babinski signs. Other symptoms and signs
are infrequent and depend mainly on the systemic effects of the invading
virus; these include sore throat, nausea and vomiting, vague weakness, pain
in the back and neck, conjunctivitis, cough, diarrhea, vomiting, rash,
adenopathy, etc. The CSF findings consist of a pleocytosis (mainly
mononuclear except in the first days of the illness, when more than half the
cells may be neutrophils), and a small and variable increase in protein. In
milder cases, in the first hours or day of the illness, there may be no
abnormalities of the spinal fluid, and the patient may erroneously be thought

to have migraine or a headache induced by a systemic infectious illness.

Micro-organisms cannot be demonstrated by conventional smear or bacterial
culture. As a rule, the glucose content of the CSF is normal; this is important
because a low glucose concentration in conjunction with a lymphocytic or
mononuclear pleocytosis usually signifies tuberculous or fungal meningitis or
certain noninfectious disorders such as carcinomatous or lymphomatous
invasion, or sarcoid of the meninges. Infrequently, a mild depression of the
CSF glucose (never below 25 mg/dL)has been reported with the meningitis
caused by mumps, HSV-2, lymphocytic choriomeningitis, or VZV.

Causes of Acute Aseptic Meningitis

Aseptic meningitis is a common occurrence, with an annual incidence rate of
11 to 27 cases per 100,000 population (Beghi et al; Ponka and Pettersson).
Most are due to viral infections. Of these, the most common are the
enteroviral infectionsechovirus and Coxsackie virus. These make up 80
percent of cases of aseptic meningitis in which a specific viral cause can be
established. Mumps is perhaps next in frequency, followed by HSV-2,
lymphocytic choriomeningitis (LCM), and adenovirus infections. EBV
(infectious mononucleosis), CMV, leptospirosis, HSV-1, and the bacterium
Mycoplasma pneumoniae (see Chap. 32). Influenza virus, adenoviruses, and
numerous sporadic and otherwise innocuous agents have at times been
isolated from the spinal fluid in cases of aseptic meningitis. The California
and West Nile viruses, which are arthropod-borne viruses (arboviruses), are
responsible for a small number of cases (usually the arboviruses cause an
encephalitis or meningoencephalitis, as discussed further on). Rarely, the
icteric stage of infectious hepatitis is preceded by mild meningitis, the nature
of which becomes evident when the jaundice appears. All these viral
infections, particularly those due to the enteroviruses together with
mycoplasmal infection, leptospirosis, and Lyme borreliosisaccount for the
largest proportion of infectious cases of aseptic meningitis in which the
etiology can be established, the remainder being due to tuberculosis, fungal
infections and rarer organisms.
II. Other Causes of Aseptic, Chronic, and Recurrent Meningitis
Several other categories of disease may cause an apparently sterile,
predominantly lymphocytic or mononuclear reaction in the leptomeninges,
and these should be considered in cases that do not conform to the usual
pattern: (1)foci of bacterial infection lying adjacent to the meninges;
(2)partially treated bacterial meningitis; (3)specific meningeal infections in
which the organism is difficult or impossible to isolatefungal and
tuberculous meningitis are at times in this category, and the group also

includes parasitic infections; (4)neoplastic invasion of the leptomeninges

(lymphomatous and carcinomatous meningitis); (5) granulomatous,
vasculitic, or
other inflammatory diseases such as sarcoidosis, Behc et disease, and
granulomatous angiitis; and (6)acute or chronic recurrent inflammatory
meningitides of unusual or obscure origin. The last of these constitutes a
vexing group in which no cause can initially be found, but, as indicated
further on, careful follow-up and repeated CSF examinations, or in some
cases meningeal biopsy, will reveal in the nature of a few, and many others
will resolve spontaneously.
Nonviral Causes of Aseptic Meningitis
1. Spirochetal infections: the most important are syphilitic meningitis and
Lyme disease.
2. Mycoplasma pneumonia:Cold agglutinins in the serum toward the end
of the first week of illness or detection of the organism by the
polymerase chain reaction is diagnostic.
3. Bacterial infections lying adjacent to meninges
4. Neoplastic invasion of the meninges by lymphoma or carcinoma
5. Chemical irritation of the meninges by blood, by contents of a
craniopharyngioma, or by substances injected intrathecally
6. Recurrent and chronic inflammatory meningitides of obscure origin

Agent

Bacterial
meningitis

Viral
meningitis

Openin
g
WBC
Pressur count
e (mm
(cells/L)
H2 O)

200-300

90-200

100-5000;
>80%
PMNs
10-300;
lymphocyt
es

Glucose
(mg/dL)

Protein
(mg/dL)

Microbiology

< 40

>100

Specific pathogen
demonstrated in
60% of Gram
stains and 80% of
cultures

Normal,
reduced
in LCM
and

Normal
Viral isolation,
but may
PCR assays
be slightly
elevated

mumps
Tuberculous
180-300
meningitis

100-500;
lymphocyt
es

Reduced,
< 40

Elevated,
>100

Acid-fast bacillus
stain, culture,
PCR

Cryptococc
al
180-300
meningitis

10-200;
lymphocyt
es

Reduced

50-200

India ink,
cryptococcal
antigen, culture

Aseptic
meningitis

90-200

10-300;
lymphocyt
es

Normal

Normal
but may
Negative findings
be slightly on workup
elevated

80-200

0-5;
lymphocyt
es

50-75

15-40

Normal
values

Negative findings
on workup

LCM = lymphocytic choriomeningitis; PCR = polymerase chain reaction;

PMN = polymorphonuclear leukocyte; WBC = white blood cell.

Essential Features
Bacterial
meningitis

Viral meningitis

Fungal meningitis

III. Acute Encephalitis

Fulminant meningitis with headache, nuchal

rigidity, and fever
Appears toxic
Prominent leukocytosis in CSF
Requires antibiotics for improvement
Subacute to acute meninigitis with headache and
some nuchal rigidity
May have fever
Mild to moderate pleocytosis in the CSF
Subacute to chronic meningitis with any headache,
cranial nerve palsies, and cognitive changes.
Meningeal signs are often absent.
More in immunocompromised host
Mild to moderate lymphocytic pleocytosis in the
CSF
Anti fungal treatment is required for improvement.

The infectious process and associated inflammatory response involves the

brain parenchyma. Many of patients with encephalitis also have evidence of
associated meninges (meningoencephalitis) and, in some cases, involvement
of
the
spinal
cord
or
nerve
roots
(encephalomyelitis,
encephalomyeloradiculitis)
ETIOLOGY
Whereas numerous viral, bacterial, fungal, and parasitic agents listed as
causes of the encephalitis syndrome, only the viral ones are considered here,
for it is to these that one usually refers when the term encephalitis is used.
According the Centers for Disease Control and Prevention, about 20,000
cases of acute viral encephalitis are reported annually in the United States.
Death occurs in 5 to 20 percent of these patients and residual signs such as
mental deterioration, amnesic defect, personality change, recurrent seizures,
and hemiparesis are seen in about other 20 percent. However, these overall
figures fail to reflect widely varying incidence of mortality and residual
neurologic normalities that follow infection by different viruses. In herpes
simplex encephalitis, for example, approximately 50 percent of patients die
or are left with some impairment, and in eastern equine encephalitis, the
figures are even higher. On the other hand, death and serious neurologic
sequelae have been observed in only 5 15 percent of those with western
equine and West Nile infections and in even lesser numbers of patients with
Venezuelan, St. Louis, and La Crosse encephalitides.
The types of viral encephalitis that occur with sufficient frequency to be of
clinical importance are relatively few. HSV is by far the most common
sporadic cause of encephalitis and has no seasonal or geographical
predilections. Its age contribution is slightly skewed and biphasic, affecting
persons mainly between ages 5 and 30 years old, and those older than 50
years. Many other viruses, exemplified by the arboviral encephalitides, have
a characteristic geographic and seasonal incidence. The most important of
these is the Japanese encephalitis serogroup (flaviviruses), of which the West
Nile virus is a member. In recent outbreaks in the United States, the latter
virus has been more frequent than any of the other arboviruses and has had
a wide geographic distribution (Solomon). After West Nile, the La Crosse
variety is perhaps the most frequent identifiable arbovirus encephalitis in the
United States.
Rabies infections occur worldwide, but in the United States they are seen
mostly in the Midwest and along the West Coast. Japanese B encephalitis
(the most common encephalitis outside of North America), Russian springsummer encephalitis, Murray Valley encephalitis (Australian X disease), and

several less common viral encephalitides are infrequent in the United States
or, as in the case of West Nile fever, have appeared only recently.
Infectious mononucleosis, which is a primary infection with EBV, is
complicated by meningitis, encephalitis, facial palsy, or polyneuritis of the
Guillain-Barre type in a small proportion of cases. Each of these neurologic
complications can occur in the absence of the characteristic fever,
pharyngitis, and lymphadenopathy of infectious mononucleosis. Varicella
zoster and CMV are other herpes-type viruses that may cause encephalitis.
They are discussed in relation to the particular clinical settings in which they
occur. Definite cases of epidemic encephalitis (encephalitis lethargica)have
not been observed in acute form since 1930, though an occasional surviving
patient with a residual parkinsonian syndrome is still seen in neurology
clinics. However, various movement disorders including parkinsonism are
being seen as a residua of encephalitis from the flaviviruses. The latency
from infection to these complications is brief, or may be present from the
outset, quite unlike encephalitis lethargica. There may also be a post
infectious-immune variety of the midbrain encephalitis.
More recently, a sometimes overwhelming encephalitis has been recognized
as a rare manifestation of influenza infection, particularly the H1N1 strain
that has infected mainly the children in Southeast Asian countries, but also
other serotypes including mundane influenza viruses that cause yearly
outbreaks. The disorder has been called encephalopathy in research
publications but convulsions, delirium, and coma suggest that the neurologic
aspects are from encephalitis.
Aside from the poliovirus, the common infective agents in cases of both
aseptic meningitis and encephalitis were group B Coxsackie virus, echovirus,
mumps virus, lymphocytic choriomeningitis virus, arboviruses, HSV, and
Leptospira, in that order.
In a contemporary and impressively large series of viral infections of the
nervous system from the United Kingdom involving more than 2000 patients,
viral identification in the CSF was tempted by means of PCR, with positive
results in only 7 percent, half of which were various enteroviruses (Jeffery et
al). The other organisms commonly identified were HSV-1, followed by VZV,
EBV, and other herpesviruses. In patients with AIDS, however, the relative
frequencies of the organisms that cause meningoencephalitis are quite
different and include special clinical presentations; applies particularly to
CMV infection of the nervous system.
CLINICAL MANIFESTATIONS:

In addition to the acute febrile illness with evidence of meningeal

involvement characteristic of meningitis, the patient with encephalitis
commonly has an altered level of consciousness (confusion, behavioral
abnormalities), or a depressed level of consciousness, ranging from mild
lethargy to coma, and evidence of either focal or diffuse neurologic signs and
symptoms. Patients with encephalitis may have hallucinations, agitation,
personality change, behavioral disorders, and, at times, a frankly psychotic
state. Focal or generalized seizures occur in many patients with encephalitis.
Virtually every possible type of focal neurologic disturbance has been
reported in viral encephalitis; the signs and symptoms reflect the sites of
infection and inflammation. The most commonly encountered focal findings
are aphasia, ataxia, upper or lower motor neuron patterns of weakness,
involuntary movements (e.g., myoclonic jerks, tremor), and cranial nerve
deficits (e.g., ocular palsies, facial weakness). Involvement of the
hypothalamic-pituitary axis may result in temperature dysregulation,
diabetes insipidus, or the development of the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH). Despite the clear neuropathologic
evidence that viruses differ in the regions of the CNS they injure, it is often
impossible to distinguish reliably on clinical grounds alone one type of viral
encephalitis (e.g., that caused by HSV) from others.
Encephalitis syndrome consists of an acute febrile illness with evidence of
meningeal involvement (sometimes only headache), added to which are
various combinations of the following symptoms and signs: convulsions,
delirium, confusion, stupor, or coma;aphasia;hemiparesis with asymmetry of
tendon reflexes and Babinski signs;involuntary movements, ataxia, and
myoclonic jerks;nystagmus, ocular palsies, and facial weakness.

LABORATORY DIAGNOSIS:

CSF Examination
CSF examination should be performed in all patients with suspected
viral encephalitis unless contraindicated by the presence of severely
increased ICP. The characteristic CSF profile is indistinguishable from
that of viral meningitis and typically consists of a lymphocytic
pleocytosis, a mildly elevated protein concentration, and a normal
glucose concentration.
CSF PCR
CSF PCR has become the primary diagnostic test for CNS infections
caused by CMV, EBV, VZV, HHV-6, and enteroviruses . In the case of

VZV CNS Infection, CSF PCR and detection of virus-specific IgM or

intrathecal antibody synthesis both provide important aids in the
diagnosis. . The sensitivity (~96%) and specificity (~99%) of HSV CSF
PCR is equivalent to or exceeds that of brain biopsy. It is important to
recognize that HSV CSF PCR results need to be interpreted after
considering the likelihood of disease in the patient being tested, the
timing of the test in relationship to onset of symptoms, and the prior
use of antiviral therapy.
CSF Culture
CSF Culture is of limited utility in the diagnosis of acute viral
encephalitis. More than 95% of patients with HSV Encephalitis have
negative CSF cultures.
Serologic Studies and Antigen Detection
In patients with HSV encephalitis, both antibodies to HSV-1
glycoproteins and glycoprotein antigens have been detected in the
CSF. Optimal detection of both HSV antibodies and antigen typically
occurs after the first week of illness, limiting the utility of these tests in
acute diagnosis. Nonetheless, HSV CSF antibody testing is of value in
selected patients whose illness is >1 week in duration and who are CSF
PCRnegative for HSV. Demonstration of WNV IgM antibodies is
diagnostic of WNV encephalitis as IgM antibodies do not cross the
blood-brain barrier, and their presence in CSF is therefore indicative of
intrathecal synthesis. Timing of antibody collection may be important
as the rate of CSF WNV IgM seropositivity increases by ~10% per day
during the first week after illness onset.
MRI, CT, EEG
Patients with suspected encephalitis almost invariably undergo
neuroimaging studies and often EEG. These tests help identify or
exclude alternative diagnoses and assist in the differentiation between
a focal, as opposed to a diffuse, encephalitic process. Focal findings in
a patient with encephalitis should always raise the possibility of HSV
encephalitis.
Brain Biopsy
Brain biopsy is now generally reserved for patients in whom CSF PCR
studies fail to lead to a specific diagnosis, who have focal abnormalities
on MRI, and who continue to show progressive clinical deterioration
despite treatment with acyclovir and supportive therapy.

Table 376-5 Use of Diagnostic Tests in Encephalitis

The best test for WNV encephalitis is the CSF IgM antibody test. The
prevalence of positive CSF IgM tests increases by about 10%/day after
illness onset and reaches 7080% by the end of the first week. Serum WNV
IgM can provide evidence for recent WNV infection, but in the absence of
other findings does not establish the diagnosis of neuroinvasive disease
(meningitis, encephalitis, acute flaccid paralysis).
Approximately 80% of patients with proven HSV encephalitis have MRI
abnormalities involving the temporal lobes. This percentage likely increases
to >90% when FLAIR and DWI MR sequences are also utilized. The absence
of temporal lobe lesions on MR reduces the likelihood of HSV encephalitis
and should prompt consideration of other diagnostic possibilities.
The CSF HSV PCR test may be negative in the first 72 h of symptoms of HSV
encephalitis. A repeat study should be considered in patients with an initial
early negative PCR in whom diagnostic suspicion of HSV encephalitis
remains high and no alternative diagnosis has yet been established.
Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio
corrected for breakdown of the blood-brain barrier) of HSV-specific antibody
may be useful in diagnosis of HSV encephalitis in patients in whom only late
(>1 week post-onset) CSF specimens are available and PCR studies are
negative. Serum serology alone is of no value in diagnosis of HSV
encephalitis due to the high seroprevalence rate in the general population.
Negative CSF viral cultures are of no value in excluding the diagnosis of HSV
or EBV encephalitis.
VZV CSF IgM antibodies may be present in patients with a negative VZV CSF
PCR. Both tests should be performed in patients with suspected VZV CNS

disease.
The specificity of EBV CSF PCR for diagnosis of CNS infection is unknown.
Positive tests may occur in patients with a CSF pleocytosis due to other
causes. Detection of EBV CSF IgM or intrathecal synthesis of antibody to
VCA supports the diagnosis of EBV encephalitis. Serological studies
consistent with acute EBV infection (e.g., IgM VCA, presence of antibodies
against EA but not against EBNA) can help support the diagnosis.
TREATMENT

Acyclovir is of benefit in the treatment of HSV and should be started

empirically in patients with suspected viral encephalitis, especially if
focal features are present, while awaiting viral diagnostic studies.
Ganciclovir and foscarnet, either alone or in combination, are often
utilized in the treatment of CMV-related CNS infections, although their
efficacy remains unproven. Cidofovir may provide an alternative in
patients who fail to respond to ganciclovir and foscarnet, although data
concerning its use in CMV CNS infections is extremely limited.

IV. Herpes Zoster

shingles or zona
Is a common viral infection of the nervous system occurring at an
overall rate of 3-5 cases per 1,000 persons per year with higher rates
in the elderly.
Rare in childhood
Characterized clinically by radicular pain, a vesicular cutaneous
eruption, and, less often, by segmental sensory and delayed motor
loss.
The pathologic changes consists of an acute inflammatory reaction in
isolatedspinal or cranial sensory ganglia and lesser degrees of reaction
in the posterior and anterior roots, the posterior gray matter of the
spinal cord, and the adjacent leptomeninges.

PATHOLOGY AND PATHOGENESIS

Consists one or more of the following:

1. An inflammatory reaction in several unilateral adjacent sensory

ganglia of the spinal or cranial nerves, frequently of such intensity
as to cause necrosis of all or part of the ganglion, with or without
hemorrhage.
2. An inflammatory reaction in the spinal roots and peripheral nerves
contiguous with the involved ganglia.
3. A less common poliomyelitis that closely resembles acute anterior
poliomyelitis but is readily distinguished by its unilaterality,
segmental localization, and greater involvement of the dorsal horn,
root, and ganglion, sometimes with necrosis
4.
A relatively mild leptomeningitis, largely limited to the involved
spinal or cranial segments or nerve roots.
These pathologic changes are the substrate of the neuralgic pains, the
pleocytosis, and the local palsies that may attend and follow the VZV
infection. There may also be a delayed cerebral vasculitis
Herpes zoster represents a spontaneous reactivation of VZV infection,
which becomes latent in the neurons of sensory ganglia following a primary
infection with chickenpox (Hope-Simpson). This mechanism is consistent with
the differences in the clinical
manifestations of chickenpox and herpes zoster, even though the same virus
causes both. Chickenpox is highly contagious by respiratory aerosol, has a
well-marked seasonal incidence (winter and spring), and tends to occur in
epidemics. Zoster, on the other hand, is not communicable (except to a
person who has not had chickenpox), occurs sporadically throughout the
year, and shows no increase in incidence during epidemics of chickenpox. In
patients with zoster, there is practically always a past history of chickenpox.
Such a history may be lacking in rare instances of herpes zoster in infants,
but in these cases there has usually been prenatal maternal contact with
VZV.
VZV DNA is localized primarily in trigeminal and thoracic ganglion cells,
corresponding to the dermatomes in which chickenpox lesions are maximal
and that are most commonly involved by VZV (Mahalingam et al) .The
supposition is that the virus makes its way from the cutaneous vesicles of
chickenpox along the sensory nerves to the ganglion, where it remains latent
until activated, at which time it progresses down the axon to the skin.
Multiplication of the virus in epidermal cells causes swelling, vacuolization,
and lysis of cell boundaries, leading to the formation of vesicles and so-called
Lipschutz inclusion bodies. Alternatively, the ganglia could be infected during
the viremia of chickenpox, but then one would have to explain why only one
or a few sensory ganglia become infected. Reactivation of virus is attributed
to waning immunity, which would explain the increasing incidence of zoster

with aging and with lymphomas, administration of immunosuppressive

drugs, AIDS, and after radiation therapy.
CLINICAL FEATURES
The incidence of herpes zoster rises with age.
The notion that one attack of zoster provides lifelong immunity is
incorrect, although recurrent attacks are rare and most localized
repeated herpetic eruptions are caused by HSV.
Both sexes are equally affected, as well as both sides of the body.
Vesicular eruption-usually preceded for several days by itching,
tingling, or burning sensations in the involved dermatome, and
sometimes by malaise and fever.
Severe localized or radicular pain
Rash which consists of clusters of tense vesicles on an erythematous
base, which become cloudy after a few days, and dry, crusted, and
scaly after 5-10 days
Pain and dysesthesia that lasts for 1-4 weeks
Impairment of superficial sensation in the affected dermatomes
Segmental weakness
Atrophy
zoster sine herpete-absence of rash
thoracic dermatomes particularly T5-T10 most common site
zoster paresis-subacute amyotrophy of a portion of a limb or trunk
Ophthalmic herpes
o the pain and rash are in the distribution of the first division of the
trigeminal nerve
o pathologic changes are centered in the gasserian ganglion
o herpetic involvement of the cornea and conjunctiva-main hazard in
this form of herpes which results to corneal anesthesia and residual
scarring
o Palsies of extraocular muscles, ptosis, and mydriasis are frequently
associated, indicating that the third, fourth, and sixth cranial nerves
are affected in addition to the gasserian ganglion.
Geniculate herpes
o facial palsy in combination with a herpetic eruption of the external
auditory meatus, sometimes with tinnitus, vertigo, and deafness
herpes occipitocollaris
o Herpes zoster of the palate, pharynx, neck, and retroauricular
region
ZOSTER ANGIITIS

A cerebral angiitis that occasionally complicates VZV infection is

histologically similar to granulomatous angiitis and to Wegener
granulomatosis.
Typically, 2 to 10 weeks after the onset specifically of ophthalmic
zoster, the patient develops an acute hemiparesis, hemianesthesia,
aphasia, or other focal neurologic or retinal deficits associated with a
mononuclear pleocytosis in the spinal fluid and elevated IgG indices in
the CSF.
CT or MRI scans demonstrate small, deep infarcts in the hemisphere
ipsilateral to the outbreak of shingles on the face.
Angiograms show narrowing or occlusion of the internal carotid artery
adjacent to the ganglia; but in some cases, vasculitis is more diffuse,
even involving the contralateral hemisphere.

TREATMENT
Analgesics and drying and soothing lotions (calamine)-applied during
the acute stage of shingles to help blunt the pain.
Acyclovir shortens the duration of acute pain and speeds the healing
of vesicles, provided that treatment is begun within approximately 48
hours
Famciclovir
Valacyclovir
VZV immune globulin (VZIG) - may protect against dissemination in
immunosuppressed patients but is not indicated for established
disease
V. NEUROLOGIC DISEASES INDUCED BY
SECONDARY OPPORTUNISTIC INFECTIONS

RETROVIRUSES

AND

Retroviruses are a large group of RNA viruses, so called because they

contain the enzyme reverse transcriptase, which permits the reverse flow of
genetic information from RNA to DNA. Two families of retroviruses are known
to infect humans. First is Lentivirus. It includes HIV, the most important and
is the cause of AIDS. Second is oncoronaviruses, which include the human Tcell lymphotropic viruses (HTLVs), the agents that induce chronic T-cell
leukemias and lymphomas (HTLVII) and tropical spastic paraparesis (HTLV-I).

ACQUIRED IMMUNODEFICIENCY SYNDROME

AIDS is primarily an immune system disorder caused by the human

immunodeficiency virus, but it can also affect the nervous system. HIV does
not appear to directly invade nerve cells but it jeopardizes the health and
function, causing symptoms.
HIV infection is characterized by an acquired and usually profound
depression of cell-mediated immunity as manifest by cutaneous anergy,
lymphopenia, reversal of T-helper-to-T-suppressor cell ratio- more accurately,
CD4-CD8+ lymphocytes, as a result of reduction in CD4+ cells- and
depressed in vitro lymphoproliferative response to various antigens and
mitogens. It is the failure of immune function that explains the development
of a wide range of opportunistic infections and unusual neoplasms. Virtually
all organ systems are vulnerable, including all parts of CNS, peripheral
nerves and roots, and muscle. Moreover the nervous system is susceptible to
a number of unusual syndromes that are direct result of AIDS virus infection.

Epidemiology
It was estimated by the World Health Organization (WHO) that
approximately 34 million persons are infected worldwide and that
approximately 1 million adults are seropositive for the virus. The incidence
will continue to increase in the immediate future. Somewhat less than 3
percent of patients who are at risk are hemophiliacs and others receive
infected blood or blood products and the disease has occurred in infants born
of mothers with AIDS.
Clinical Features
Infection with HIV produces a spectrum of disorders, ranging from
clinically inevident seroconversion to wide spreading lymphadenopathy and
other relatively benign systemic manifestations such as diarrhea, malaise
and weight loss, and to full blown AIDS, which comprises direct effects of
virus on all organ systems as well as the complicating effects of a multiplicity
of parasitic, fungal, viral and bacterial infections and a number of neoplasms,
all of which require cell-mediated immunity for containment.
Neurologic abnormalities have been noted in about one-third of patients
with AIDS, but at autopsy the nervous system is affected in nearly all of
them.
HIV infection may present as an acute asymptomatic meningitis with a
mild lymphocytic pleocytosis and modest elevation of CSF protein. The acute
illness may also take the form of meningoencephalitis or even a myelopathy
or neuropathy. Most patients recover from the initial acute neurologic

illnesses. The relationship to AIDS may pass unrecognized, as these illnesses

are quite nonspecific clinically and may precede or coincide with
seroconversion. Once seroconversion has occurred, the patient becomes
vulnerable to all the late complications of HIV infection. In adults, the interval
between infection and the development of AIDS ranges from several months
to 15 years or even longer; the mean latency is 8- 10 years and 1 year or
less in infants. It is believed that practically all seropositive individuals will
sooner or later develop AIDS, although new drugs are constantly lengthening
the latent period.
AIDS DEMENTIA COMPLEX
The most common neurologic complication is a subacute or chronic HIV
encephalitis presenting as a form of dementia; formerly it was called AIDS
encephalopathy or encephalitis, but it is now generally referred to as the
AIDS dementia complex. It has been estimated that only 3 % of AIDS cases
present in this manner, but the frequency is far higher, close to 2/3, after the
constitutional symptoms and opportunistic infections, more than 60% of
children eventually being affected.
In adults, it takes the form of a slowly or subacutely progressive dementia
accompanied variably by abnormalities of motor function. Patients complain
of being unable to follow conversations, taking longer to complete daily
tasks, and becoming forgetful. Incoordination of the limbs, ataxia of gait,
impairment of smooth pursuit and saccadic eye movements maybe early
accompaniments of the dementia. Heightened tendon reflexes, Babinski
signs, grasp and suck reflexes, weakness of the legs progressing to
paraplegia, bladder and bowel incontinence reflecting spinal cord or cerebral
involvement and abulia or mutism are prominent in the later stages of
disease.
For the untreated case, dementia evolves, over weeks or months.
Survival after the onset of dementia evolves is generally 3-6 months but
maybe considerably longer if treatment is instituted. Tests of psychomotor
speed seem to be most sensitive in the early stages of dementia. The
disease in children is characterized by an impairment of cognitive functions,
spastic weakness and secondarily by impairment of brain growth.
The CSF in patients with AIDS dementia maybe normal or show only a
slight elevation of protein content and less frequently a mild lymphocytosis.
HIV can be isolated from the CSF. In the CT scan there is widening of the sulci
and enlargement of the ventricles. MRI may show patchy but confluent or
diffuse white matter changes with ill-defined margins. These findings are
useful in diagnosis although CMV infection of the brain in AIDS patients
produces similar MRI appearance.

The pathologic basis of dementia appears to be a diffuse and multifocal

rarefraction of the cerebral white matter accompanied by scanty perivascular
infiltrates of lymphocytes and clusters of a few foamy macrophages,
microglial nodules and multinucleated giant cells. Evidence of CMV maybe
added, but accumulating virologic evidence indicates that the AIDS dementia
complex is a result of direct infection of HIV. The pathologic changes in AIDS
dementia are actually not uniform in one group of patients, there is a diffuse
pallor of the cerebral white matter, most obvious with myelin stains,
accompanied by reactive astrocytes and macrophages; the myelin pallor
seems to reflect a breakdown of the blood brain barrier. In another form, it is
referred to as diffuse polydystrophy. There is widespread astrocytosis and
micoglial activation in the cerebral cortex, with little recognizable neuronal
loss. These forms of pathologic change may occur singly or together and all
correlate poorly with the severity of the dementia. Progressive multifocal
leukoencephalopathy also occurs in patients with AIDS and is stimulated by
the primary white matter encephalopathy.

AIDS MYELOPATHY, PERIPHERAL, NEUROPATHY AND MYOPATHY

A myelopathy taking the form of a vacuolar degeneration that bears a
striking pathologic resemblance to subacute combined degeneration
because of vitamin B12 deficiency, is sometimes associated with the AIDS
dementia complex; or the myelopathy may occur in isolation as the leading
manifestation of the diseases.
AIDS may also be complicated by several forms of peripheral neuropathy.
A distal, symmetrical, axonal polyneuropathy, predominantly sensory and
dysesthetic in type has been the most common neuropathic pattern. The HIV
virus has been isolated from the peripheral nerves and ganglia. In other
patients, a painful mononeuropathy multiples occurs, seemingly related to
focal vasculitis, or there maybe a subacute inflammatory cauda equina
syndrome that is usually caused by an accompanying CMV infection. Most of
these patients had a mild pleocytosis in addition to an elevated CSF protein
content. Most patients with inflammatory demyelinating neuropathy have
recovered- either spontaneously or in response to plasma exchange suggesting an immunopathogenesis similar to that of the Guillain- Barre
syndrome.
Facial palsy is being reported with increasing frequency as a feature of
AIDS; its relationship to the generalized polyneuritis of AIDS is uncertain. In
the rare complication of AIDS, called diffuse infiltrative lymphocytosis

syndrome(DILS), a variety of clinical syndromes have been described

including all patterns of the usual AIDS polyneuropathies. Some instances of
polyneuropathy in AIDS are probably caused by the nutritional depletion that
characterizes advanced stages of the disease and to the effects of
therapeutic agents.
A primary myopathy, taking form of an inflammatory polymyositis has
been described in AIDS patients at any stage of the disease. In some cases,
the myopathy has improved with corticosteroid therapy. The original antiAIDS drug, zidovudine has caused a myopathy, probably because of its effect
on mitochondria, but some investigators have attributed almost all such
cases to be attributable to the AIDS virus itself.
Opportunistic infections refer to infections that post no threat to
individuals under normal circumstances, but instead in individuals who's
immune functions are supressed or compromised (immunocompromised).
People are usually not susceptible to fungal infections. A fungal
infection in an individual usually only occurs if immune functions are
supressed, hence being fungally infected is usually a reliable sign of being
immunocompromised. Most opportunistic infections are fungal, but there are
still a few non-fungal opportunistic infections; bacterial (Pseudomonas),
protozoan (Toxoplasma) and viral (Cytomegalovirus).
There are a number of diseases and instances that supress the
immune function in individuals such as; AIDS, cancer, chemotherapy, organ
transplantation, severe burns, leukemia, lymphoma, diabetes, collagen
vascular disease or prolonged corticosteroid therapy.

Fungal Infections of the CNS:

Cryptococcosis (Torulosis, European Blastomycosis)
Candidiasis (Moniliasis)
Aspergillosis
Mucormycosis (Zygomycosis, Phycomycosis)
Coccidioidomycosis,
Actinomycosis

Histoplasmosis,

Blastomycosis

Cryptococcosis (Torulosis, European Blastomycosis)

and

Cryptococcosis also known as Torulosis, is caused by Cryptococcus

neoformans and Cryptococcus gattii. Cryptococcosis has a high mortality
rate and can occur in both normal and immunocompromised hosts. Infective
form for Cryptococcosis is found in pigeon droppings and the portal of entry
is the respiratory tract. Cryptococcus takes the form of granulomatous
meningitis with both granuloma and/or cyst formations in the cerebral
cortex. These cysts contain gelatinous material with a large number of
organisms.
Clinical manifestation of Crytpococcus lacks the usual symptoms found
in patients with meningitis; headache, fever and stiff neck. There however is
a gradual increase in intracranial pressure and may be accompanied with
confussion, dementia, cerebellar ataxia and spastic paraparesis. Onset may
sometimes be explosive. Cryptococcus may also take the form of
meningiovascular lesions in which case will present as small deep strokes
and would manifest with pure motor hemiplegia similar to hypertensive
lacunae (most common type of stroke).
Cryptococcus has a variable course. Crytpococcus can prove fatal
withing a couple of weeks, progress over a span of months or in indolent
instances last for years.

Diagnosis is usually done through CSF studies where glucose is

reduced, protein is increased as well as detecting C. neoformans antigens. C.
neoformans can be demsontrated with the use of india ink preparations.

Treatment for Cryptococcus is amphotericin B (IV). Flucocystine is

sometimes used in combination with amphotericin to reduce the risk of
failure, relapse and nephrotoxicity. Additional fluconazole is used in patients
with AIDS.

Candidiasis (Moniliasis)
Candidiasis is the most frequent opportunistic fungus infection, and
has a grave prognosis. The most notable antecedent of Candida sepsis is
severe burns. The primary sites of infection are the heart and lungs.
Candidiasis has no special feature to distinguish it from the likes of
meningitis, meningiocephalitis and cerebral abscess. Treatment for
Candidiasis is amphotericin B (IV)

Aspergillosis
Aspergillosis usually presents as chronic sinustis. Other manifestations
include osteomyelitis at the base of the skull, brain abscess, formation of
cranial and spinal granulomas, occurences of thrombus, necrosis and
hemorrhage and infectious vasculitis. The most common presentation that is
cause for suspect in Aspergillosis is pulmonary infection that is unresponsive
to antibiotics. Proper diagnosis and confirmation is done by identifying the
organism from a biopsy of a lesion.
Treatment for Aspergillosis Liposoma amphotericin in combination with
voriconazole.
Additional
itraconazole
is
recommended
in
less
immunocompromised patients.

Mucormycosis (Zygomycosis, Phycomycosis)

Mucormycosis is a malignant infection of the cerebral vessels with one

of the Mucorales. Mucormycosis is a rare complication of diabetes, diabeteic
acidosis which is usually found in drug addicts and patients with leukemiam
and lymphoma.
Cerebral infections of Mucormycosis begins with the nasal turbinates
and paranasal sinuses. From the paranasal sinuses it spreads along the
infected vessels of the retroorbital tissues manifesting as proptosis in the
infected. Further spread will infect the brain causing hemorrhagic infarction.
Numerous hyphae are present within the thrombi and vessel wall, often
invading surrounding parenchyma.
Due to the insidious nature of Mucormycosis, treatment requires rapid
correction of hyperglycemia and acidosis. Liposomal amphotericin or
posaconazole are also used.
VI. Viral infection of the Developing Nervous System
Throughout the intrauterine period the embryo and fetus are subject to
particular infections. Until the third to fourth month of gestation, the large
microbial organismssuch as bacteria, spirochetes, protozoa, and fungi
cannot invade the embryo, even if the mother harbors the infection. Viruses,
however, may do so, specifically rubella, CMV, HIV, and possibly others.
The rubella virus enters embryonal tissues during the first trimester.
Treponema pallidum in the fourth to fifth postconceptional months.

 Toxoplasma after that period.

Bacterial
meningitis
(except
for
that
caused
by
Listeria
monocytogenes, described below) is essentially a perinatal infection
contracted during or immediately after parturition.
Neonatal herpes simplex encephalitis, as a result of the type 2 (genital)
virus, is also usually acquired by passage through an infected birth
canal.
Some cases of HIV infection may be acquired during delivery, but most
are a result of transplacental transmission.
MAIN NEONATAL INFECTION
TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and
herpes simplex)
LATCH (Listeria, AIDS, toxoplasmosis, cytomegalovirus, and herpes
simplex)

CONGENITAL TOXOPLASMOSIS
Toxoplasma gondii- occurring freely or in pseudocyst form, is a frequent
cause of meningoencephalitis in utero or in the perinatal period of life.
The mother is most often infected by exposure to cat feces, handling
uncooked infected mutton or other meat, or eating partially cooked meat,
but she is nearly always asymptomatic or has only a mild fever and cervical
lymphadenopathy.
The precise times of placental and fetal invasion are unknown, but
presumably they occur late in the gestational period. The clinical syndrome
usually becomes manifest in the first days and weeks of postnatal life, when
seizures, impaired alertness, hypotonia, weakness of the extremities,
progressive hydrocephalus, and chorioretinitis appear. The retinal lesions
consist of large pale areas of destroyed retina surrounded by deposits of
pigment. If the infection is severe, the maculae are destroyed; optic atrophy
and microphthalmos follow. We have several times observed hemiplegias in
older infants, first on one side and then on the other, followed by tension
hydrocephalus.
Diagnosis
The CSF contains a moderate number of white blood cells, mostly
lymphocytes and mononuclear cells, and the protein content is in the
range of 100 to 400 mg/dL (i.e., a higher protein content than all other
neonatal infections except bacterial meningitis). The glucose values
are normal. Fewer than 10 percent of infected children recover; the

others are mentally retarded, with seizures and paralysis. In those

without symptoms of infection at birth, the outcome is better.
Granulomatous masses and zones of inflammatory necrosis abut the
ependyma and meninges. The organisms, 6 to 7 mm in length and 2 to
4 mm in width, are visible in and near the lesions. Microcysts may also
be found, lying free in the tissues without surrounding inflammatory
reaction. The necrotic lesions calcify rapidly and, after several weeks or
months, are readily visible in plain films of the skull. These appear in
periventricular and other regions of the brain as multiple nodular
densities
The most reliable means of diagnosis is the IgM indirect fluorescent
antibody test, performed on umbilical cord blood. Passive transfer of
IgG antibody from mother to fetus takes place, but its presence in the
fetus is not proof of active infection.

Treatment:
In women who develop antibodies in the first 2 or 3 months of
pregnancy, treatment with spiramycin (Rovamycine) prevents fetal
infection. Once the fetus is infected, pyrimethamine and sulfadiazine
must be used. A later second pregnancy is not affected.
CONGENITAL RUBELLA
Tetrad diagnosis of disease
1.
Cataracts
2.
Deafness
3.
congenital heart disease
4.
mental retardation

A virus could affect so many tissues, causing in essence a

noninflammatory developmental disorder of multiple organs
Most instances of congenital rubella infection occur in the first 10
weeks of gestation and that the earlier the infection occurs, the greater
the risk to the fetus. However, there may be some risk beyond the first
trimester, up to the twenty-fourth week

Congenital rubella syndrome

- low birth weight
- sensorineural deafness, sometimes unilateral (the most common
complication)
- microphthalmia; pigmentary degeneration of the retina (salt-andpepper chorioretinitis)
- glaucoma, cloudy corneas, and cataracts of special type (the latter two
abnormalities usually cause visual impairment)

hepatosplenomegaly, jaundice, and thrombocytopenic purpura

patent ductus arteriosus or interventricular septal defect
Severe mental retardation may be accompanied by seizures and motor
defects such as hemiplegia or spastic diplegia and rarely by seizures.
Psychiatric symptoms, some resembling autism

Diagnosis:
Diagnosis can be verified in the neonate by demonstrating
immunoglobulin (Ig) M antibodies to the virus or by the isolation of the
virus from the throat, urine, stool, or CSF. Also, the virus has been
obtained from cells in the amniotic fluid. In subsequent pregnancies,
the fetus has been normal in our experience.
Treatment:
No treatment for the active infection, the obvious approach to the
problem of congenital rubella infection is to make sure that every
woman of childbearing age has been vaccinated against rubella or has
antibodies as a result of infection prior to pregnancy.
CONGENITAL CYTOMEGALOVIRUS
For many years it was known that there were swollen cells containing
intranuclear and cytoplasmic inclusions in the tissues of some infants who
died in the first weeks and months of life.
Mode of Transmission
Transplacentally (Infection of the fetus usually occurs in the first
trimester of pregnancy, sometimes later, by way of an inapparent
maternal viremia and infection of the placenta)
The newborn can also be infected in the course of delivery or afterward
by the mother's milk or by transfusions.

The likelihood of the fetus being infected is much greater if the

seronegative mother becomes infected for the first time during pregnancy.
In mothers with recurrent CMV infection, the infants were asymptomatic at
birth, and only a few developed serious sequelae. Evidently, the presence
of maternal antibodies before conception protects against congenital CMV
infection.
Early infection of the fetus may result in a malformation of the brain;
later, there is only inflammatory necrosis from encephalitis in parts of the

normally formed brain. Disseminated inflammatory foci have been observed

in the cerebrum, brainstem, and retinae. Here there were aggregates of
lymphocytes, mononuclear cells, and plasma cells. The mononuclear
histiocytes (microglia cells) contain inclusion bodies; some astrocytes are
similarly affected. Granulomas form and later calcify, particularly in the
periventricular regions. Often there is hydrocephalus. In the low-birth-weight
or full-term infant, the clinical picture is one of jaundice, petechiae,
hematemesis, melena, direct hyperbilirubinemia, thrombocytopenia,
hepatosplenomegaly, microcephaly, mental defect, and convulsions. Cells in
the urine may show cytomegalic changes. There is a pleocytosis and an
increased protein in the CSF.
Diagnosis:
The difficulties in prenatal diagnosis of maternal infection preclude
planned abortion. Routine serologic testing should be done on every
young woman of childbearing age.
Treatment:
no known treatment.
CONGENITAL HIV AND AIDS
In children, practically all instances of AIDS come from an HIV-infected
mother ("vertical transmission"). The infection may be acquired in utero,
during delivery, or from breast-feeding.
It is estimated that HIV infection and AIDS occur in 15 to 30 percent of
infants born to HIV-seropositive mothers. Infected infants present special
difficulties in diagnosis, and the infection runs a more accelerated course in
them than in adults. In the perinatal period, infected and noninfected infants
can only rarely be distinguished clinically, and laboratory diagnosis is
hampered by the presence of maternally derived antibody to HIV.
The initial clinical signs usually appear within a few months after birth;
practically all infected infants become ill before their first birthday, and very
few are asymptomatic beyond 3 years of age.
Early signs:
- lymphadenopathy
- splenomegaly
- hepatomegaly
- failure to thrive
- oral candidiasis
- parotitis

There is often a delay in the attainment of psychomotor milestones. Or

after a period of normal development, a psychomotor decline begins, with
corticospinal or peripheral nerve signs, often with pleocytosis in the CSF.
Infected children are also subject to a variety of opportunistic infections,
including bacterial meningitis, toxoplasmosis, CMV encephalitis, fungal
infections (cryptococcosis, aspergillosis, candidiasis), herpes simplex,
syphilis, zoster, and mycobacterial meningitis. There may also be vascular
lesions, with infarction or hemorrhage and lymphoid neoplasia.
OTHER VIRAL AND BACTERIAL INFECTIONS
Meningitis as a result of the small gram-positive rod L. monocytogenes
may be acquired in the usual way, at the time of passage through an
infected birth canal or in utero, as a complication of maternal and fetal
septicemia because of this organism. In the latter case, it causes
abortion or premature delivery.
Neonatal bacterial meningitis with this organism is a particularly
devastating and often fatal type of bacterial infection, not easily
diagnosed unless the pediatrician is alert to the possibility of a silent
meningitis in every case of neonatal infection.
Coxsackievirus B, polioviruses, other enteroviruses, and arboviruses
(western equine) seem to be able to cross the placental barrier late in
pregnancy and cause encephalitis or encephalomyelitis in the nearterm fetus, which is indistinguishable from the disease in the very
young infant.
Herpes zoster may occur in utero, leaving cutaneous scars and
retarding development. Or zoster may appear soon after birth, the
infection having been contracted from the mother.
Epstein-Barr virus is another frequent cause of meningoencephalitis. In
some instances, it may present as aseptic meningitis or a GuillainBarr type of acute polyneuritis.
o This infection tends to affect the nervous system of children
rather than that of adults, but there are exceptions to this
comment. It is estimated that approximately 2 percent of
children and adolescents with this infection have some type of
neurologic dysfunction; rarely will this be the only manifestation
of the disease. Stupor, chorea, and aseptic meningitis were the
main neurologic findings in the case reported by Friedland and
Yahr, and acute cerebellar ataxia and deafness were observed in
the case of Erzurum and associates.

VII. Acute Anterior Poliomyelitis

Background
Acute poliomyelitis is a disease of the anterior horn motor neurons of the
spinal cord and brain stem caused by poliovirus. Flaccid asymmetric
weakness and muscle atrophy are the hallmarks of its clinical manifestations,
due to loss of motor neurons and denervation of their associated skeletal
muscles. Because of the success of poliovirus vaccine, poliomyelitis, once
one of the most feared human infectious diseases, is now almost entirely
preventable by proper immunization.
Pathophysiology
Acute poliomyelitis is caused by small ribonucleic acid (RNA) viruses of the
enterovirus group of the picornavirus family. The single-stranded RNA core is
surrounded by a protein capsid without a lipid envelope, which makes
poliovirus resistant to lipid solvents and stable at low pH. Three antigenically
distinct strains are known, with type I accounting for 85% of cases of
paralytic illnesses. Infection with one type does not protect from the other
types; however, immunity to each of the 3 strains is lifelong.
The enteroviruses of poliomyelitis infect the human intestinal tract mainly
through the fecal-oral route (hand to mouth). The viruses multiply in
oropharyngeal and lower gastrointestinal tract mucosa during the first 1-3
weeks of the incubation period. Virus may be secreted in saliva and feces
during this period, causing most host-to-host transmission. After the initial
alimentary phase, the virus drains into the cervical and mesenteric lymph
nodes and then into the blood stream. Only 5% of infected patients have
selective nervous system involvement after viremia. It is believed that
replication in extraneural sites maintains the viremia and increases the
likelihood that the virus will enter the nervous system.
The poliovirus enters the nervous system by either crossing the blood-brain
barrier or by axonal transportation from a peripheral nerve. It can cause
nervous system infection by involving the precentral gyrus, thalamus,
hypothalamus, motor nuclei of the brainstem and surrounding reticular
formation, vestibular and cerebellar nuclei, and neurons of the anterior and
intermediate columns of the spinal cord. The nerve cells undergo central
chromatolysis along with an inflammatory reaction while multiplication of the
virus precedes onset of paralysis. As the chromatolysis process goes on
further, muscle paralysis or even atrophy appears when fewer than 10% of
neurons survive in the corresponding cord segments. Gliosis develops when

the inflammatory infiltrate has subsided, but most surviving neurons show
full recovery.
Mortality/Morbidity
Of acute poliovirus infections, 4-8% show only nonspecific illness, and 1-2%
of infections finally result in neurologic symptoms. The incidence of paralytic
diseases increases with young age, advanced age, recent hard exercise,
tonsillectomy, pregnancy, and impairment of B-lymphocyte defenses. The
mortality from acute paralytic poliomyelitis is 5-10%, but it can reach 20-60%
in cases of bulbar involvement.
Race
Acute poliomyelitis has no racial predilection.
Sex
The male-to-female ratio for acute poliomyelitis is 1:1.
Age
Most cases of acute poliomyelitis occur in the pediatric population. Infection
or immunization against poliovirus provides lifelong protection.
History
Most patients (95%) with poliomyelitis virus infections are asymptomatic or
have only mild systemic symptoms, such as pharyngitis or gastroenteritis.
These cases are referred to as minor illness or abortive poliomyelitis. The
mild symptoms are related to viremia and immune response against
dissemination of the virus. Only 5% of patients exhibit different severities of
nervous system involvement, from nonparalytic poliomyelitis to the most
severe form of paralytic poliomyelitis.

o
o

Nonparalytic poliomyelitis or preparalytic poliomyelitis

The prodromal symptoms include generalized, nonthrobbing
headache; fever of 38-40 C; sore throat; anorexia; nausea; vomiting; and
muscle aches. These symptoms may or may not subside in 1-2 weeks.
Headache and fever, as well as signs and symptoms of nervous
system involvement (eg, irritability, restlessness, apprehensiveness,
emotional instability, stiffness of the neck and back) and Kernig and
Brudzinski signs because of meningitis, then may follow.
Children generally exhibit milder systemic symptoms than do
adults.
Preparalytic symptoms also may develop into paralytic ones.
Paralytic poliomyelitis

o
o

o
o

o
o
o
o

The incubation period from virus exposure to the neurologic

phase can last 4-10 days but may extend to 4-5 weeks.
Severe muscle pain and spasms, followed by weakness, develop.
Muscle weakness tends to become maximal within 48 hours but may
develop for longer than a week. No progression of weakness should be
noted after the temperature drops to normal for 48 hours. Weakness is
asymmetric, with the lower limbs affected more than upper limbs.
Muscle tone is flaccid, and the reflexes initially are brisk but then
become absent. The transient or occasionally persistent coarse
fasciculations also are observed frequently in patients with paralytic
poliomyelitis.
Patients also complain of paresthesias in the affected limbs
without real sensation loss.
Paralysis remains for days or weeks before slow recovery occurs
over months or years. Which factors favor development of paralytic
disease remains unclear, but some evidence exists that physical activity
and intramuscular injections during the prodrome may be important
exacerbating factors.[4]
Paralytic poliomyelitis with bulbar involvement
The purely bulbar form of poliomyelitis without limb weakness
may occur in children, particularly in those whose tonsils and adenoids
have been removed.
Bulbar paralysis with spinal involvement is more common in
adults, most frequently involving the medulla and leading to dysphagia,
dysphonia, respiratory failure, and vasomotor disturbance.
Patients may have symptoms and signs, such as hiccough,
shallowness and slowing of respiration, cyanosis, restlessness, and
anxiety.
When paralysis of diaphragmatic and intercostal musculature
also occurs, patients need immediate respiratory assistance and intensive
care because of life-threatening respiratory failure. Cranial nerve and
bulbar involvement can cause obstruction, due to decreased respiratory
drive and associated problems with mucus plugging or actual pharyngeal
weakness-induced direct airway obstruction. The loss of vasomotor control
with circulatory collapse also contributes to high mortality.
The encephalitic form of poliomyelitis
This form is very rare and manifests as agitation,
confusion, stupor, and coma.
Autonomic dysfunction is common, and it has a high
mortality.

Physical Assesment
Vital signs are the key to monitoring patients with poliovirus infection.

Muscle weakness can be assessed by muscle strength testing.

Usually asymmetric proximal weakness is present with more

involvement of lumbar than cervical segments and more spinal cord than
brainstem segments.
o
The trunk muscles are affected least.
o
Sensation should be within normal limits objectively.
o
Deep tendon reflexes are diminished or absent.
o
Atrophy of muscle may be detected 3 weeks after onset of
paralysis, which becomes maximal at 12-15 weeks and remains
permanent.

Fifty percent of adult patients with poliomyelitis experience transient

acute urinary retention.

Stiffness and pain in the neck and back because of meningeal

irritation, as well as abnormalities of autonomic function, also can be seen
in some patients.

Cranial nerve involvement

o
Approximately 10-15% of cases affect the lower brainstem motor
nuclei.
o
When the ninth and tenth cranial nerve nuclei are involved,
patients develop paralysis of pharyngeal and laryngeal musculature.
Unilateral or bilateral facial muscles, as well as the tongue and mastication
muscles, may become paralyzed.
o
External oculomotor weakness with pupil sparing may occur in
rare cases.
o
Direct infection of the brainstem reticular formation can cause
breathing and swallowing disruption, as well as loss of control of the
cardiovascular system.
o

Diagnostic Considerations
These include the following:

Acute meningitides
Other motor polyneuropathies
Acute intermittent porphyria
Acute transverse myelitis
Acute encephalitides caused by coxsackievirus and echoviruses
Other enteroviruses (Coxsackie)
Flaviviruses (Japanese encephalitis, West Nile)
HIV neuropathy
Diphtheria
Borrelia burgdorferi infection

Botulism
Differential Diagnoses

Guillain-Barre Syndrome

West Nile Virus

Laboratory Studies

Order lumbar puncture test.

o
Cerebrospinal fluid (CSF) pressure may be increased.
o
Pleocytosis (neutrophils in the first few days, then lymphocytes)
may be noted in the CSF during the period before onset of paralysis in
acute poliomyelitis.
o
The CSF protein content may be elevated slightly with a normal
glucose, except in patients with severe paralysis, who may demonstrate
protein elevations to 100-300 mg/dL for several weeks.

Order a complete blood count (CBC), because leukocytosis may be

present.

Perform virus recovery from throat washing, stool culture, blood

culture, and CSF culture. Viral studies in stool specimens are essential for
the diagnosis of poliomyelitis.
o
Recover virus from throat washing during the first week and stool
culture from the first 2-5 weeks.
o
In rare cases, the virus may be isolated from CSF or serum, in
contrast to the paralytic illnesses caused by other enteroviruses.
o
These tests require additional demonstration of a 4-fold rise in
the virus antibody titer to make a specific diagnosis.

Polymerase chain reaction is routinely used to differentiate wild-type

strains from vaccine strains.
Imaging Studies
Magnetic resonance imaging (MRI) may show localization of inflammation to
the spinal cord anterior horns.
Procedures
Electromyography
o
The earliest electromyographic finding in poliomyelitis is a
reduction in the recruitment pattern and a diminished interference pattern
due to acute motor axon fiber involvement.
o
Fibrillations develop in 2-4 weeks and persist indefinitely;
fasciculations also may be observed.
o
Motor unit action potentials initially have decreased amplitude
and then become large in amplitude with increased duration. Later,
polyphasic motor units are observed because of nerve reinnervation.

The motor nerve conduction velocities remain within normal

limits; however, the compound muscle action potential (CMAP) is reduced
in direct proportion to the number of motor axons that are affected.
Sensory nerve conduction studies remain within normal parameters, due
to sparing of the dorsal root ganglion.

Histologic Findings
Under microscopy, the spinal anterior horn cells are surrounded by
inflammatory cells. Spongiosis of the gray matter, containing many scattered
inflammatory cells, also is noted. Most inflammatory cells are neutrophil
leukocytes.
Treatment
Physical therapy
Physical therapy plays an important role in rehabilitation for patients with
poliomyelitis. Patients with muscle paralysis benefit from frequent passive
range of motion (PROM) and splinting of joints to prevent contracture and
joint ankylosis. Chest physical therapy (CPT) helps patients with bulbar
involvement prevent any pulmonary complications, such as atelectasis.
Frequent repositioning of paralyzed patients helps to prevent bedsores.
Vaccine
IPV contains formalin-inactivated poliovirus strains of the 3 different
serotypes (Mahoney, MEF-1, Saukett). Administered through injection,
stimulates serum IgM, IgG, and IgA. Data have confirmed that 90-100% of
children develop protective antibodies to all 3 types of poliovirus after
administration of 2 doses of currently available IPV, and 99-100% develop
protective antibodies after 3 doses.
High-risk adults (eg, travelers to epidemic areas, members of community
with poliovirus disease, health care workers with close contact of patients
who might excrete wild poliovirus, unvaccinated adults whose children will
receive oral polio vaccine) should be vaccinated.
IPV is the only vaccine recommended for vaccination of immunodeficient
persons and their household contacts.
Medical issues and complications
All patients should be placed on bedrest in an isolation unit. Monitor patients'
vital signs carefully; focus especially on the swallowing function, vital
capacity, pulse, and blood pressure, in anticipation of respiratory or
circulatory complications. Patients who develop respiratory failure because of

depression of the brainstem respiratory center, in addition to paralysis of the

intercostal and diaphragmatic muscles, may require immediate positive
pressure ventilation and/or tracheotomy in the respiratory intensive care
unit.
Urinary tract infection usually is transient during acute phase poliomyelitis.
Other complications (eg, atelectasis, pneumonia, pulmonary edema,
myocarditis) also may occur. Respiratory failure may be the result of
respiratory muscle paralysis or airway obstruction from lesions of the cranial
nerve nuclei or respiratory center. Related problems caused by central and
spinal loss of respiratory drive with mucus plugging or actual pharyngeal
weakness may induce direct airway obstruction.
Surgical intervention
In severe cases of contracture from limb immobilization, the patient may
benefit from orthopedic surgery to release the contracture and restore limb
function
Prognosis
The overall prognosis for patients with poliomyelitis is good. Only 5-10%
mortality (slightly higher in pediatric and elderly populations) results from
acute paralytic poliomyelitis because of respiratory and cardiovascular
impairments. Most patients recover from respiratory failure, and only a small
percentage of patients need chronic respirator care. Muscle strength from
paralyzed muscles may achieve approximately 60% recovery in the first 3-4
months, probably because of reinnervation of the denervated muscle fibers.
Slow recovery may continue for about a year because of hypertrophy of the
undamaged muscle.
VIII. Subacute and Chronic Viral Infection

1920- the concept that viral infections may lead to chronic disease,
especially the nervous system.
The established human slow infections of the nervous system caused
by conventional viruses include:
o Subacute sclerosing panecephalitis (Measles virus)
o Progressive multifocal leukoencephalopathy (JC virus)

SUBACUTE SCLEROSING PANENCEPHALITIS

This disease was first described by Dawson in 1934 under the name
inclusion body encephalitis and extensively studied by Van Bogaert,
who renamed it subacute sclerosing panencephalitis.
It is now recognized to be the result of chronic measles virus infection.

CLINICAL FEATURES:
o Children and adolescents were affected for the most part, the
disease rarely appearing beyond the age of 10 years.
o Typically there is a history of primary measles infection at a very
early age, often before 2 years, followed by a 6- to 8-year
asymptomatic period.
o The illness evolved in several stages. Initially there was a decline
in proficiency at school. temper outbursts and other changes in
personality, difficulty with language, and loss of interest in usual
activities.
o Severe and progressive intellectual deterioration in association
with focal or generalized seizures, widespread myoclonus, ataxia,
and sometimes visual disturbances caused by progressive
chorioretinitis
o As the disease advances, rigidity, hyperactive reflexes, Babinski
signs, progressive unresponsiveness, and signs of autonomic
dysfunction appear. In the final stage, the child lies insensate,
virtually "decorticated."
o Death in 1-3 years
DIAGNOSIS:
o The CSF contains few or no cells, but the protein content is
increased
o MRI changes begin in the subcortical white matter and spread to
the periventricular region (Anlar et al)
PATHOLOGY:
o Lesions involve the cerebral cortex and white matter of both
hemispheres and the brainstem; cerebellum usually spared
o Destruction of nerve cells, neuronophagia and perivenous cuffing
by lymphocytes and mononuclear cells
o Eosinophillic inclusions (hallmark of the disease) in the cytoplasm
and nuclei of neurons and glial cells
o Delay in the development of immune responses during the initial
infection and later development of immune responses that are
incapable of clearing the suppressed infection
TREATMENT:
o No effective treatment available; anticonvulsants: clonazepam
o Amantadine and inosiplex may lead to improvement and prolong
survival

SUBACUTE
SCLEROSING
IMMUNOSUPPRESSION

PANENCEPHALITIS

WITH

In children and adults with defective cell-mediated immune responses

1-6 months after exposure to measles
Seizures, focal neurologic signs, stupor and coma are the main features
Lesions similar to SSPE (eosinophilic inclusions in neurons and glia) but
no inflammatory changes
An opportunistic infection of the brain in an immunocompromised
patient: short interval between exposure and onset, rapid course, lack
of antibodies
Either congenital or acquired rubella syndromes

PROGRESSIVE RUBELLA PANENCEPHALTIS

Either congenital or acquired rubella syndromes

CLINICAL FEATURES:
o
o
o
o

Deterioration in behavior and school performance

Gait clumsiness, followed by frank ataxia of the gait and limb
Seizures, progressive impairment in mental functions
Pallor of the optic discs, ophthalmoplegia, spastic quadriplegia and
mutism

DIAGNOSIS:
o CSF: mild increase in lymphocytes, elevated protein, marked increase
in the proportion of gamma globulin
o Elevated CSF and serum rubella-antibody titers
PATHOLOGY: widespread progressive subacute panencephalitis mainly
affecting the white matter; no inclusion-bearing cells

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

PATHOGENESIS:
o Viral infection with papovavirus: JC virus (JCV)
o Initially dormant until an immunocompromised state permits its active
replication

TREATMENT:
o Untreatable in the non-AIDS patient
o In AIDS patients, aggressive treatment with antiretroviral drug
combinations, including protease inhibitors, slows down the
progression of the disease
CLINICAL FEATURES:
o Develops in a patient with neoplasm or chronic immunodeficiency
states
o Personality changes, intellectual impairment
o Hemiparesis, visual field defects, cortical blindness, aphasia, ataxia,
dysarthria, dementia
o Confusional states, coma
o Death in 1-6 months
o CSF is normal; CT scan and MRI localize the lesions with striking clarity
ENCEPHALITIS LETHARGICA

Von Economo Disease; Sleeping Sickness

First recognized slow virus infection of the nervous system

CLINICAL FEATURES:
Ophthalmoplegia and pronounced somnolence
Some patients are overly active
Movement disorder: bradykinesia, mutism, chorea or myoclonus
20% die within a few weeks; survivors with varying impairment of
mental function
o A high proportion of survivors develop a parkinsonian syndrome
o
o
o
o

Pathology: typical of viral infection localized in the midbrain, subthalamus

and hypothalamus
PRION DISESASES
I.

Creutzfeldt-Jakob
Encephalopathy)

Disease

(Subacute

THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

Spongiform

Cause of infection is neither a virus nor a viroid (nucleic acid alone,

without a capsid structure)

Transmissible pathogen is a proteinaceous infectious particle, devoid of

nucleic acid and resists the action of enzymes that destroy RNA and
DNA

Agent does not produce an immune response and does not have the
structure of a virus

Conversion of the normal cellular protein to the infectious form

involves a conformational change in the protein structure

Also known as prion diseases

Creutzfeldt-Jakob Disease

Rapidly progressive and profound dementia with cerebellar ataxia,

diffuse myoclonic jerks, visual and other neurologic abnormalities

Major pathologic changes: widespread neuronal loss and gliosis,

vacuolation (spongy state) in cerebral and cerebellar cortices

The only clearly demonstrated mechanism of spread is iatrogenic (e.g.,

transplantation of cornea or dural grafts, implantation of infected depth
electrodes, injection of human growth hormone prepared from pooled
cadaveric sources)

SUBACUTE SPONGIFORM ENCEPHALOPATHY

Epidemic of mad cow disease transmitted to humans is a new variant

of Creutzfeldt-Jakob disease

Conversion of a normal cellular protein, PrPc to an abnormal isoform,

PrPSc: a helical proportion of the protein decreases and the B-pleated
sheet increases

Altered prions aggregate and this may be the mode of cellular

destruction that leads to the disease

CLINICAL FEATURES
o Middle age, young adults; sexes equally affected
o Prodrome: fatigue, depression, weight loss, disorders of sleep and
appetite
o Changes in behavior, emotional response and intellectual function

o Ataxia and dysarthria

o Visual abnormalities: distortion of shape and alignment of objects,
poor visual acuity
o Confusion with hallucinations, delusions and agitation
o Myoclonic contractions of muscle groups
o Mute state, stupor and coma
o Death in less than a year

DIAGNOSIS
o EEG: high-voltage slow and sharp wave complexes with periodicity
o MRI: hyperintensity of the lenticular nuclei on T2-weighted images
DIFFERENTIAL DIAGNOSIS
o Carcinomatous meningitis, lithium intoxication
o Alzheimer disease with myoclonus; Lewy-body disease
o Subacute sclerosing panencephalitis
o Limbic-brainstem-cerebellar encephalitis
o AIDS dementia
MANAGEMENT
o Isolation not necessary; relatives of infected patients are at no risk
with casual contact
o Transmissible agent resistant to boiling, formalin, alcohol and
utraviolet radiation
o Transmissible agent can be inactivated by autoclaving at 132 C and
15 lb/sq inch for 1 hr in 5% sodium hypochlorite (household bleach)
o Workers exposed to infected materials should wash with ordinary
soap
o Special precautions in doing brain biopsy; no donor organs in

patients who have been demented

FATAL
FAMILIAL
5GERSTMANN-STRAUSSLER-SCHEINKER SYNDROME

INSOMNIA

FATAL FAMILIAL INSOMNIA

Rare; intractable insomnia, sympathetic overactivity and dementia

Death in 7-15 months

Neuronal loss and gliosis in the median raphe nuclei

Rare; intractable insomnia, sympathetic overactivity and dementia

Death in 7-15 months

Neuronal loss and gliosis in the median raphe nuclei

Autosomal dominant; insidious; midlife

Progressive cerebellar ataxia; corticospinal tract signs, dysarthria and

nystagmus

Mild dementia

Characteristic spongiform changes as in SSE

KURU

The first slow infection due to a nonconventional transmissible agent

documented in humans

Afebrile, progressive cerebellar ataxia with abnormalities of extraocular

movements

Weakness, immobility, incontinence

Death in 3-6 months

Pathology: noninflammatory loss of neurons and spongiform change

(cerebellar cortex)

PAS-positive stellate plaques of amyloid-like material

Common in ritual cannibalism: infected tissue is ingested, rubbed over

the body and absorbed through conjunctivae, mucous membranes and
skin abrasions

Reference:
Adams and Victors Principles of Neurology, 10th edition