Transcript HIV Neuropathy - braininfectionsuk.org

HIV
NEUROPATHY
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
HIV Neuropathy and
Myelopathy
Sam Nightingale
Sam Nightingale is a neurology registrar and MRC clinical research
fellow. He is currently working with the Liverpool HIV Pharmacology
Group and the Liverpool Brain Infections Group on studies of the
CNS penetration of antiretroviral drugs for HIV.
This session provides an overview of the
peripheral nervous system effects of HIV
infection and antiretroviral therapy.
Edited by Prof Tom Solomon, Dr Agam Jung and
Dr Sam Nightingale
Learning Objectives
HIV
NEUROPATHY
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
By the end of this session you will be able to:
•State the causes of peripheral nerve damage in HIV
•List the medications used in HIV that commonly cause
peripheral nerve damage
•Summarise the clinical features of nerve damage
associated with the following: antiretroviral treatment,
chronic HIV infection and HIV seroconversion
•Describe an appropriate strategy for diagnosing and
investigating an HIV positive individual presenting with
painful numb feet
•List the treatment and symptomatic management options
for HIV-associated peripheral sensory neuropathy
Introduction
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Although there has been a decline in opportunistic infections
related to HIV, the prevalence of peripheral neuropathy has
increased due to improved longevity and the use of
neurotoxic medications.
Symptomatic peripheral neuropathy occurs in 30-50% of
those in the late stages of HIV, however pathological
changes in the nerves can be demonstrated in nearly all.
Although most common in advanced disease, neuropathy
can occur at any stage. It may be related to:
•The HIV virus itself
•Neurotoxic medications
•Nutritional deficiencies
•Alcohol excess
•Autoimmune demyelination
•Opportunistic infections such as CMV, hepatitis C or
syphilis
Distal Sensory Periperal
Neuropathy/DSPN
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
The most common peripheral nerve disorder encountered due to HIV
is a distal sensory peripheral neuropathy (DSPN), sometimes called
distal symmetrical sensory polyneuropathy (DSSP) or distal painful
sensorimotor neuropathy (DPSN).
DSPN usually becomes symptomatic in the later stages of infection
when the CD4 count is below 200 cells/ml. However, it is not an AIDS
defining illness in itself.
The risk of developing DSPN
is higher if there are other
neuropathic risk factors, such
as diabetes, excess alcohol
intake,
nutritional/vitamin
deficiencies
and
genetic
neuropathies.
Pathophysiology
HIV
NEUROPATHY
Neurones are damaged by direct HIV infection, as well as by
locally infiltrating activated macrophages that secrete
neurotoxic cytokines or other toxic metabolites.
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
This process causes axonal degeneration with some
demyelination. Histologically there is prominent perivascular
infiltration by T-cells and macrophages and mild loss of
dorsal root ganglion neurons, some of which are directly
infected with HIV as demonstrated by in situ PCR.
Symptoms and Signs
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
The typical presentation is painful numb feet in an individual in the late
stages of HIV infection or AIDS. Significant weakness is unusual and
the upper limbs are rarely involved. Symptoms progress slowly over
the course of months to years. Although pain is not universal, 30-50%
complain of burning or stabbing pain. This can be quite disabling and
sometimes even makes walking difficult.
Small sympathetic and parasympathetic nerve fibres can also be
affected, causing dizziness due to postural hypotension, impaired
bladder and bowel control and erectile dysfunction.
The neurological signs are characteristic of
a small fibre neuropathy. Decreased
vibration sense at the toe or ankle,
decreased
sensitivity
to
pain
and
temperature in a stocking distribution, and
depressed or absent ankle reflexes.
Proprioception is usually normal. Weakness
and wasting is usually mild and atrophy of
intrinsic foot muscles is rarely a prominent
feature. Upper limb involvement usually only
occurs when the lower limb features are
advanced.
Diagnosis
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Nerve conduction studies can show mild axonal damage, but may
fail to demonstrate any abnormality. Thermal thresholds, which are
raised with small fibre damage, are usually abnormal.
Blood glucose, vitamin B12 and folate should be checked to exclude
common reversible causes of neuropathy. However, if clinical
features are typical of DSPN, further investigation may not be
necessary.
The presence of upper limb or trunk involvement, significant lower
limb weakness or decreased proprioception should prompt
investigation for other disorders. Nerve biopsy may be required to
exclude vasculitis, demyelination or lymphomatous infiltration.
Abnormalities rarely effect the
upper limbs unless disease is
very advanced
Medication related toxic
neuropathy I
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
A dose dependent peripheral neuropathy occurs in about 10-30 % of
patients treated with didanosine (ddI), zalcitabine (ddC) or stavudine
(d4T). These nucleoside reverse transcriptase inhibitors (NRTIs) are
known collectively as dideoxynucleoside agents or 'd-drugs'.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease
inhibitors (PIs) and other NRTIs are not generally associated with a
peripheral neuropathy.
Drug related toxic neuropathy is indistinguishable from HIV induced
DSPN, both on clinical and neurophysiological grounds. The two
conditions frequently co-exist. Presentation is the same as DSPN with
a distal, symmetrical, predominantly lower limb, predominantly
sensory, often painful, axonal neuropathy
Medication related toxic
neuropathy II
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
After stopping the offending medication, neuropathic symptoms
may worsen for 4–8 weeks (sometimes referred to as 'coasting')
after which symptoms improve, although recovery can be slow
and residual nerve damage is not uncommon. In some cases
incomplete resolution may be due to coincident DSPN.
The underlying mechanism may be mitochondrial toxicity from
inhibition of DNA polymerase. The same mechanism could also
account for the other side effects with this class of 'd drugs' e.g.
pancreatitis, fulminant hepatic failure and lactic acidosis. Serum
lactate is elevated in over 90% of patients with 'd-drug' related
neuropathy.
Electron microscopy
showing mitochondria
in pancreatic tissue.
Other Drug Treatments
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
In addition to antiretrovirals, several other drugs used in the
treatment of HIV can cause neuropathy. These include:
• Dapsone -used in the treatment of pneumocystis jiroveci
pneumonia
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Isoniazid - used in the treatment of TB, can cause B6 deficiency
• Metronidazole – used in the treatment of amoebic dysentery and
microsporidiosis
• Vincristine – used in the treatment of Kaposi's sarcoma and non –
Hodgkin's lymphoma
• Thalidomide – used in the treatment of various cancers, wasting
syndrome and severe mouth ulcers.
Demyelination I
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Although many of the complications of HIV are related to
immunodeficiency, there is also a general state of immune
activation, which can result in autoimmunity, with T-cell activation
and hypergammaglobulinemia.
As such, HIV infection is an important cause of inflammatory
demyelinating neuropathies such as Guillain-Barré syndrome (GBS)
and chronic inflammatory demyelinating polyneuropathy (CIDP).
Demyelination II
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Guillain-Barré Syndrome (GBS)/Acute Inflammatory Demyelinating
Polyneuropathy
HIV infection should be excluded in any patient presenting with GBS as
it can be clinically indistinguishable from GBS in HIV-seronegative
individuals. It usually occurs at primary infection or seroconversion, but
is rarely associated with immune reconstitution.
The typical clinical presentation is an areflexic, symmetrical ascending
weakness with relatively little sensory involvement. Cranial neuropathies
and involvement of respiratory muscles can lead to respiratory or
pharyngeal insufficiency. Autonomic involvement can cause cardiac
arrhythmias and severe fluctuations in arterial blood pressure. These
possible life-threatening complications require close monitoring.
Symptoms progress over a maximum of four weeks, before spontaneous
improvement. If there has been secondary axonal damage, recovery
may be slow. Around 30% have varying degrees of residual disability.
GBS due to HIV is associated with more frequent recurrent acute
episodes and relapses than is seen in sero-negative individuals.
CSF shows raised protein. In contrast to HIV-seronegative individuals,
there is often a mild CSF pleocytosis, up to 50 cells/ml.
Demyelination III
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Chronic, Inflammatory, Demyelinating Polyneuropathy
(CIDP)
Whereas GBS is an acute, self-limiting illness, CIDP is
characterised by chronic progression over months, with
periods of fluctuating weakness and sensory disturbance. As
with GBS, CSF pleocytosis can help identify those with HIV
infection.
CIDP can occur at any stage of HIV infection. The reason for
chronic persistence of the autoimmune demyelinating
process is not known.
Other Neuropathies I
Vasculitic neuropathy
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
A necrotizing vasculitis is a rare cause of neuropathy in HIV. It typically
causes a mononeuritis multiplex, involving multiple individual nerves to
different extents, rather than the length dependent neuropathy described
earlier. The vasculitic process may also involve other organs such as
heart, kidneys and muscle. Cryoglobulinaemia associated with hepatitis
C co-infection can also also cause a vasculitic neuropathy.
Diffuse Infiltrative Lymphocytosis Syndrome (DILS)
An axonal neuropathy can occur in association with the DILS syndrome. This
is a hyperimmune reaction against HIV characterised by a persistent CD8+
lymphocytosis and lymphocytic infiltration of various organs.
The reported prevalence varies between 0.85 – 3%, and appears to be more
common in Africans.
Symptoms can resemble Sjögren's syndrome. Most patients present with
bilateral parotid gland enlargement and features of the Sicca syndrome.
Lymphadenopathy, splenomegaly, pneumonitis and renal dysfunction may
occur.
Therapeutic trials are lacking, although there can be a good response to
antiretroviral and steroid therapy.
Other Neuropathies II
CMV Neuropathy
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
CMV infection can cause an asymmetric axonal polyneuropathy in the
late stages of HIV infection, usually at CD4 counts less than 100cells/ul
and often with involvement of other organs.
CMV encephalitis can also occur. CMV can be detected by PCR in the
plasma and is present in the CSF in 90%. Treatment is with ganciclovir
or foscarnet therapy. Relapse is common unless immune function can
be improved.
The image below shows a gross micrograph of a coronal slice of brain
from a patient with HIV disease who has CMV ventriculitis (ependymitis).
It shows dilated lateral ventricles adjacent to the basal ganglia. The
lining of the ventricles (the ependyma) is reddened and inflamed.
Other Neuropathies III
Neuropathy Due to Other Diseases
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Syphilis should always be excluded by serology and there should be
a low threshold for treatment. Tuberculosis or lymphoma affecting
nerve roots, cauda equina or meninges can cause an acute or
subacute polyradiculopathy with flaccid paraparesis of the lower
limbs, bowel dysfunction and a sensory level.
Other important causes of a neuropathy are alcohol abuse, diabetes
mellitus and malnutrition, particularly in patients with malignancy,
gastrointestinal diseases or wasting syndromes.
The images below show cutaneous secondary syphilis.
Treatment
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Discontinue neurotoxic drugs if possible. HIV should be
treated with a fully suppressive regime and superimposed
infections such as CMV treated appropriately. Intravenous
immunoglobin and plasmapheresis may be required in GBS
and CIDP depending on the severity.
Poor nutrition needs addressing and if in doubt, vitamin
supplements should be given. Alcohol should be avoided and
high blood sugars controlled. Individuals with peripheral
sensory neuropathy should receive advice on foot care to
avoid painless injury to numb toes or feet.
Treatment II
Pain Relief
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Pain can be a big problem in HIV infection. 80% of HIV
infected individuals with pain receive inadequate analgesia
compared with 40% with cancer. This may be due to
stoicism and reluctance to report symptoms or the stigma of
substance abuse.
Neuropathic pain can be managed with anticonvulsants,
antidepressants, analgesics and topical treatments, however
neuropathic pain is notoriously refractory to treatment.
Gabapentin tends to be first line and Lamotrigine has been
shown to be effective in HIV neuropathy. Pregabalin and
Amitriptyline are used because of their effectiveness in
diabetic neuropathy, although a small trial of Amitriptyline in
HIV neuropathy failed to show benefit. Topical analgesics
Capsaicin and Lignocaine patch have demonstrated efficacy.
HIV associated Myelopathy I
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
HIV myelopathy is most common in those with advanced
immunosuppression and often coincides with neurocognitive
symptoms. Before antiretroviral therapy, HIV myelopathy
was seen in up to 20% but is now much less common.
In contrast to HIV encephalopathy, astrocytes and neurons
do not appear to be directly infected and the exact
mechanism of damage is not clear.
Post-mortem histology shows vacuoles with lipid-laden
macrophages in the spinal cord, so HIV myelopathy is often
referred to as 'vacuolar myelopathy'. Although such features
are common at autopsy, much fewer have clinically evident
myelopathy during life.
HIV associated Myelopathy II
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Myelopathy typically presents in the legs with a slowly progressive
symmetrical weakness, stiffness and sensory loss and sphincter
dysfunction. There may be signs of spasticity with increased tone,
hyper-reflexia and extensor plantar responses.
Limbs may be numb or
dysaesthetic, but as the
damage is diffuse in HIV
myelopathy,
a
discrete
sensory level is unusual
and suggests a different
cause.
Imaging with MRI is often
normal, or may show nonspecific features such as
spinal cord atrophy or
diffuse non-enhancing high
signal area
HIV associated Myelopathy III
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
CSF examination is usually normal, or has non-specific
abnormalities, such as a raised white cell count (up to 50 cells/μl).
HIV myelopathy is a diagnosis of exclusion.
Imaging and lumbar puncture are important to rule out other causes
of myelopathy, such as:.
Spinal cord compression
•Sub-acute combined degeneration of the cord due to B12
deficiency
•Infections with cytomegalovirus, varicella-zoster virus, herpes
simplex virus and HTLV-1
There is no specific treatment. Antiretroviral therapy may initially
lead to significant improvement and may slow the usual disabling
progression.
Key Points
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
• Neuropathy in HIV is common and has a number of
different causes.
• Most commonly neuropathy is due to HIV itself, or one of
a number of neurotoxic medications used in HIV. These
causes are clinically indistinguishable and frequently
overlap.
• HIV infection can be associated with a Gullian-Barre
Syndrome, particularly at seroconversion. HIV testing should
be considered in all presenting with GBS.
• Specific treatment should be aimed at the underlying
cause. HIV neuropathy is frequently painful and there are a
number of symptomatic treatments.
Summary
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Having completed this session you will now be able to:
• State the causes of peripheral nerve damage in HIV
• List the medications used in HIV that commonly cause peripheral nerve
damage
• Summarise the clinical features of nerve damage associated with the
following: antiretroviral treatment, chronic HIV infection and HIV
seroconversion
• Describe an appropriate strategy for diagnosing and investigating a HIV
positive individual presenting with painful numb feet
• List the treatment and symptomatic management options for HIVassociated peripheral sensory neuropathy
References and Further Reading
1. Attala N et al. EFNS guidelines on the pharmacological treatment of
neuropathic pain: 2010 revision. European Journal of Neurology 2010;17:
1113–1123.
2. Simpson DM et al. Pregabalin for painful HIV neuropathy: a randomized,
double-blind, placebo-controlled trial. Neurology. 2010;74(5):413-20.
3. Simpson DM et al. HIV neuropathy natural history cohort study:
assessment measures and risk factors. Neurology. 2006;66(11):1679-87.
4. Verma A. Epidemiology and clinical features of HIV-1 associated
neuropathies. J Peripher Nerv Syst. 2001;6(1):8-13.
5. Simpson DM. Selected peripheral neuropathies associated with
humanimmunodeficiency virus infection and antiretroviral therapy. J
Neurovirol. 2002;8 Suppl 2:33-41.
Question 1
HIV
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Learning Objectives
Introduction
DSPN
Pathophysiology
Symptoms and
Signs
Diagnosis
Medication related
toxic neuropathy
Demyelination
Other Neuropathies
Treatment
HIV Myelopathy
Key Points
Summary
Questions
Select the single best answer from the options given. Click on the
answer to see if it is correct and read an explanation.
A 37-year-old lady complains of numb feet. She has a
burninglady
sensation
and they
painful
Shea
Aconstant
37-year-old
complains
of are
numb
feet.to touch.
She has
has beenburning
on ART
for 12 years
andare
currently
Atripla
constant
sensation
and they
painful takes
to touch.
She
(efavirenz/emtricitabine/tenofovir). Despite treatment her CD4
has been on ART for 12 years and currently takes Atripla
is 120 cells/ul. She is overweight and has recently been
(efavirenz/emtricitabine/tenofovir).
Despite treatment her
diagnosed with type 2 diabetes.
CD4 is 120 cells/ul. She is overweight and has recently been
diagnosed
typefrom
2 diabetes.
Select onewith
answer
the list below.
a. Distal
neuropathy
Select
onesensory
answerperipheral
from the list
below. (DSPN)
b. Medication related toxic neuropathy
c.Distal
Demyelination
a.
sensory peripheral neuropathy (DSPN)
d. Nutritional deficiency
b. Medication related toxic neuropathy
e. Other cause of neuropathy
c. Demyelination
d. Nutritional deficiency
e. Other cause of neuropathy