The Neurology of Hiv Infection: H Manji, R Miller
The Neurology of Hiv Infection: H Manji, R Miller
The Neurology of Hiv Infection: H Manji, R Miller
H Manji, R Miller
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J Neurol Neurosurg Psychiatry 2004; 75(Suppl I):i29i35. doi: 10.1136/jnnp.2003.034348
ince the onset of the AIDS pandemic in 1981, infection with the human immunodeficiency
virus (HIV) has spread exponentially throughout the world with currently an estimated 40
million adults and children affected. Worldwide there are approximately 16 000 new
infections per day. Every day 8000 HIV infected patients die. In the UK, there are currently about
50 000 individuals living with HIV/AIDS.
Since the introduction of highly active anti-retroviral therapy (HAART), in communities where
this is available, HIV/AIDS has become a chronic disorder with dramatic reductions in mortality
and morbidity both from the effects of HIV itself as well as from opportunistic infections and
tumours.
In the UK, the clinician will encounter two broad groups of patients. The first group comprises
individuals who have been infected with HIV for a number of years and are receiving HAART.
This group is composed largely of homosexual men and those who acquired their infection in the
UK. The second group consists of patients who present with opportunistic infections and tumours
and who have late stage HIV infection. This is a situation that was previously encountered in the
late 1980s and early 1990s. This cohort largely consists of men and women infected by
heterosexual intercourse outside Europe.
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c Due to HIV
Distal sensory peripheral neuropathy (DSPN)
HIV dementia (HAD)
Vacuolar myelopathy (usually in association with HAD)
HIV polymyositis
c Opportunistic infections
Toxoplasmosis
Cryptococcal meningitis
Tuberculosismeningitis, abscesses, tuberculoma
Cytomegalovirus (CMV) encephalitis, retinitis, lumbar
polyradiculopathy, vasculitic peripheral neuropathy
Progressive multifocal leucoencephalopathy (PML)
c Tumours
Primary CNS lymphoma
Metastatic systemic lymphoma
c Drug related complications
Peripheral neuropathy caused by ddI, ddC and d4T; isoniazid
Myopathy (zidovudine)
Table 2
meningitis or CSF VDRL (venereal disease research laboratory) in suspected neurosyphilis (a negative test does not
exclude the diagnosis, whereas a non-reactive CSF-FTA (fluorescent treponemal antibody) does exclude active infection).
Before HAART, the CD4 count was a useful guide in
attempting to determine the specific aetiologies of the
opportunistic infections and tumours. For example, toxoplasmosis and cryptococcal meningitis occur with CD4 counts
below 200 cells/mm3; CMV retinitis, encephalitis, and polyradiculopathy occur with CD4 counts , 50 cells/mm3.
Following institution of HAART, there is usually a rise in
peripheral blood CD4 counts, although these cells may not all
be fully functional (since some of the antigen specific clones
are lost). HAART has led to a number of complications
hitherto not encountered in HIV medicine. These include
immune reconstitution inflammatory syndrome (IRIS) which
has been defined as a paradoxical deterioration in clinical
status attributable to recovery of the immune system.
Clinically, within a few weeks of starting treatment there
may be an exacerbation or an unusual manifestation of a
specific infection. Neurological reconstitution syndromes
described include progressive multifocal leucoencephalopathy (PML), cryptococcal meningitis, and cytomegalovirus
(CMV) syndromes such as encephalitis and retinitis.
More recently, a rare, severe leucoencephalopathy has been
described in patients who failed treatment with HAART.
Infection
Toxoplasmosis
Acute phase (for 6 weeks)
First line treatment:
Pyrimethamine loading dose (100 mg orally for
3 days, then 75 mg/day)
+
Sulfadiazine 68 g/day orally/iv
+
Folinic acid 15 mg/day
Second line treatment:
Clindamycin 600900 mg/day by mouth/iv instead
of sulfadiazine
Maintenance treatment
Pyrimethamine 2550 mg/day
+
Sulfadiazine 24 g/day
+
Folinic acid 10 mg/day
Clindamycin 600 mg/day instead of sulfadiazine
Cryptococcal meningitis
Acute phase treatment for 46 weeks or until CSF
culture negative
Amphotericin B 0.71.0 mg/kg/day (via central line)
Side effects
Marrow suppression
Rash, diarrhoea
Rash, hepatitis
Stopping maintenance may be considered if after HAART is started the CD4 count remains above 200/mm3 for
over four months.
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Figure 1
overall assessment using data from serological and radiological investigations may help in differentiating between
the possible aetiologies. The country of origin may also be
helpful, particularly with respect to the likelihood of
tuberculosis and to a lesser extent toxoplasmosis. However,
even in areas where tuberculosis is endemic, the most
common cause of a mass lesion(s) is toxoplasmosis. See
table 2 for the drug treatment regimens for toxoplasmosis.
Toxoplasma serology
In HIV, toxoplasmosis is almost always a reactivation and
serology is positive in 85% of cases. Seronegative cases occur
as a result of loss of antibody with increasing immunosuppression or rarely a primary infection. The prevalence of
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CRYPTOCOCCAL MENINGITIS
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PROGRESSIVE MULTIFOCAL
LEUCOENCEPHALOPATHY
PML is caused by the reactivation of the Jamestown Canyon
virus (JCV), a common polyoma virus, which infects 75% of
the general population. It is usually a mild childhood
respiratory tract infection. Cell mediated immunity is the
chief predisposing factor for the development of PML, and
before the AIDS epidemic was generally encountered in
patients with lymphoproliferative disorders or those treated
with immunosuppressive drugsfor example post-transplant surgery and sarcoidosis.
Abbreviations
CMV: cytomegalovirus
CNS: central nervous system
CT: computed tomography
EBV: Epstein-Barr virus
DSPN: distal sensory peripheral neuropathy
HAART: highly active anti-retroviral therapy
HAD: HIV dementia
HIV: human immunodeficiency virus
JCV: Jamestown Canyon virus
MRI: magnetic resonance imaging
NCT: nerve conduction tests
NRTI: nucleoside reverse transcriptase inhibitor
PCNSL: primary CNS lymphoma
PCR: polymerase chain reaction
PML: progressive multifocal leucoencephalopathy
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Table 4
Drug
Nucleoside reverse transcriptase inhibitors (NRTIs)
Class associated
Drug specific
Zidovudine
Stavudine (d4T)
Zalcitabine (ddC)
Didanosine (ddI)
Lamivudine (3TC)
Non-NRTIs
Efavirenz
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Nevirapine
Protease inhibitors
Class associated
Drug specific
Nefinavir
Indinivir
Ritonivir
Amprenivir
Lopinivir
HIV DEMENTIA
Prior to HAART, HIV developed in 20% of patients with AIDS.
The risk factors identified included low CD4 count, high
plasma viral load, older age group, intravenous drug use,
female sex, and constitutional symptoms such as anaemia.
Since HAART, the incidence of HAD has been reduced by 50%
although the prevalence has increased as a result of improved
survival.
The clinical features of HIV dementia (HAD) in the early
stages may be mild with symptoms of poor concentration,
mental slowing, and apathy which may mimic depression.
Later on, as the syndrome progresses, more specific cognitive
changes develop with memory loss and personality change
associated with motor and sphincter difficulties as a result of
an associated vacuolar myelopathy. Examination may show
impaired saccadic eye movements, generalised hyperreflexia,
and cerebellar and frontal release signs.
Investigations are indicated to exclude other causesMRI
typically shows evidence of atrophy and diffuse white matter
signal changes. The CSF shows non-specific cytochemical
abnormalities but must be examined for conditions such as
neurosyphilis, CMV, and PML. The CSF viral load correlates
with severity of the dementia. However, this test is not
sensitive enough for diagnostic purposes.
Neuropsychological assessment typically shows abnormalities in the following cognitive domains: psychomotor speed,
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Toxicity
Lactic acidosis, hepatic steatosis, lipodystrophy
Myelosuppression, myopathy
Peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy, pancreatitis
? Neuropathy
Dysphoria, mood changes, vivid dreams,
hypercholesterolaemia
Hepatitis, Stevens-Johnson syndrome
Lipodystrophy, hyperlipidaemia, diabetes
Diarrhoea
Nephrolithiasis
Perioral dysaesthesia, flushing, diarrhoea, hyperuricaemia
Diarrhoea
Diarrhoea
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Authors affiliations
H Manji*, National Hospital for Neurology and Neurosurgery, Queen
Square, London, UK
R Miller, Royal Free and University College School of Medicine, London,
UK
*Also at the Ipswich Hospital, Ipswich, UK
REFERENCES
1 Brew B. HIV neurology. Contemporary Neurology Series. Oxford: Oxford
University Press, 2001.
c An excellent reference book for all those involved in the management
of HIV/AIDS patients.
4 Keswani S, Pardo CA, Cherry CL, et al. HIV associated sensory neuropathies.
AIDS 2002;16:2105117.
c An up-to-date review of the most common problem in HIV neurology
clinics.
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