DISEASE MANAGEMENT CNS Drugs 2000 Aug; 14 (2): 95-113

1172-7047/00/0008-0095/$20.00/0

© Adis International Limited. All rights reserved.

Management Strategies for

Herpesvirus Infections of the CNS
Immunocompetent and Immunocompromised Patients
Paola Cinque and Adriano Lazzarin
Division of Infectious Diseases, San Raffaele Hospital, Milan, Italy

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
1. General Aspects of Herpesvirus Infections of the CNS . . . . . . . . . . . . . . . . . . . . . . . . . 96
2. Principles of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
3. Herpes Simplex Virus (HSV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
3.1 Immunocompetent Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
3.1.1 Herpes Simplex Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
3.1.2 HSV Type 2 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.2 Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4. Varicella-Zoster Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
4.1 Immunocompetent Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
4.2 Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
5. Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.1 Immunocompetent Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.2 Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
6. Epstein-Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
6.1 Immunocompetent Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
6.2 Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
7. Human Herpesvirus 6 (HHV-6), HHV-7 and HHV-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
7.1 Immunocompetent and Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . 108
8. Concluding Remarks and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Abstract The known human herpesviruses (HHVs) include herpes simplex viruses type
1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and HHVs
6, 7 and 8. Almost all of them may induce CNS diseases, which can vary from
mild to life threatening and are significantly different in immunocompetent and
immunocompromised patients. An aetiological diagnosis is essential for optimal
disease management, and the recently developed molecular diagnostic techniques
have provided a rapid and sensitive means for herpesvirus identification.
Effective antiherpesvirus agents have long been available, but the only regi-
men that can be recommended on the basis of proven efficacy in controlled trials
is aciclovir (acyclovir) for herpes simplex encephalitis (HSE). Nevertheless, anti-
viral agents are empirically used in the treatment of various herpes-induced CNS
complications and a number of examples of their efficacy have been reported.
Most frequently, CNS disease results from direct virus-induced cytotoxicity. How-
96 Cinque & Lazzarin

ever, immune-mediated mechanisms may be involved in some cases, and corti-

costeroids are also empirically employed.
Despite the diagnostic advances and broader availability of antiviral com-
pounds, the management of herpes-induced CNS complications is still difficult.
A significant number of patients with HSE die, fail to regain normal function or
relapse despite an initial therapeutic response. The current antiviral approaches
are often unsatisfactory in immunocompromised patients and no optimal treat-
ment has yet been established for the majority of herpes diseases of the CNS.
Information regarding new treatment strategies, including different aciclovir re-
gimens and the use of newer compounds or drug combinations, is needed and can
only be provided by large multicentre studies.

1. General Aspects of Herpesvirus
Infections of the CNS
The known human herpesviruses (HHVs) in-
clude herpes simplex viruses type 1 and 2 (HSV-1,
HSV-2), varicella-zoster virus (VZV), cytomegalo-
virus (CMV), Epstein-Barr virus (EBV), and HHV-
6, HHV-7 and HHV-8. Almost all of these viruses
can induce CNS complications, but these are rela-
tively rare in relation to the widespread nature of
herpesviruses. Herpesvirus infections of the CNS
vary greatly in terms of their pathogenic mechan-
isms and clinico-pathological patterns. Furthermore,
different forms are observed in immunocompetent
and immunocompromised patients. Nevertheless,
some common features can be recognised. Herpes-
viruses are ubiquitous and usually cause asymp-
tomatic or mild infection (table I). However, fol-
lowing primary infection, they remain latent in the
body and may be subsequently reactivated under
particular circumstances such as immunodeficiency.
During primary infection or reactivation, herpes-
viruses may enter the CNS by nerve pathways or
by crossing the blood-brain barrier.
Most frequently, the CNS injury results directly
from the herpesvirus invasion of the CNS tissues.
In some instances, however, a virus-induced im-
mune reaction may further account for tissue in-
jury, as observed in the case of herpes simplex en-
cephalitis (HSE). In this disease, tissue destruction
is initially sustained by the direct cytotoxic effect
of the virus and thereafter continued by immune
mechanisms.[1] The relative importance of either
mechanism in determining the CNS disease will
most likely depend on the balance between virus
replication and the host inflammatory response. For
instance, direct virus cytotoxicity is likely to be the
most important pathogenic mechanism in the im-
munocompromised patient with HSE, in whom wide-
spread parenchymal destruction is associated with
the presence of virus, but in whom there is a limited
inflammatory response.[2]
Immune-mediated processes are also involved
in cases of postinfectious encephalitis, which in-
cludes syndromes such as acute demyelinating en-
cephalitis or acute disseminated encephalomyelitis.
Postinfectious encephalitis typically follows an ex-
anthem or a respiratory infection, caused by viruses
or nonviral agents, e.g. Mycoplasma pneumoniae.
It may also be associated with vaccinations.Among
herpesviruses, VZV, EBV and HSV-1 can all be in-
volved.[3,4] In these forms, the virus is not commonly
found within the CNS lesions, although there is ev-
idence of viral persistence in some cases, such as in
postvaricella cerebellitis.[5] CNS tissue injury usually
consists of perivascular inflammation and demyelin-
ation. Although the underlying events are mostly un-
known, it is possible that viral infection of lympho-
cytes is followed by deregulation of normal immune
mechanisms, resulting in an aberrant, autoimmune-
like response.[3]
Some common diagnostic considerations can also
be outlined for herpesvirus infections of the CNS.
Although the clinical presentation, neuroimaging,
standard CSF analysis and other examinations may
prove useful, optimal therapy can be introduced
only on the basis of an aetiological diagnosis. This
requires virus identification in the CSF or brain

 Adis International Limited. All rights reserved. CNS Drugs 2000 Aug; 14 (2)
 Herpesvirus Infections of the CNS
© Adis International Limited. All rights reserved.

Table I. Human herpesviruses and their associated infections

Virus Primary infection Reactivated infection Proven or Principal CNS diseases in Principal CNS diseases in Registered drugs for
presumed site immunocompetent patients immunocompromised patients systemic infections
of latency

HSV-1 Oral herpes Herpes labialis Sensory ganglia Herpes encephalitis (classical), Encephalitis (focal, Aciclovir (acyclovir),
herpes encephalitis (atypical ventriculoencephalitis), myelitis valaciclovir, famciclovir,
forms) foscarnet

HSV-2 Herpes genitalis Herpes genitalis Sensory ganglia Aseptic meningitis, recurrent Encephalitis (focal, Aciclovir, valaciclovir,
aseptic meningitis (Mollaret’s ventriculoencephalitis), myelitis famciclovir, foscarnet
meningitis)

VZV Varicella Herpes zoster Sensory ganglia Varicella complications (cerebellar
ataxia, meningitis, encephalitis,
myelitis, polyradiculomyelitis),
herpes zoster complications or
CNS disease without skin lesions
(meningitis, encephalitis, myelitis,
vasculitis)
Varicella complications Aciclovir, valaciclovir,
(encephalitis), herpes zoster famciclovir, foscarnet
complications or CNS disease
without skin lesions (meningitis,
encephalitis, myelitis, vasculitis)

CMV CMV-mononucleosis Organ disease [e.g. Monocytes, Meningitis, encephalitis Encephalitis (focal, Ganciclovir, foscarnet,
retina, gastrointestinal endothelial cells periventricular, micronodular), cidofovir
tract (immuno- polyradiculomyelitis
compromised)]

EBV Mononucleosis Hairy leucoplakia; B lymphocytes Meningitis, encephalitis, myelitis Lymphoproliferative diseases Ganciclovir, foscarnet,
lymphoproliferative (organ transplantation), primary cidofovir
syndromesa, lymphomaa CNS lymphoma (HIV infection)
(immunocompromised)

HHV-6 Exanthema subitum Organ disease? T lymphocytes Febrile seizures, encephalitis Encephalitis None
(variants A (sixth disease) (immunocompromised)
and B)b

HHV-7 Exanthema subitum Unknown T lymphocytes Febrile seizures, encephalitis Unknown None
CNS Drugs 2000 Aug; 14 (2)

HHV-8 Kaposi’s sarcoma? Kaposi’s sarcoma? B lymphocytes Unknown Unknown None

a Resulting from EBV-induced B cell transformation.

b Variant B is associated with primary infection; either the A or B variant has been observed in CNS diseases.

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpesviruses; HSV = herpes simplex virus; VZV = varicella-zoster virus.

97
98
tissue, or the demonstration of a specific intrathe-
cal immune response. In this regard, the applica-
tion of the polymerase chain reaction (PCR) to CSF
has led to revolutionary advances in the diagnosis
of herpesvirus CNS infections because of its extra-
ordinary sensitivity.[6,7] Furthermore, PCR allows
a result to be obtained within one day of CSF sam-
pling, thus impacting substantially on treatment de-
cision making.
This review briefly introduces the herpesvirus
infections of the CNS in both immunocompetent
and immunocompromised patients, and concentrates
on the most relevant studies and clinical observa-
tions concerning the use of rapid diagnostic pro-
cedures and treatment modalities. Treatment rec-
ommendations are provided for those diseases for
which a given approach has been well established
by clinical trials, or where experts in the field have
reached a consensus.[8] Further suggestions based
on personal or anecdotal experiences are also pro-
vided. Neither the encephalopathy caused by con-
genital or neonatal herpesvirus infections nor her-
pes-induced retinopathies are considered. Special
mention is made of the herpesvirus CNS infections
occurring in the context of HIV infection. These
infections have caused severe diseases and mortal-
ity in the past, but have become much less frequent
since the introduction of highly active antiretroviral
therapies (HAARTs) directed against HIV, which
have dramatically impacted on the outcome of HIV
infection.[9] Herpesvirus CNS infections can still
be observed as the first disease manifestation in
patients with newly recognised HIV infection, or
in those who fail to respond to, or are intolerant of,
HAARTs. However, because of the paucity of cases
of herpesvirus CNS disease, it is still not known
whether the combined use of HAART and specific
antiviral therapy might favourably affect their out-
come, as observed in other HIV-related opportunis-
tic infections.[10]
2. Principles of Treatment
The aetiological treatment of herpesvirus infec-
tions of the CNS is currently based on the use of
antiviral agents. These drugs act by inhibiting viral
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
replication and include nucleoside analogues and
other herpesvirus DNA polymerase inhibitors. CSF
pharmacokinetic studies suggest that penetration
of these drugs into the CNS is variable, although
CSF concentrations above inhibitory concentrations
are likely to be achieved in several instances (table
II). With the exception of HSE, for which compar-
ative trials have demonstrated the beneficial effect
of aciclovir (acyclovir),[21,22] no information based
on clinical trial results is currently available for
herpesvirus infections of the CNS. The relatively
few cases observed, as well as diagnostic problems,
have hampered research into specific treatments.
Nevertheless, antiviral drugs are empirically given
in a number of herpes-induced CNS complications,
with variable benefit. Recently, the use of antiviral
drugs in combination has received attention. Drug
combinations can increase drug potency and pre-
vent the development of antiviral resistance, which
can be of particular concern in immunocompro-
mised patients. Resistance results from alterations
of viral enzymes that are critical for drug function-
ing, and resistance to a nucleoside analogue will
most likely confer resistance to other drugs of the
same class (table II).[23]
In cases of CNS diseases that are likely to be
caused by an immunotoxic mechanism rather than
direct viral cytotoxicity, corticosteroids are empir-
ically used because of their anti-inflammatory ef-
fects. Intravenous high dose glucocorticoids (e.g.
methylprednisolone up to 500mg daily for 3 to 5
days) has been the standard treatment for postinfec-
tious encephalitis,[24,25] but its efficacy has not been
proven. Alternative treatments, including intrave-
nously administered immunoglobulin (IVIG)[26-28]
and plasmapheresis,[29,30] have recently been used
in these conditions. Based on the successful res-
ponse observed in some patients, including pati-
ents who had failed to respond to corticosteroids,
IVIG and plasmapheresis appear to be promising
options for the treatment of acute demyelinating
encephalitis and warrant further evaluation. At pre-
sent, an empirical combined use of glucocorticoids
and plasmapheresis or IVIG, that takes into account
the pathogenic role of both cellular and humoral
CNS Drugs 2000 Aug; 14 (2)
 Herpesvirus Infections of the CNS
© Adis International Limited. All rights reserved.

Table II. Antiviral drugs with antiherpesvirus activity licensed for systemic use

Drug Class Highly sensitive Poorly or Administration Potentially severe CSF concentration Known basis of viral Recommended
moderately route adverse effects (% of plasma resistance regimen in CNS disease
sensitive concentration)

Aciclovir Nucleoside HSV-1, HSV-2, CMV, EBV, HHV-6, IV, oral Renal toxicity Approximately Altered or deficient 10 mg/kg every 8h for
(acyclovir)[11] analogue VZV HHV-7, HHV-8 (rare) 50[12] virus thymidine kinase 10-14 days, IVa
(HSV-1, HSV-2, VZV)

Valaciclovir[13] Nucleoside HSV-1, HSV-2, CMV, EBV, HHV-6, Oral Not reported Not available Altered or deficient Not evaluated
analogue VZV HHV-7, HHV-8 virus thymidine kinase
(aciclovir (HSV-1, HSV-2, VZV)
prodrug)

Famciclovir[14] Nucleoside HSV-1, HSV-2, CMV, EBV, HHV-6, Oral Not reported Not available Altered or deficient Not evaluated
analogue VZV HHV-7, HHV-8 thymidine kinase
(penciclovir (HSV-1, HSV-2, VZV)b
prodrug)

Ganciclovir[15] Nucleoside HSV-1, HSV-2, IV, oral Granulocytopenia, 24-67[16] Altered CMV UL97- 10 mg/kg once daily for
analogue VZV, CMV, thrombocytopenia encoded phospho- 14-21 days (IV) then 5
EBV, HHV-6, transferase or mg/kg/day
HHV-7, HHV-8 UL54-encoded (maintenance)c
polymerase

Foscarnet[17] Non- HSV-1, HSV-2, IV Renal toxicity, 5-72[18] Altered virus 180 mg/kg once daily
nucleoside VZV, CMV, electrolyte polymerase (HSV-1, for 14-21 days (IV) then
pyropho- EBV, HHV-6, imbalances, HSV-2, VZV) 90 mg/kg/day
sphate HHV-7, HHV-8 anaemia (maintenance)c
analogue

Cidofovir[19] Nucleoside HSV-1, HSV-2, IV Renal toxicity, 2-4[20]d Altered CMV UL54- 5 mg/kg once weekly
phosphonate VZV, CMV, granulocytopenia, encoded polymerase for 2 wks (IV) then 5
EBV, HHV-6, iritis (CMV) mg/kg every 2 wks
HHV-7, HHV-8 (maintenance)e

a 10 mg/kg every 8h for 10 days (IV) has been used in clinical trials[21,22] and proven to be effective.
CNS Drugs 2000 Aug; 14 (2)

b HSV-1, HSV-2 or VZV aciclovir-resistant strains frequently exhibit cross-resistance to penciclovir in vitro.

c The combination of ganciclovir and foscarnet should be considered for treatment of CMV encephalitis.

d These data were obtained 1h after cidofovir administration, and its long half-life should be considered.

e To be accompanied by aggressive IV hydration and oral administration of probenecid (2g 3h prior to cidofovir infusion and 1g at 2 and 8h after completion of the infusion).

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpesviruses; HSV = herpes simplex virus; IV = intravenous; VZV = varicella-zoster virus.

99
100
immunity, can be recommended to treat these forms
of encephalitis.
Along with aetiological treatments, a number of
life-support measures are required in the clinical
management of severe cases of acute encephalitis
and meningitis caused by herpesviruses. These in-
clude providing nutrition and controlling tempera-
ture and electrolyte balance, as well as treatment of
organ dysfunction other than that of the CNS. In-
tensive medical supportive care is almost invari-
ably required, including control of cerebral oedema
and seizures, and assisted ventilation in those who
develop deepening coma or other signs of brain-
stem dysfunction. Computed tomography (CT) and
magnetic resonance imaging (MRI) scans are of
value in monitoring cerebral oedema, whereas elec-
trophysiological monitoring and blood flow studies
provide precious functional information. Moreover,
intracranial pressure (ICP) monitoring should be
used for management of severe cases.
In order to reduce cerebral oedema, the use of
corticosteroids (e.g. high doses of dexamethasone
up to 16 to 20mg daily) is advocated by some for
the first 4 or 5 days of the illness, although this is
a matter of dispute. The immune-suppression in-
duced by corticosteroids can theoretically favour
virus replication and thus worsen the outcome of
CNS infection. However, a recent study using a rat
model of HSE has shown that corticosteroids do
not significantly inhibit the antiviral effect of aci-
clovir on the HSV-1 load in brain tissue and are also
effective in decreasing the extent of brain infection
if used without aciclovir.[31] These observations, if
confirmed, will provide an important experimental
rationale supporting controlled clinical evaluations
of corticosteroids in combination with antivirals
in acute viral CNS infections. In an acute cerebral
oedema, a rapid reduction of elevated ICP is best
achieved by hyperventilation. In order to rapidly
decrease ICP, intravenous administration of man-
nitol (1.5 to 2 g/kg, followed by 0.25 g/kg every 4
hours, or intermittent small doses of 0.25 to 1 g/kg)
may also be effective. The use of surgical decom-
pression is controversial because, although ICP may
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
be lowered by this procedure, the oedema could be
aggravated.
Effective control of seizures may be achieved
with the use of phenytoin at an initial dosage of 20
mg/kg/day, administered intravenously 3 times daily,
and a maintenance dosage of 7 to 10 mg/kg/day,
with concomitant monitoring of plasma drug con-
centrations.[32,33]
3. Herpes Simplex Virus (HSV)
3.1 Immunocompetent Patients
3.1.1 Herpes Simplex Encephalitis
HSE is the most common sporadic encephalitis.
It may present at any age, with most of the cases
occurring during the first decade or in patients over
50 years. Although HSE may affect young chil-
dren, it needs to be distinguished from neonatal
HSV encephalitis, which differs greatly in terms of
aetiopathogenesis, clinical presentations and out-
come. In the neonatal disease, different treatment
strategies may be required because of the lower rate
of responses compared with the ‘adult’ forms.[34]
In adults and children above the neonatal age, HSE
is caused by HSV-1 in over 90% of the cases, and
by HSV-2 in the remaining cases. Inflammatory to
haemorrhagic-necrotising lesions are characteristic-
ally located in the temporal lobes, but other adjacent
areas may also be involved.[34] The onset of HSE
is typically acute, with nonspecific focal neurolog-
ical signs and symptoms and impaired conscious-
ness. A broader spectrum of clinical presentations
of HSV-1 CNS infections has been recognised over
the last few years, including mild and chronic en-
cephalitis, and neurological syndromes related to
specific anatomic locations.[35-38]
The identification of HSV in brain tissue biop-
sies used to be the only conclusive means of estab-
lishing an aetiological diagnosis of HSE, but this
has more recently been replaced by the PCR detec-
tion of HSV-1 DNA in the CSF as the diagnostic
method of choice.[38] A number of retrospective and
prospective studies have clearly established the di-
agnostic reliability of the PCR, showing a more
than 90% sensitivity and virtually 100% specific-
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
ity.[39-41] This technique is rapid, which allows a
diagnosis to be established in time for management
decision making. Furthermore, it enables the diag-
nosis of uncommon forms of HSV CNS infection
that may otherwise go unrecognised.[35,36] The dem-
onstration of an intrathecal anti-HSV antibody syn-
thesis is also diagnostically useful, but can only be
applied in prolonged or chronic cases because a
response can usually only be detected 7 to 10 days
after the onset of symptoms.[39,41]
The first antiviral agents used for the treatment
of HSE were idoxuridine, cytarabine and vidarab-
ine.[42-44] The first clinical trial involved idoxurid-
ine and showed that this drug had low effectiveness
and was unacceptably toxic for the treatment of
HSE.[45] A subsequent controlled study of vidarab-
ine, conducted in the late 1970s, showed that the
rates of survival and normalisation of neurological
function were higher in patients treated with this
drug than in those receiving placebo.[46] Less than
a decade later, 2 large studies conducted indepen-
dently in Sweden and the US demonstrated that
mortality was significantly lower in patients receiv-
ing aciclovir than in those treated with vidarabine
(19 to 28% vs 50 to 54%, respectively). Further-
more, 38 to 56% of the patients treated with aci-
clovir were left with no or only minor sequelae
after 6 months, compared with 13 to 14% of those
receiving vidarabine.[21,22] The efficacy of aciclo-
vir was greater in patients treated early after dis-
ease onset and in those who were younger and had
less severe neurological impairment. Aciclovir, in
contrast to vidarabine, was not associated with sig-
nificant toxicity.
In these clinical trials, aciclovir 10 mg/kg was
intravenously administered every 8 hours for 10
days. In order to increase the likelihood of obtaining
complete virus suppression, however, 2 full weeks
of therapy are often used in clinical practice. Intra-
venous aciclovir 10 mg/kg 3 times daily for 10 to
14 days is therefore the current recommended reg-
imen for HSE. Although the vast majority of HSE
cases are caused by HSV-1, this dosage recommen-
dation also applies to encephalitis caused by HSV-2.
 Adis International Limited. All rights reserved.
101
In order to maintain sufficiently high exposures
in the brain to meet the inhibitory concentration for
HSV, it is necessary that aciclovir is administered
intravenously. Following oral intake, the absorb-
ence rate of the drug is low (15 to 30%), and plasma
concentrations warranting sufficient penetration in
the CNS are not achieved by this route.[11,12]
Although aciclovir is highly effective in reduc-
ing HSE-associated mortality and morbidity, a sig-
nificant number of patients still die or are left with
severe neurological sequelae. For these reasons,
more potent antiviral regimens have been propo-
sed. These include increasing the duration of treat-
ment to 21 days, increasing the dosage to 15 mg/kg
every 8 hours or making use of antiviral drug com-
binations. In this regard, new anti-herpes compounds
have become available over recent years, thus pro-
viding additional therapy options (table II).
Another important concern regarding HSE out-
come is the occurrence of relapse following a fa-
vourable response to therapy.[47-51] In a recent pae-
diatric series, HSE relapse was observed in 26% of
HSE cases, usually days to weeks following the
resolution of a first episode. Of note, relapse cases
were found to be significantly more frequent in
patients receiving lower total doses of aciclovir
during the initial episode.[51] Relapse may be asso-
ciated with either a rebound of viral replication or
an immune-mediated mechanism. Indeed, reported
cases show inconsistent evidence of viral replication
in the CSF,[49-52] and neuropathological studies in-
dicate that both mechanisms can be involved.[4,47,48]
The administration of additional aciclovir courses
has been shown to be useful in patients with relapse
of the disease[51] and, because of the possible virus
persistence in the CNS, we believe that this strat-
egy should always be used in similar cases. On the
other hand, anti-inflammatory drugs, i.e. cortico-
steroids, do not have proven efficacy and their use
remains controversial.
In clinical practice, aciclovir is often initiated
empirically in patients with suspected HSE. How-
ever, a newer approach based on the use of CSF
PCR (an example of which is shown in figure 1),
is currently used in several centres and is strongly
CNS Drugs 2000 Aug; 14 (2)
102 Cinque & Lazzarin

Clinical neurological assessmenta

CT scan/MRIa Suspected Begin aciclovir
CSF chemistry HSE (acyclovir)b
Microbiology tests

CSF PCR for HSV-DNA

HSV-specific intrathecal Ab syntesisc

Other
Ab
negative diagnosis
probable
PCR PCR
positive negative
Ab
positive

Continue
aciclovir

Repeat CSF
at the end of treatment

PCR PCR
negative positive

Clinical
improvement

Stop Continue
aciclovir aciclovir

Fig. 1. Polymerase chain reaction (PCR)–based algorithm for the management of patients with suspected herpes simplex encephalitis
(HSE). (a) Before CSF sampling, to exclude the presence of mass lesions that may contraindicate the lumbar puncture. (b) Standard
treatment: 10 mg/kg/day every 8 hours intravenously for 10 to 14 days. (c) Herpes simplex virus (HSV) intrathecal antibody synthesis
detection may be of help after the first week from onset of symptoms. Ab = antibody; CT = computed tomography; MRI = magnetic
resonance imaging.

recommended.[38] In a recent decision analysis mo-
del, a PCR-based approach was shown to be associ-
ated not only with a better outcome than that offered
by empirical therapy, but also with a significant
reduction in the use of aciclovir.[53] These results
are due to a lower rate of inappropriate aciclovir
discontinuation in patients with HSE and a higher
rate of correct discontinuation in PCR-negative pa-
tients. In using such a PCR-based approach, how-
ever, it is important that PCR results are interpreted
cautiously in relation to the clinical presentation
and the duration of antiviral therapy. Examples ex-
ist of initially negative PCR results obtained very
early after the onset of HSE symptoms, which are
likely to reflect limited virus replication and initial
CNS lesions. In these cases, however, HSV DNA
can be detected in CSF samples drawn a few days
later.[52]
On the other hand, the likelihood of finding a
positive CSF PCR result is reduced following a few
days of aciclovir treatment, and in untreated pa-
tients from whom CSF is obtained late after the
onset of neurological symptoms. A delayed exam-
ination of the CSF by PCR can still be diagnosti-

 Adis International Limited. All rights reserved. CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
cally helpful, since HSV DNA has been found in
the CSF as late as 2 weeks after HSE onset, even
in patients who had received aciclovir.[39,40,52] More
recently, quantitative PCR techniques have reveal-
ed a correlation between high CSF HSV DNA lev-
els and poor disease outcome and also a decrease
in HSV DNA levels during therapy,[54] thus sug-
gesting that HSV DNA quantitation in CSF may
also gain a role in the diagnostic stages and during
HSE treatment.
3.1.2 HSV Type 2 Meningitis
HSV-2 can cause aseptic meningitis, a form that
is mainly observed in women, and may be associated
with primary HSV-2 genital infection.[55] Further-
more, HSV-2 meningitis may recur over months or
years (‘Mollaret’s meningitis’), often in association
with recurrences of genital HSV-2 infection.[56,57]
HSV-2 meningitis can be easily recognised when
genital lesions are present; virus isolation from CSF,
the demonstration of an intrathecal HSV antibody
response and seroconversion against HSV-2 have
all been used to confirm such a diagnosis or to
formulate it when it is less obvious.[55] Over the
last few years, the PCR detection of HSV-2 has
been found to be more sensitive than these meth-
ods. Although no systematic studies of CSF PCR
have been reported to date, sufficient data have ac-
cumulated to suggest that it may be the method of
choice in both primary and recurrent forms.[57-59]
Primary and recurrent meningitis are benign and
recover spontaneously even in the absence of ther-
apy.[55,57] However, published case reports and cli-
nical observations indicate that intravenous aciclo-
vir at 5 or 10 mg/kg every 8 hours is useful in
relieving the symptoms of HSV-2 meningitis and
shortening disease duration.[58,60] Intravenous aci-
clovir at these dosages is indicated in hospitalised
patients with HSV-2 meningitis. However, the use
of valaciclovir, an orally administered ester of aciclo-
vir, can be considered in milder recurrent cases. Fol-
lowing oral administration of valaciclovir 1000mg
every 8 hours, plasma aciclovir concentrations are
similar to those achieved after intravenous admin-
istration of aciclovir 5 mg/kg every 8 hours.[61] Val-
aciclovir at the dosage of 1000mg 3 times daily
 Adis International Limited. All rights reserved.
103
may therefore be an option in patients who have
already experienced HSV-2 meningitis episodes and
in whom an initial CNS or genital recurrence can
be recognised. Furthermore, oral aciclovir 400mg
twice daily,[62,63] valaciclovir 500 to 1000mg once
daily or 250mg twice daily,[64] and famciclovir 250mg
twice daily[65] have all been proven to efficiently
suppress recurrences of genital infection. Intermit-
tent or continuous prophylaxis using these regi-
mens is thus likely to be also effective in the pre-
vention of CNS episodes.
3.2 Immunocompromised Patients
CNS infections due to HSV-1 or HSV-2 are an
infrequent complication in both HIV-infected[66,67]
and other immunosuppressed patients.[68] In HIV-
infected patients with a relatively conserved im-
munity, the neuropathology findings and clinical
presentations are similar to those observed in clas-
sical HSE, but these are different in patients with
a severely impaired immune system. Most of these
cases have combined HSV-1 or HSV-2 and CMV
infection, and present clinically with a subacute
and progressive encephalitis that is similar to that
observed in patients with pure CMV encephalitis.[69]
Extensive necrosis with no or mild inflammation,
often located in the periventricular areas, is revealed
at neuropathology.[66-68] HSV encephalitis occurring
in HIV-infected and other severely immunosuppre-
ssed patients is clinically difficult to recognise. How-
ever, CSF PCR has also been shown to be highly
reliable in these patients, with a sensitivity and spe-
cificity of 100 and 99.5%, respectively.[69]
In addition to aciclovir, HSV-1 and HSV-2 are
also susceptible to ganciclovir, foscarnet and cido-
fovir, antiviral agents that are approved for the treat-
ment of CMV infections (table II). Although these
drugs are less well tolerated than aciclovir, their
use is indicated in patients with concomitant HSV
and CMV infections. However, HIV-infected pa-
tients with HSV and CMV or pure HSV infection
respond poorly to standard aciclovir, ganciclovir
or foscarnet therapy and their survival is low. Fur-
thermore, a relapse of encephalitis following an
initial response has also been observed.[69] In re-
CNS Drugs 2000 Aug; 14 (2)
104
lapses of HSE observed in HIV-infected patients,
the neuropathological findings and the persistence
of HSV DNA in the CSF suggest that CNS damage
results principally from residual virus replication.
It is likely that standard antiviral regimens are not
sufficient to clear extensive CNS infections in the
absence of adequate host immune control. How-
ever, drug resistance to aciclovir has also been re-
ported.[70] For these reasons, the use of drug com-
binations may represent a reasonable strategy in
this particular patient population.
4. Varicella-Zoster Virus
4.1 Immunocompetent Patients
VZV CNS disease may complicate both chicken-
pox and herpes zoster, but may also occur in the
absence of skin lesions. The most frequent compli-
cation of varicella is acute and usually benign cer-
ebellar ataxia, whereas other CNS localisations are
less commonly observed (table I). Cerebellar atax-
ia, as well as some cases of encephalomyelitis, are
thought to originate from postinfectious immune-
mediated mechanisms. Herpes zoster–related neu-
rological disease generally occurs in the elderly and
may be severe. This consists of vasculitis, enceph-
alitis, meningitis, myelitis or mixed forms.[71] VZV
vasculitis is now a well defined syndrome that re-
sults from infection of large vessels in the CNS
(granulomatous arteritis) and leads to thrombosis
and cerebral infarcts.[72]
CSF PCR is the most sensitive method for diag-
nosing VZV CNS infections, whereas other viro-
logical techniques are rarely successful.[73] With the
use of CSF PCR, VZV DNA has been found in the
majority of patients with herpes zoster and neurolo-
gical complications, in patients with VZV CNS in-
fection and no cutaneous lesions, but also in patients
with herpes zoster and no CNS symptoms.[5,41,61,73,74]
Remarkably, the VZV genome is also found in the
CSF of approximately half of the children with cer-
ebellar ataxia,[5] suggesting that VZV persistence
in the CNS might play a role in sustaining the im-
mune processes presumably associated with this
disease. The detection of intrathecal VZV-specific
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
antibody production is also diagnostically useful
for VZV-induced neurological complications, but
reliable results appear only days to weeks after the
onset of neurological symptoms.[41,75]
Intravenous aciclovir is usually given to pati-
ents with VZV disease of the CNS and there is ev-
idence for the efficacy of this approach.[72,76,77] On
the basis of reported and direct experience with
these patients, and taking into account the informa-
tion collected in the HSE treatment trials, intrave-
nous aciclovir at 10 mg/kg 3 times daily for 10 to
14 days appears indicated for the treatment of VZV-
associated neurological diseases. Because the in-
hibitory aciclovir concentrations required for VZV
are higher than those required for HSV-1 or HSV-
2,[12] the use of 15 mg/kg every 8 hours has also
been suggested to treat the most severe forms.[71]
Corticosteroids are frequently employed in the
treatment of cerebellar ataxia, but antiviral therapy
is also indicated because of the possible association
of this complication with virus replication in the
CNS. However, cerebellar ataxia is usually a self-
limiting disease and the benefit of anti-inflamma-
tory or antiviral regimens has not yet been estab-
lished.
4.2 Immunocompromised Patients
In HIV-infected patients, different clinico-path-
ological forms of VZV infections of the CNS have
been recognised, including multifocal leucoence-
phalitis, ventriculo-encephalitis, meningomyelo-
radiculitis, myelitis and vasculitis.[78] Unlike vas-
culitis of the immunocompetent host, in whom VZV
infection principally involves large arteries, a small
vessel vasculitis is observed in HIV-infected or other
immunosuppressed patients.[72] Herpes zoster pre-
cedes or accompanies CNS disease in approxim-
ately half of the cases, whereas no cutaneous le-
sions are otherwise observed.[78,79] VZV infection
can also spread to the visceral organs (including the
CNS), in other immunocompromised patients.[80]
This was of great concern in children with leukae-
mia or other malignancies who contracted varice-
lla; however, this risk has now been drastically re-
duced by preventive strategies based on the use of
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
vaccination, passive immunisation and the treat-
ment of varicella with intravenous aciclovir.[81] In
HIV-infected patients, VZV DNA can be found by
CSF PCR in the case of proven VZV CNS dis-
ease,[79,82,83] although the virus has also been re-
covered in the CSF of patients in whom there was
no clear evidence of VZV CNS involvement.[79]
Clinical responses to aciclovir, at the doses used
in immunocompetent patients, have also been repor-
ted in HIV-infected patients with encephalitis or
myelitis.[72,79,84-86] Furthermore, VZV DNA is clear-
ed from the CSF in the majority of treated cases.[79,83]
Intravenous high dose aciclovir can therefore be
recommended for the treatment of VZV neurolog-
ical complications in immunocompromised pati-
ents.
However, clinical failure is not uncommon and
may be associated with virus persistence in the
CSF.[79,83] Lack of clinical and virological response
might result from inadequate CNS drug concentra-
tions, which might support the use of increased
aciclovir dosages, i.e. 15 mg/kg 3 times daily, for
treating severe VZV neurological disease. How-
ever, treatment failure might also result from the
development of aciclovir resistant VZV strains.[87]
Alternative approaches, for example, the use of other
drugs or drug combinations, therefore need to be
considered. New antiviral agents that are highly
effective against VZV, such as famciclovir and so-
rivudine, have recently been developed, but no in-
formation is so far available on their use in CNS
infections. Famciclovir, an orally administered es-
ter of penciclovir, has been proven to be at least as
effective as aciclovir for the treatment of herpes
zoster in immunocompetent patients.[88,89] Sorivu-
dine, an extremely potent inhibitor of VZV DNA
polymerase, was even more effective than aciclovir
in accelerating cutaneous healing of herpes zoster in
HIV-infected patients.[90,91] This drug, however, has
not been approved for clinical use because it cau-
sed lethal toxicity in patients concomitantly treated
with fluorouracil.[92]
 Adis International Limited. All rights reserved.
105
5. Cytomegalovirus
5.1 Immunocompetent Patients
CNS infections due to CMV, including menin-
gitis or encephalitis, are rare in immunocompetent
patients.[93-95] The serological demonstration of a
primary CMV infection, i.e. immunoglobulin (Ig)
G (IgG) seroconversion or the demonstration of
specific IgM, concomitant with neurological symp-
toms strongly supports a CMV-induced CNS dis-
ease. Although a number of methods have been
used to achieve a definite diagnosis, including the
demonstration of intrathecal antibody production,
virus isolation from CSF or virus detection by im-
munohistochemistry, CSF PCR is the most sensi-
tive diagnostic technique for the demonstration of
CMV DNA.[94-96] Furthermore, the application of
CSF PCR has been of major importance in defining
the clinical spectrum of CMV-associated neurolog-
ical manifestations.[94]
The outcome of CNS complications due to CMV
is usually good, although the symptoms may occa-
sionally persist for some months.[94] In anecdotal
cases of CMV encephalitis, the use of intravenous
ganciclovir at standard doses has been followed by
a recovery of neurological symptoms.[97] Because
of the paucity of clinical experiences, there is no
clear indication on whether or not to treat CMV
complications in the CNS in immunocompetent pa-
tients. Both disease severity and possible adverse
effects of anti-CMV drugs, that are more relevant
than those caused by aciclovir, should be taken into
account in treatment decision making (table II).
5.2 Immunocompromised Patients
CMV infections of the CNS in HIV-infected pa-
tients include the well described syndromes of en-
cephalitis and polyradiculomyelitis.[95,98,99] CMV
encephalitis used to be observed in up to 25% of
autopsied cases, although it has become infrequent
since the introduction of HAARTs. Its main neu-
ropathological forms are ventriculo-encephalitis,
focal encephalitis and diffuse micronodular ence-
phalitis, which all present clinically as a subacute
encephalopathy.[98] The prognosis is poor, with death
CNS Drugs 2000 Aug; 14 (2)
106
ensuing within weeks despite antiviral treatment.
CMV polyradiculomyelitis is due to infection of
the cauda equina and lumbosacral rootlets. It is cha-
racterised by a subacute onset of leg weakness and
sensory loss, with sphincter dysfunction, rapidly
progressing to ascending paraparesis.[99]
Although infrequent, other immunocomprom-
ised patients such as liver, bone marrow, heart and
kidney transplant recipients, may also develop CMV
encephalitis. Symptoms may be severe in these pa-
tients, but the extensive necrosis commonly obser-
ved in HIV-infected patients is rarely observed at
histopathological examination.[95]
CSF viral isolation and antigen detection in po-
lymorphonuclear leucocytes have low sensitivity
in cases of encephalitis. These techniques, how-
ever, may be useful in cases of polyradiculopathy,
in which a typical CSF polymorphonuclear pleo-
cytosis is observed.[99] CSF PCR for the detection
of CMV DNA is highly sensitive and specific for
both polyradiculomyelitis and encephalitis, with a
diagnostic sensitivity of 80 to 95% and specificity
of 90 to 100% in HIV-infected patients.[7,100-103]
Since CMV DNA can be found in the CSF of pati-
ents with either mild or extensive CNS lesions, fur-
ther investigations using quantitative PCR can help
to distinguish forms with different severity.[104,105]
Although there is considerably less experience in
this area, CSF PCR has also been shown to be help-
ful in other immunocompromised patients.[106]
Although no information from controlled studies
is available, there is abundant clinical experience
with the use of ganciclovir and, to a lesser extent,
foscarnet in HIV-infected patients. Neither is very
effective in cases of CMV encephalitis, the occur-
rence of which is actually common in patients under-
going maintenance treatment with these drugs.[107]
However, CSF CMV DNA titres often decrease fol-
lowing ganciclovir therapy and may also become un-
detectable; in some cases these findings have been
associated with partial neurological improvement.[104]
A good clinical response has also been shown in 2
patients with CMV encephalitis following cidofo-
vir, but further experience is clearly needed to de-
fine the effectiveness of this drug.[108,109]
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
More recently, clinical improvement or stabil-
isation of CNS CMV disease has been reported in
more than half of the patients receiving a combina-
tion of ganciclovir and foscarnet, whereas therapy
discontinuation due to adverse effects was observed
in approximately one-third of the patients treated
with this regimen.[110] Unlike encephalitis, CMV
polyradiculitis responds to ganciclovir in approxi-
mately 50% of cases, and responses have also been
reported following foscarnet therapy.[99,111]
The failure of anti-CMV drugs in the treatment
of CMV infections of the CNS may be due to inad-
equate CNS drug concentrations in relation to the
viral burden or to the presence of irreversible tissue
damage caused by extensive necrosis. However, dev-
elopment of drug-resistant CMV strains may also
occur. In this regard, viral strains resistant to gan-
ciclovir and CMV-UL 97 gene mutations confer-
ring resistance to this drug have been detected in
the CSF of patients with CMV neurological dis-
eases.[112,113]
An induction course of ganciclovir, foscarnet or
cidofovir, followed by lifelong maintenance treat-
ment, at the dosage recommended for treatment of
extracerebral CMV infections (table II), is the stan-
dard treatment for CMV-induced neurological com-
plications. However, more potent regimens are clearly
necessary in the majority of cases. A combination
of ganciclovir and foscarnet, each used at standard
doses, has been proposed for the treatment of se-
vere CMV infections of the CNS, and is strongly
recommended in patients who have received pre-
vious anti-CMV therapy.[110,114,115] The 2 drugs have
a synergistic effect in vitro[116] and different resis-
tance and toxicity profiles,[15,17] and their combi-
nation has been shown to provide some benefit in
patients with CNS CMV disease.[110] Along with
the clinical assessment, it is important to monitor
the local virological response to treatment, and this
can be best accomplished by CSF quantitative nu-
cleic acid amplification techniques. Studies of se-
quential CSF specimens collected before and after
treatment with ganciclovir, foscarnet or both have
shown that CMV replication is not adequately su-
ppressed in the CSF following 3 weeks of treat-
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
ment.[117] Longer induction courses than those cur-
rently recommended would probably be required
to clear the infection from the CSF, but in this re-
gard, drug toxicity is expected to be an important
limiting factor.
Patients with CMV retinitis receiving HAART
show prolonged responses to anti-CMV therapy[10]
and, currently, maintenance anti-CMV therapy is
no longer recommended in HAART-treated patients
in whom immunological conditions have signifi-
cantly improved.[115] If practicable, therapeutic ap-
proaches combining anti-CMV and anti-HIV drugs
appear to be a reasonable option for the manage-
ment of CMV complications of the CNS. Experience
with CMV encephalitis is limited in immunosup-
pressed patients other than those with HIV infec-
tion. In these patients, CMV encephalitis is also
a severe, potentially life-threatening complication.
Therefore, treatment with anti-CMV agents is strong-
ly recommended. Nevertheless, the fact that their
immunosuppression may be transitory and less pro-
nounced than in patients with AIDS suggests that
they may respond better to anti-CMV agents.[106,118]
6. Epstein-Barr Virus
6.1 Immunocompetent Patients
Headache and CSF pleocytosis are not infrequ-
ent in patients with uncomplicated acute mononu-
cleosis, which suggests possible CNS involvement
at the time of primary EBV infection.[119] More se-
vere CNS involvement has been shown in the form
of meningoencephalitis, although cerebellitis and
myelitis have also been described.[120,121] The di-
rect role of EBV replication in causing brain dam-
age is not obvious, and a number of the reported
cases of EBV-associated encephalopathies are con-
sistent with an immune-mediated postinfectious me-
chanism.[122,123] EBV-induced neurological compli-
cations are classically diagnosed by means of the
serological demonstration of a recent primary in-
fection, proven by the detection of serum IgG and
IgM against replicative EBV antigens, in the ab-
sence of antibodies to the EBV nuclear antigens. A
more reliable diagnosis can be obtained by demon-
 Adis International Limited. All rights reserved.
107
strating specific intrathecal antibody production or
by PCR detection of EBV DNA in CSF.[124-126] How-
ever, in line with the hypothesis of immunotoxic
damage to the CNS, EBV amplification from CSF
has failed in a number of cases.[123] Of note, EBV
has also been found in the CSF of patients with
other herpesvirus CNS infections.[127] This finding
suggests that EBV might be locally reactivated by
other CNS infections;[126] however, the clinical sig-
nificance of such CSF coinfection, if any, is poorly
understood.
The prognosis of mild EBV disease is generally
good, but neurological sequelae can be observed in
up to 40% of patients with meningoencephalitis,
and fatal cases have also been reported.[121,122] No
treatment for EBV complications of the CNS has
yet been validated and treatment decisions are fur-
ther hampered by an incomplete knowledge of the
underlying pathogenic mechanisms. Both aciclo-
vir and corticosteroids have been used in the treat-
ment of CNS EBV diseases, although the benefit
of these approaches is uncertain.[128-131] The use of
aciclovir and corticosteroids, alone or in combina-
tion, has been found to offer no substantial clinical
benefit in clinical trials involving patients with un-
complicated acute mononucleosis.[132,133] Further-
more, neurological complications have been repor-
ted in patients with acute mononucleosis receiving
corticosteroids.[134] In vitro, ganciclovir has been
shown to be more efficient than aciclovir in inhibit-
ing EBV replication. Therefore, the use of this drug
deserves consideration in the treatment of poten-
tially severe EBV-induced CNS complications.[135]
6.2 Immunocompromised Patients
EBV encephalitis or meningitis are exceptional
in the setting of HIV infection. However, EBV is
constantly associated with HIV-related primary CNS
lymphomas.[136] Although EBV detection in the CSF
or brain of patients with lymphomas may have diag-
nostic implications,[137] management of this neo-
plasm is beyond the scope of this article.
In patients who have had a transplant, neurolog-
ical involvement can be observed in the context of
EBV-related lymphoproliferative disorders. EBV
CNS Drugs 2000 Aug; 14 (2)
108
encephalitis or meningoencephalitis has also been
observed, and treatment with aciclovir or ganciclovir
has been followed by clinical improvement.[135,138]
7. Human Herpesvirus 6 (HHV-6), HHV-7
and HHV-8
7.1 Immunocompetent and
Immunocompromised Patients
Febrile convulsions and other neurological symp-
toms can occur in young children with exanthe-
ma subitum or unrecognised primary HHV-6 infec-
tion.[139,140] Furthermore, encephalitis presumably
due to HHV-6 has recently been described in imm-
unocompetent adults[141,142] and cases of CNS dis-
ease resulting from HHV-6 are increasingly being
recognised among bone marrow transplant recip-
ients.[143-146] The virus does not seem to play a pro-
minent role in inducing clinical neurological disease
in HIV-infected adults,[147] although CNS compli-
cations of primary HHV-6 infections may be fatal
in HIV-infected children.[148] Two distinct HHV-6
variants exist: A and B. Variant B is associated with
uncomplicated primary HHV-6 infection and is also
identified in the CSF or brain of children with neu-
rological complications of primary infections.[149]
Both variants can be found in paediatric and adult
immunocompetent patients with encephalitis, as well
as in immunocompromised patients.[144,147,149,150]
HHV-7 infection of the CNS might be responsi-
ble for febrile seizures or other focal neurological
signs in association with HHV-7 exanthema.[151]
Currently, there is no strong evidence of an aetio-
logical association of HHV-8 with any CNS dis-
ease.
In children with seizures, CNS involvement by
HHV-6 can be suggested by serological evidence
of acute HHV-6 infection.[140,141] Furthermore, HHV-
6 DNA can be detected in the CSF by PCR, al-
though this finding is not specific.[152] HHV-6 has
also been identified, through the use of CSF PCR,
in transplant recipients with encephalitis and in HIV-
infected patients. In these latter patients, however,
HHV-6 detection in the CSF was not associated
with clinically significant HHV-6–induced CNS dis-
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
ease, suggesting that this test should be used cau-
tiously for diagnostic purposes.[147] HHV-7 has spo-
radically been found in the CSF of children with
febrile seizures.[151]
There is no established treatment for HHV-6 in-
fections of the CNS. Febrile seizures of childhood
are usually benign and antiviral agents are not em-
ployed. However, different considerations are re-
quired for HHV-6 encephalitis. There is increasing
evidence showing successful responses to ganci-
clovir or foscarnet in immunocompetent and bone
marrow transplant patients with encephalitis.[145-147]
On the basis of these preliminary observations, and
on the high susceptibility of A and B HHV-6 vari-
ants to both ganciclovir and foscarnet,[153] the use
of these drugs at the doses employed in the treat-
ment of CMV infections (table II), is indicated in
cases of HHV-6 encephalitis. These same drugs are
also effective against HHV-7[153] but, in this regard,
no clinical data have yet been reported.
8. Concluding Remarks and
Future Prospects
Progress towards the optimal management of her-
pesvirus infections of the CNS has continued since
the dramatic decline in mortality and morbidity fol-
lowing the introduction of aciclovir for HSE. New
clinical manifestations have been defined, and mo-
lecular techniques have provided clinicians with an
invaluable diagnostic tool to be used in combina-
tion with classical examinations. New compounds
have been developed and mechanisms of action,
pharmacokinetics properties and patterns of viral
resistance further delineated.
However, despite these optimistic remarks, much
remains to be done. A number of herpes diseases of
the CNS are still poorly characterised, especially
in terms of virus-host interactions, and diagnostic
techniques, particularly those based on CSF molec-
ular analysis, still suffer from a lack of standard-
isation. In cases of less frequently encountered dis-
eases, even the real diagnostic reliability of CSF
PCR is poorly defined. Frequently, treatment reco-
mmendations cannot be formulated because of lim-
ited clinical experience. Moreover, the current treat-
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
ment strategies are unsatisfactory in a number of
instances.
The first steps towards the evaluation of new
treatment strategies will involve quality control stu-
dies of the current diagnostic procedures and stan-
dardisation of the diagnostic criteria for neurolog-
ical complications of herpesvirus infections. New
aciclovir regimens, as well as newer antiviral agents
or drug combinations, clearly warrant evaluation
in the context of controlled trials. Given the low
frequency of herpesvirus CNS infections, clinical
assessments of antiviral regimens can only be done
in the context of large multicentre studies. These
will not only require close collaboration among phy-
sicians, virologists and pathologists, but also sub-
stantial support from health programmes and drug
companies.
Acknowledgements
We wish to thank Lucia Angelini and the members of the
European Union Concerted Action on Viral Encephalitis and
Meningitis for helpful advice.
References
1. Esiri MM. Herpes simplex encephalitis. An immunohistologi-
cal study of the distribution of viral antigen within the brain.
J Neurol Sci 1982; 54: 209-26
2. Price R, Chernik NL, Horta-Babosa L, et al. Herpes simplex
encephalitis in an anergic patient. Am J Med 1973; 54: 222-8
3. Johnson RT. Acute encephalitis. Clin Infect Dis 1996; 23: 219-26
4. Koenig H, Rabinowitz SG, Day E, et al. Post-infectious ence-
phalomyelitis after successful treatment of herpes simplex
encephalitis with adenine-arabinoside: ultrastructural obser-
vations. N Engl J Med 1979; 300: 1089-93
5. Puchhammer-Stöckl E, Popow-Kraupp T, Heinz FX, et al. De-
tection of varicella-zoster virus DNA by polymerase chain
reaction in the cerebrospinal fluid from patients suffering from
neurological complications associated with chickenpox or her-
pes zoster. J Clin Microbiol 1991; 29: 1513-6
6. Tyler KL. Polymerase chain reaction and the diagnosis of viral
central nervous system diseases. Ann Neurol 1994; 6: 809-11
7. Cinque P, Scarpellini P, Vago L, et al. Diagnosis of central nerv-
ous system complications in HIV-infected patients: cerebro-
spinal fluid analysis by the polymerase chain reaction. AIDS
1997; 11: 1-17
8. Gross PA, Barrett TL, Dellinger EP, et al. Purpose of quality
standards for infectious diseases. Infectious Diseases Society
of America. Clin Infect Dis 1994; 18 (3): 421
9. Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining mor-
bidity and mortality among patients with advanced human
immunodeficiency virus infection. HIV Outpatient Study In-
vestigators. N Engl J Med 1998; 338: 853-60
10. Mitchell SM, Membrey WL, Youle MS, et al. Cytomegalovirus
retinitis after the initiation of highly active antiretroviral ther-
 Adis International Limited. All rights reserved.
109
apy: a 2 year prospective study. Br J Ophthalmol 1999; 83:
652-5
11. Wagstaff AJ, Faulds D, Goa KL. Aciclovir. A reappraisal of its
antiviral activity, pharmacokinetic properties and therapeutic
efficacy. Drugs 1994; 47: 153-205
12. Whitley RJ, Blum MR, Barton N, et al. Pharmacokinetics of
acyclovir in humans following intravenous administration.
Am J Med 1982; 73 Suppl.: 165-71
13. Perry CM, Faulds D. Valaciclovir. A review of its antiviral ac-
tivity, pharmacokinetics properties and therapeutic efficacy
in herpesvirus infections. Drugs 1996; 52: 754-72
14. Perry CM, Wagstaff AJ. Famciclovir. A review of its pharma-
cological properties and therapeutical efficacy in herpesvirus
infections. Drugs 1995; 50: 396-415
15. Markham A, Faulds D. Ganciclovir. An update of its therapeutic
use in cytomegalovirus infection. Drugs 1994; 48: 455-84
16. Fletcher C, Sawchuck R, Chinnok B, et al. Human pharmaco-
kinetics of the antiviral drug DHPG. Clin Pharmacol Ther
1986; 40: 281-6
17. Chrisp P, Clissold SP. Foscarnet. A review of its antiviral activity,
pharmacokinetic properties and therapeutic use in immuno-
compromised patients with cytomegalovirus retinitis. Drugs
1991; 41: 104-29
18. Hengge UR, Brockmeyer NH, Malessa R, et al. Foscarnet pen-
etrates the blood-brain barrier: rationale for therapy of cyto-
megalovirus encephalitis. Antimicrob Agents Chemother 1993;
37: 1010-4
19. Lea AP, Bryson HM. Cidofovir. Drugs 1996; 52: 225-30
20. De Wit S, Snoeck R, Rossi C, et al. Treatment of progressive
multifocal leukoencephalopathy with cidofovir in an AIDS
patient [abstract P106]. Third International Congress on Drug
Therapy in HIV Infection: 1996 Nov 3-7; Birmingham, UK
21. Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus
vidarabine in herpes simplex encephalitis. Randomised mul-
ticentre study in consecutive Swedish patients. Lancet 1984;
II: 707-11
22. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus
acyclovir therapy in herpes simplex encephalitis. N Engl J
Med 1986; 314: 144-9
23. Field AK, Biron KK. ‘The end of innocence’ revisited: resis-
tance of herpesviruses to antiviral drugs. Clin Microbiol Rev
1994; 7: 1-13
24. Pasternak JF, De Vivo DC, Prensky AL. Steroid-responsive en-
cephalomyelitis in childhood. Neurology 1980; 30: 481-6
25. Hawley RJ. Early high-dose methylprednisolone in acute dis-
seminated encephalomyelitis. Neurology 1998; 51: 644-5
26. Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin
therapy in recurrent acute disseminated encephalomyelitis.
Neurology 1996; 46: 1173-4
27. Daaboul Y, Vern BA, Blend MJ. Brain SPECT imaging and
treatment with IVIg in acute post-infectious cerebellar ataxia:
case report. Neurol Res 1998; 20: 85-8
28. Assa A, Watemberg N, Bujanover Y, et al. Demyelinative brain-
stem encephalitis responsive to intravenous immunoglobulin
therapy. Pediatrics 1999; 104: 301-4
29. Kanter DS, Horensky D, Sperling RA, et al. Plasmapheresis in
fulminant acute disseminated encephalomyelitis. Neurology
1995; 45: 824-7
30. Balestri P, Grosso S, Acquaviva A, et al. Plasmapheresis in a
child affected by acute disseminated encephalomyelitis. Brain
Dev 2000; 22: 123-6
31. Thompson KA, Blessing WW, Wesselingh SL. Herpes simplex
replication and dissemination is not increased by corticoste-
CNS Drugs 2000 Aug; 14 (2)
110
roids treatment in a rat model of focal herpes encephalitis. J
Neurovirol 2000; 6: 25-32
32. Bhabha SK, Bharucha NE, Bharucha EP. Viral infections. In:
Bradley WG, Daroff RB, Ferrichel GM, et al., editors. Neuro-
logy in clinical practice. 2nd ed. Boston (MA): Butterworth-
Heineman, 1996: 1259-75
33. Wald SL. Disorders of cerebrospinal fluid circulation and brain
edema. In: Bradley WG, Daroff RB, Ferrichel GM, et al.,
editors. Neurology in clinical practice. 2nd ed. Boston (MA):
Butterworth-Heineman, 1996: 1431-58
34. Whitley RJ. Herpes simplex virus. In: Scheld WM, Whitley RJ,
Durack DT, editors. Infections of the central nervous system.
2nd ed. New York (NY): Raven Press, 1997: 73-90
35. Domingues RB, Tsanaclis AM, Pannuti CS, et al. Evaluation of
the range of clinical presentations of herpes simplex enceph-
alitis by using polymerase chain reaction assay of cerebrospi-
nal fluid samples. Clin Infect Dis 1997; 25: 86-91
36. Fodor PA, Levin MJ, Weinberg A, et al. Atypical herpes simplex
virus encephalitis diagnosed by PCR amplification of viral
DNA from CSF. Neurology 1998; 51: 554-9
37. Nakajima H, Furutama D, Kimura F, et al. Herpes simplex virus
myelitis: clinical manifestations and diagnosis by the poly-
merase chain reaction method. Eur Neurol 1998; 39: 163-7
38. Cinque P, Cleator GM, Weber T, et al., and The European Union
Concerted Action on Viral Encephalitis and Meningitis Group.
The role of laboratory investigation in the diagnosis and man-
agement of patients with suspected herpes simplex encepha-
litis. A consensus report. J Neurol Neurosurg Psychiatry 1996;
61: 339-45
39. Aurelius E, Johansson B, Sköldenberg B, et al. Rapid diagnosis
of herpes simplex encephalitis by nested polymerase chain
reaction assay of cerebrospinal fluid. Lancet 1991; 337: 189-92
40. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to her-
pes simplex virus in cerebrospinal fluid from patients with
herpes simplex encephalitis. J Infect Dis 1987; 155 (6): 1172-8
41. Linde A, Klapper PE, Monteyne P, et al. Specific diagnostic
methods for herpesvirus infections of the central nervous sys-
tem: a consensus review by the European Union Concerted
Action on Virus Meningitis and Encephalitis. Clin Diagn Virol
1997; 8: 83-104
42. Nolan DC, Lauter CB, Lerner AM. Idoxuridine in herpes sim-
plex virus (type 1) encephalitis. Experience with 29 cases in
Michigan, 1966 to 1971. Ann Intern Med 1973; 78: 243-6
43. Hryniuk W, Foerster J, Shojania M, et al. Cytarabine for herpes-
virus infections. JAMA 1972; 219: 715-8
44. Aronson MD, Phillips CF, Gump DW, et al. Vidarabine therapy
for severe herpesvirus infections. An unusual syndrome of
chronic varicella and transient immunologic deficiency. JAMA
1976; 235: 1339-42
45. Boston Interhospital Virus Study Group and the NIAID Spon-
sored Cooperative Antiviral Clinical Study. Failure of high
dose 5-iodo-2’-deoxyuridine in the therapy of herpes simplex
virus encephalitis. Evidence of unacceptable toxicity. N Engl
J Med 1975; 292: 599-603
46. Whitley RJ, Soong SJ, Dolin R, et al. Adenosine arabinoside
therapy of biopsy proven herpes simplex encephalitis. N Engl
J Med 1977; 297: 289-94
47. Barthez MA, Billard C, Santini JJ, et al. Relapse of herpes sim-
plex encephalitis. Neuropediatrics 1987; 18: 3-7
48. VanLandingham KE, Marsteller HB, Ross GW, et al. Relapse
of herpes simplex encephalitis after conventional acyclovir
therapy. JAMA 1988; 259: 1051-3
49. Kimura H, Aso K, Kuzushima K, et al. Relapse of herpes sim-
plex encephalitis in children. Pediatrics 1992; 89: 891-4
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
50. Dennett C, Klapper PE, Cleator GM. Polymerase chain reaction
in the investigation of ‘relapse’ following herpes simplex en-
cephalitis. J Med Virol 1996; 48: 129-32
51. Ito Y, Kimura H, Yabuta Y, et al. Exacerbation of herpes simplex
encephalitis after successful treatment with acyclovir. Clin
Infect Dis 2000; 30: 185-7
52. Rozenberg F, Lebon P. Amplification and characterization of
herpesvirus DNA in cerebrospinal fluid from patients with
acute encephalitis. J Clin Microbiol 1991; 29: 2412-7
53. Tebas P, Nease RF, Storch GA. Use of the polymerase chain
reaction in the diagnosis of herpes simplex encephalitis: a
decision analysis model. Am J Med 1998; 105: 287-95
54. Domingues RB, Lakeman FD, Mayo MS, et al. Application of
competitive PCR to cerebrospinal fluid samples from patients
with herpes simplex encephalitis. J Clin Microbiol 1998; 36:
2229-34
55. Bergstrom T, Vahlne A, Alestig K, et al. Primary and recurrent
herpes simplex virus type 2-induced meningitis. J Infect Dis
1990; 162: 322-30
56. Mollaret P. La Méningite endothélio-leucocytaire multirécur-
rent benigne: syndrome nouveau or maladie nouvelle? Rev
Neurol (Paris); 1944; 76: 57-76
57. Tedder DG, Ashley R, Tyler KL, et al. Herpes simplex virus
infection as a cause of benign recurrent lymphocytic menin-
gitis. Ann Intern Med 1994; 121: 334-8
58. Schlesinger Y, Tebas P, Gaudreault-Keener M, et al. Herpes
simplex virus type 2 meningitis in the absence of genital le-
sions: improved recognition with use of the polymerase chain
reaction. Clin Infect Dis 1995; 20: 842-8
59. Read SJ, Kurtz JB. Laboratory diagnosis of common viral in-
fections of the central nervous system by using a single multi-
plex PCR screening assay. J Clin Microbiol 1999; 37: 1352-5
60. Bergstrom T, Alestig K. Treatment of primary and recurrent
herpes simplex virus type 2 induced meningitis with acyclo-
vir. Scand J Infect Dis 1990; 22: 239-40
61. Haanpaa M, Dastidar P, Weinberg A, et al. CSF and MRI find-
ings in patients with acute herpes zoster. Neurology 1998; 51:
1405-11
62. Straus SE, Takiff HE, Seidlin M, et al. Suppression of frequently
recurring genital herpes. A placebo-controlled double-blind
trial of oral acyclovir. N Engl J Med 1984; 310: 1545-50
63. Douglas JM, Critchlow C, Benedetti J, et al. A double-blind
study of oral acyclovir for suppression of recurrences of gen-
ital herpes simplex virus infection. N Engl J Med 1984; 310:
1551-6
64. Reitano M, Tyring S, Lang W, et al. Valaciclovir for the sup-
pression of recurrent genital herpes simplex virus infection: a
large-scale dose range-finding study. International Valaciclo-
vir HSV Study Group. J Infect Dis 1998; 178: 603-10
65. Diaz-Mitoma F, Sibbald RG, Shafran SD, et al. Oral famciclovir
for the suppression of recurrent genital herpes: a randomized
controlled trial. Collaborative Famciclovir Genital Herpes Re-
search Group. JAMA 1998; 280: 887-92
66. Chretien F, Belec L, Hilton DA, et al. Herpes simplex virus type
1 encephalitis in acquired immunodeficiency syndrome. Neu-
ropathol Appl Neurobiol 1996; 22: 394-404
67. Vago L, Sala E, Nebuloni M, et al. Coinfection of the central
nervous system (CNS) by cytomegalovirus and herpes sim-
plex virus type 1 or 2 in AIDS patients: autopsy study on 82
cases by immunocytochemistry and polymerase chain reac-
tion. Acta Neuropathol (Berl) 1996; 92: 404-8
68. Schiff D, Rosenblum MK. Herpes simplex encephalitis (HSE)
and the immunocompromised: a clinical and autopsy study of
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
HSE in the settings of cancer and human immunodeficiency
virus-type 1 infection. Hum Pathol 1998; 29: 215-22
69. Cinque P, Vago L, Marenzi R, et al. Herpes simplex viruses
infections of the nervous system in human immunodeficiency
virus-infected patients: clinical management by polymerase
chain reaction analysis of cerebrospinal fluid. Clin Infect Dis
1998; 27: 303-9
70. Gateley A, Gander RM, Johnson PC, et al. Herpes simplex virus
type 2 meningoencephalitis resistant to acyclovir in a patient
with AIDS. J Infect Dis 1990; 161: 711-5
71. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al.
Neurologic complications of the reactivation of varicella-zos-
ter virus. N Engl J Med 2000; 342: 635-45
72. Amlie-Lefond C, Kleinschmidt-DeMasters BK, Mahalingam
R, et al. The vasculopathy of varicella-zoster virus encepha-
litis. Ann Neurol 1995; 37: 784-90
73. Echevarria JM, Casas I, Martinez-Martin P. Infections of the
nervous system caused by varicella-zoster virus: a review.
Intervirology 1997; 40: 72-84
74. Echevarria JM, Casas I, Tenorio A, et al. Detection of varicella-
zoster virus-specific DNA sequences in cerebrospinal fluid of
patients with acute aseptic meningitis and no cutaneous le-
sions. J Med Virol 1994; 43: 331-5
75. Echevarria JM, Martinez-Martin P, Tellez A, et al. Aseptic men-
ingitis due to varicella-zoster virus: serum antibody levels and
local synthesis of specific IgG, IgM, and IgA. J Infect Dis
1987; 155: 959-67
76. Johns DR, Gress DR. Rapid response to acyclovir in herpes
zoster-associated encephalitis. Am J Med 1987; 82: 560-2
77. Peterslund NA. Herpes zoster associated encephalitis: clinical
findings and acyclovir treatment. Scand J Infect Dis 1988; 20:
583-92
78. Gray F, Belec L, Lescs MC, et al. Varicella-zoster virus infec-
tion of the central nervous system in the acquired immune
deficiency syndrome. Brain 1994; 117: 987-99
79. Cinque P, Bossolasco S, Vago L, et al. Varicella-zoster virus
(VZV) DNA in cerebrospinal fluid of patients infected with
human immunodeficiency virus: VZV disease of the central
nervous system or subclinical reactivation of VZV infection?
Clin Infect Dis 1997; 25: 634-9
80. Peterson LR, Ferguson RM. Fatal central nervous system infec-
tion with varicella-zoster virus in renal transplant recipients.
Transplantation 1984; 37: 366-8
81. Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996; 9:
361-81
82. Burke DG, Kalayjian RC, Vann VR, et al. Polymerase chain
reaction detection and clinical significance of varicella-zoster
virus in cerebrospinal fluid from human immunodeficiency
virus-infected patients. J Infect Dis 1997; 176: 1080-4
83. Iten A, Chatelard P, Vuadens P, et al. Impact of cerebrospinal
fluid PCR on the management of HIV-infected patients with
varicella-zoster virus infection of the central nervous system.
J Neurovirol 1999; 5: 172-80
84. Poscher ME. Successful treatment of varicella zoster virus me-
ningoencephalitis in patients with AIDS: report of four cases
and review. AIDS 1994; 8: 1115-7
85. Lionnet F, Pulik M, Genet P, et al. Myelitis due to varicella-zos-
ter virus in two patients with AIDS: successful treatment with
acyclovir. Clin Infect Dis 1996; 22: 138-40
86. de Silva SM, Mark AS, Gilden DH, et al. Zoster myelitis: im-
provement with antiviral therapy in two cases. Neurology
1996; 47: 929-31
87. Snoeck R, Gerard M, Sadzot-Delvaux C, et al. Meningoradi-
culoneuritis due to acyclovir-resistant varicella-zoster virus
 Adis International Limited. All rights reserved.
111
in an acquired immunodeficiency syndrome patient. J Med
Virol 1994; 42: 338-47
88. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valaciclovir
compared with aciclovir for improved therapy for herpes zos-
ter in immunocompetent adults. Antimicrob Agents Chemo-
ther 1995; 39: 1546-53
89. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the
treatment of acute herpes zoster: effects on acute disease and
postherpetic neuralgia. A randomized, double-blind, placebo-
controlled trial. Collaborative Famciclovir Herpes Zoster Study
Group. Ann Intern Med 1995; 123: 89-96
90. Bodsworth NJ, Boag F, Burdge D, et al. Evaluation of sorivudine
(BV-araU) versus acyclovir in the treatment of acute localized
herpes zoster in human immunodeficiency virus-infected ad-
ults. The Multinational Sorivudine Study Group. J Infect Dis
1997; 176: 103-11
91. Gnann Jr JW, Crumpacker CS, Lalezari JP, e al. Sorivudine
versus acyclovir for treatment of dermatomal herpes zoster in
human immunodeficiency virus-infected patients: results from
a randomized, controlled clinical trial. Collaborative Antivi-
ral Study Group/AIDS Clinical Trials Group, Herpes Zoster
Study Group. Antimicrob Agents Chemother 1998; 42: 1139-45
92. Okuda H, Ogura K, Kato A, et al. A possible mechanism of
eighteen patient deaths caused by interactions of sorivudine,
a new antiviral drug, with oral 5-fluorouracil prodrugs. J
Pharmacol Exp Ther 1998; 287: 791-9
93. Bale Jr JF. Human cytomegalovirus infection and disorders of
the nervous system. Arch Neurol 1984; 41: 310-20
94. Studahl M, Ricksten A, Sandberg T, et al. Cytomegalovirus
infection of the CNS in non-compromised patients. Acta Neu-
rol Scand 1994; 89: 451-7
95. Arribas JR, Storch GA, Clifford DB, et al. Cytomegalovirus
encephalitis. Ann Intern Med 1996; 125: 577-87
96. Prosch S, Schielke E, Reip A, et al. Cytomegalovirus (HCMV)
encephalitis in an immunocompetent young person and diag-
nostic reliability of HCMV DNA PCR using cerebrospinal
fluid of nonimmunosuppressed patients. Clin Microbiol 1998;
36: 3636-40
97. Pantoni L, Inzitari D, Colao MG, et al. Cytomegalovirus en-
cephalitis in a non-immunocompromised patient: CSF diag-
nosis by in situ hybridization cells. Acta Neurol Scand 1991;
84: 56-8
98. McCutchan JA. Cytomegalovirus infections of the nervous sys-
tem in patients with AIDS. Clin Infect Dis 1995; 20: 747-54
99. Anders HJ, Goebel FD. Cytomegalovirus polyradiculopathy in
patients with AIDS. Clin Infect Dis 1998; 27: 345-52
100. Cinque P, Vago L, Brytting M, et al. Cytomegalovirus infection
of the central nervous system in patients with AIDS: diagnosis
by DNA amplification from the cerebrospinal fluid. J Infect
Dis 1992; 166: 1408-11
101. Wolf DG, Spector SA. Diagnosis of human cytomegalovirus
central nervous system disease in AIDS patients by DNA am-
plification from cerebrospinal fluid. J Infect Dis 1992; 166:
1412-5
102. Gozlan J, Salord JM, Roullet E, et al. Rapid detection of cyto-
megalovirus DNA in cerebrospinal fluid of AIDS patients
with neurologic disorders. J Infect Dis 1992; 166: 1416-21
103. Fox DJ, Brink NS, Zuckermann MA, et al. Detection of herpes-
virus DNA by nested PCR in CSF of HIV-infected persons
with neurological disease: a prospective evaluation. J Infect
Dis 1995; 172: 1087-90
104. Cinque P, Baldanti F, Vago L, et al. Ganciclovir therapy for
cytomegalovirus (CMV) infection of the central nervous sys-
CNS Drugs 2000 Aug; 14 (2)
112
tem in AIDS patients: monitoring by CMV DNA detection in
cerebrospinal fluid. J Infect Dis 1995; 171: 1603-6
105. Arribas JR, Clifford DB, Fichtenbaum CJ, et al. Level of cyto-
megalovirus (CMV) DNA in cerebrospinal fluid of subjects
with AIDS and CMV infection of the central nervous system.
J Infect Dis 1995; 172: 527-31
106. Bamborschke S, Wullen T, Huber M, et al. Early diagnosis and
successful treatment of acute cytomegalovirus encephalitis in
a renal transplant recipient. J Neurol 1992; 239: 205-8
107. Berman SM, Kim RC. The development of cytomegalovirus
encephalitis in AIDS patients receiving ganciclovir. Am J Med
1994; 96 (5): 415-9
108. Sadler M, Morris-Jones S, Nelson M, et al. Successful treatment
of cytomegalovirus encephalitis in an AIDS patient using ci-
dofovir. AIDS 1997; 11: 1293-4
109. Blick G, Garton T, Hopkins U, et al. Successful use of cidofovir
in treating AIDS-related cytomegalovirus retinitis, encepha-
litis, and esophagitis. J Acquir Immune Defic Syndr Hum
Retrovirol 1997; 15: 84-5
110. Anduze-Faris BM, Fillet AM, Gozlan J, et al. Induction and
maintenance therapy of cytomegalovirus central nervous sys-
tem infection in HIV-infected patients. AIDS 2000; 14: 517-24
111. Cohen BA. Prognosis and response to therapy of cytomegalo-
virus encephalitis and meningomyelitis in AIDS. Neurology
1996; 46: 444-50
112. Smith IL, Shinkai M, Freeman WR, et al. Polyradiculopathy
associated with ganciclovir-resistant cytomegalovirus in an
AIDS patient: phenotypic and genotypic characterisation of
sequential virus isolates. J Infect Dis 1996; 173: 1481-4
113. Wolf DG, Lee DJ, Spector SA. Detection of human cytomega-
lovirus mutations associated with ganciclovir resistance in
cerebrospinal fluid of AIDS patients with central nervous sys-
tem disease. Antimicrob Agents Chemother 1995; 39: 2552-4
114. Cinque P, Cleator GM, Weber T, et al. Diagnosis and clinical
management of neurological disorders caused by cytomega-
lovirus in AIDS patients. European Union Concerted Action
on Virus Meningitis and Encephalitis. J Neurovirol 1998; 4:
120-32
115. Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for
the treatment of cytomegalovirus diseases in patients with
AIDS in the era of potent antiretroviral therapy: recommen-
dations of an international panel. International AIDS Society
– USA. Arch Intern Med 1998; 158: 957-69
116. Manischewitz JF, Quinnan GV, Lane HC, et al. Synergistic ef-
fect of ganciclovir and foscarnet on cytomegalovirus replica-
tion in vitro. Antimicrob Agents Chemother 1990; 34: 373-5
117. Cinque P, Pisa E, Racca S, et al. Efficacy of different antiviral
treatments in cytomegalovirus neurological compliocations:
evaluation by quantitative polymerase chain reaction on cere-
brospinal fluid [abstract OP3.3]. 3rd International Congress
on Drug Therapy in HIV Infection: 1996 Nov 3-7; Birming-
ham, UK
118. Van Droogenbroeck J, De Ceuninck M, Snoeck HW, et al. Suc-
cessful treatment of cytomegalovirus encephalitis in a patient
with Hodgkin’s disease in remission. Ann Hematol 1998; 76:
179-81
119. Gautier-Smith PC. Neurological complications of glandular fe-
ver (infectious mononucleosis). Brain 1965; 88: 323-34
120. Grose C, Henle W, Henle G, et al. Primary Epstein-Barr-virus
infections in acute neurologic diseases. N Engl J Med 1975;
292: 392-5
121. Domachowske JB, Cunningham CK, Cummings DL, et al. Acute
manifestations and neurologic sequelae of Epstein-Barr virus
encephalitis in children. Pediatr Infect Dis J 1996; 15: 871-5
 Adis International Limited. All rights reserved.
Cinque & Lazzarin
122. Schellinger PD, Sommer C, Leithauser F, et al. Epstein-Barr
virus meningoencephalitis with a lymphoma-like response in
an immunocompetent host. Ann Neurol 1999; 45: 659-62
123. Imai S, Usui N, Sugiura M, et al. Epstein-Barr virus genomic
sequences and specific antibodies in cerebrospinal fluid in
children with neurologic complications of acute and reacti-
vated EBV infections. J Med Virol 1993; 40: 278-84
124. Landgren M, Kyllerman M, Bergstrom T, et al. Diagnosis of
Epstein-Barr virus-induced central nervous system infections
by DNA amplification from cerebrospinal fluid. Ann Neurol
1994; 35: 631-5
125. Kaji M, Shoji H. Detection of Epstein-Barr virus genome in
peripheral leucocytes and CSF by the polymerase chain reac-
tion in two patients with Epstein-Barr virus related to aseptic
meningitis [letter]. J Neurol Neurosurg Psychiatry 1995; 59
(1): 99
126. Tselis A, Duman R, Storch GA, et al. Epstein-Barr virus enceph-
alomyelitis diagnosed by polymerase chain reaction: detec-
tion of the genome in the CSF. Neurology 1997; 48: 1351-5
127. Studahl M, Hagberg L, Rekabdar E, et al. Hematogenously spread
herpesviruses are detected as frequently as neuronally spread
herpesviruses in cerebrospinal fluid by polymerase chain re-
action assay. Clin Infect Dis 1999; 29: 216-8
128. Frenkel EP. Shiver CB, Berg P, et al. Meningoencephalitis in
infectious mononucleosis: report of a case treated with corti-
sone. JAMA 1956; 162: 885-6
129. Mizutani T, Murashima A, Shiozawa R, et al. Unusual neuro-
logic manifestations associated with Epstein-Barr virus infec-
tion. Intern Med 1993; 32: 36-8
130. Paskavitz JF, Anderson CA, Filley CM, et al. Acute arcuate fiber
demyelinating encephalopathy following Epstein-Barr virus
infection. Ann Neurol 1995; 38: 127-31
131. Corssmit EP, Leverstein-van Hall MA, Portegies P, et al. Severe
neurological complications in association with Epstein-Barr
virus infection. J Neurovirol 1997; 3 (6): 460-4
132. Andersson J, Britton S, Ernberg I, et al. Effect of acyclovir on
infectious mononucleosis: a double-blind, placebo-controlled
study. J Infect Dis 1986; 153: 283-90
133. Tynell E, Aurelius E, Brandell A, et al. Acyclovir and pred-
nisolone treatment of acute infectious mononucleosis: a mul-
ticenter, double-blind, placebo-controlled study. J Infect Dis
1996; 174: 324-31
134. Waldo RT. Neurologic complications of infectious mononucle-
osis after steroid therapy. South Med J 1981; 74: 1159-60
135. Dellemijn PL, Brandenburg A, Niesters HG, et al. Successful
treatment with ganciclovir of presumed Epstein-Barr meningo-
encephalitis following bone marrow transplant. Bone Marrow
Transplant 1995; 16: 311-2
136. MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr
virus in AIDS-related primary central nervous system lym-
phoma. Lancet 1991; 338: 969-73
137. Cinque P, Brytting M, Vago L, et al. Epstein-Barr virus DNA in
cerebrospinal fluid of patients with AIDS-related primary lym-
phoma of the central nervous system. Lancet 1993; 342: 398-401
138. Davis K, Hinrichs S, Fidler J, et al. Post-transplant Epstein-Barr
virus-associated meningoencephalitis and lymphoid intersti-
tial pneumonitis. Bone Marrow Transplant 1999; 24: 443-4
139. Suga S, Yoshikawa T, Asano Y, et al. Clinical and virological
analyses of 21 infants with exanthem subitum (roseola in-
fantum) and central nervous system complications. Ann Neu-
rol 1993; 33: 597-603
140. Kondo K, Nagafiji H, Hata A, et al. Association of human her-
pesvirus 6 infection of the central nervous system with recur-
rence of febrile convulsions. J Infect Dis 1993; 167: 1197-200
CNS Drugs 2000 Aug; 14 (2)
Herpesvirus Infections of the CNS
141. McCullers JA, Lakeman FD, Whitley RJ. Human herpesvirus
6 is associated with focal encephalitis. Clin Infect Dis 1995;
21: 571-6
142. Kimberlin DW, Whitley RJ. Human herpesvirus-6: neurologi-
cal implications of a newly described herpesvirus. J Neu-
rovirol 1998; 4: 474-85
143. Drobyski W, Knox KK, Majewski D, et al. Brief report: fatal
encephalitis due to variant B human herpesvirus-6 infection
in a bone marrow-transplant recipient. N Engl J Med 1994;
330: 356-60
144. Wang F-Z, Linde A, Hägglund H, et al. Human herpesvirus-6
DNA in cerebrospinal fluid from allogeneic bone marrow trans-
plant patients: does it have a clinical significance? Clin Infect
Dis 1999; 28: 562-8
145. Mookerjee BP, Vogelsang G. Human herpesvirus-6 encephalitis
after bone-marrow transplantation: successful treatment with
ganciclovir. Bone Marrow Transplant 1997; 20: 905-6
146. Bethge W, Beck R, Jahn G, et al. Successful treatment of human
herpesvirus-6 encephalitis after bone marrow transplantation.
Bone Marrow Transplant 1999; 24: 1245-8
147. Bossolasco S, Marenzi R, Dahl H, et al. Human herpesvirus 6
in cerebrospinal fluid of patients infected with HIV: frequ-
ency and clinical significance. J Neurol Neurosurg Psychiatry
1999’ 67 (6): 789-92
 Adis International Limited. All rights reserved.
113
148. Knox KK, Harrington DP, Carrigan DR. Fulminant human her-
pesvirus six encephalitis in a human immunodeficiency vi-
rus-infected infant. J Med Virol 1995; 45: 88-92
149. Braun DK, Dominguez G, Pellet PE. Human herpesvirus 6. Clin
Microbiol Rev 1997; 10: 521-67
150. Hall CB, Caserta MT, Schnabel KC, et al. Persistence of human
herpesvirus 6 according to site and variant: possible greater
neurotropism of variant A. Clin Infect Dis 1998; 26: 132-7
151. Torigoe S, Koide W, Yamada M, et al. Human herpesvirus-7
infection associated with central nervous system manifesta-
tions. J Pediatr 1996; 129 (2): 301-5
152. Caserta MT, Hall CB, Schnabel K, et al. Neuroinvasion and
persistence of human herpesvirus 6 in children. J Infect Dis
1994; 170: 1586-9
153. Yoshida M, Yamada M, Tsukazaki T, et al. Comparison of anti-
viral compounds against human herpesvirus 6 and 7. Antiviral
Res 1998; 40: 73-84
Correspondence and offprints: Dr Paola Cinque, Division of
Infectious Diseases, San Raffaele Hospital, Via Stamira
d’Ancona, 20, 20127 Milan, Italy.
E-mail: cinque.paola@hsr.it
CNS Drugs 2000 Aug; 14 (2)