World Journal of AIDS, 2012, 2, 265-269
doi:10.4236/wja.2012.23035 Published Online September 2012 ( 1
Autonomic Neuropathy in HIV: A Case Report and
Review of Potential Symptoms in an Advanced-Stage, HIV
Jessica Robinson-Papp, Kathryn J. Elliott, Maria Pizzirusso, Susan Morgello
Department of Neurology, Mount Sinai School of Medicine, New York, USA.
Received July 19th, 2012; revised August 19th, 2012; accepted August 27th, 2012
A woman with a seventeen-year history of HIV infection on effective antiretroviral therapy presented with signs and
symptoms of distal symmetric polyneuropathy (DSP). She developed significant side effects (dizziness, nausea, edema)
with medications for pain management. Chart review revealed a history of similar intolerance to multiple antiretrovirals,
which was not explained by known cardiac or gastrointestinal disease or psychological factors. Specialized testing re-
vealed the presence of an autonomic neuropathy, which provided an explanation for her medication intolerance. The
patient was educated on the symptoms of autonomic neuropathy and its relationship to DSP and subsequent symptom-
matic medications were initiated at the lowest possible doses. Although symptom management remained challenging,
the patient exhibited lower frustration and greater acceptance of medication trials. Review of 168 advanced stage HIV
infected individuals demonstrated that 81% experienced at least one, and 33% three or more, symptoms potentially at-
tributable to autono mic neuropathy. Potentially autono mic symptoms were significantly associated with the presence of
symptomatic DSP. Autonomic neuropathy is difficult to diagnose without specialized testing, as its symptoms are
non-specific and overlap with a large number of somatic disorders. The high prevalence of autonomic-type symptoms in
chronic HIV, and their association with peripheral neuropathy, may warrant further investigation of the potential for
autonomic dysfunction in individuals with HIV-related symptomatic DSP.
Keywords: HIV; Neuropathy; Autonomic
1. Introduction
HIV-associated distal symmetric polyneuropathy (HIV-
DSP) is a common complication of HIV, and its symp-
toms include pain, paresthesias and numbness, usually
beginning symmetrically in the feet [1,2]. Recent publi-
cations have documented the continued high prevalence
of HIV-DSP and its impact on quality of life. It is esti-
mated that between 30% - 60% of HIV-infected indi-
viduals have signs of HIV-DSP and that neuropathic pain
is associated with unemployment, poorer quality of life
and reduced ability to perform activities of daily living
[1,3]. Dysfunction of small caliber nociceptive nerve
fibers (c-fibers) is thought to underlie the pain of HIV-
DSP, and loss of small fibers has been demonstrated in
skin biopsies [4]. Autonomic nerves are also comprised
of small fibers, and are responsible for control of crucial
homeostatic mechanisms such as regulation of heart rate
and blood pressure, gastrointestinal motility, urination
and thermoregulation. Autonomic neuropathy is well-
known to accompany DSP in other diseases such as dia-
betes. However, symptoms of autonomic neuropathy su ch
as orthostatic dizziness or fainting, nausea or vomiting
especially with meals, diarrhea and/or constipation, uri-
nary incontinence, sexual dysfunction, and changes in
sweating, are not typically though t of as part of the HIV-
DSP symp tom c ompl ex. These symp toms seld om el ici t a
diagnostic work up for autonomic dysfunction, as they
are thought to more commonly be aspects of systemic
illnesses or medication intolerance occurring in the con-
text of HIV. Herein, we present a patient with HIV-DSP,
who was subsequently found to have an associated, un-
recognized autonomic neuropathy that may have ac-
counted for her systemic symptoms and intolerance to
multiple medications. We review potentially autonomic
symptoms and their relationship to HIV-DSP in 168 pa-
tients followed by the Manhattan HIV Brain Bank, a lon-
gitudinal study of advanced-stage, chronically HIV-in-
fected individuals with high prevalence of antiretroviral
therapy and HIV-DSP.
2. Case Report
The patient was a 46 year-old HIV-infected woman who
Copyright © 2012 SciRes. WJA
Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort
had acquired HIV 17 years previously via heterosexual
transmission. She was adherent to her antiretroviral
regimen of abacavir-lamivudine and atazanavir, which
had been unchanged for about 18 months. She had been
on multiple previous antiretroviral regimens (over 15
different agents), which had to be discontinued due to
side effects, the most severe of which was intractable
nausea and vomiting. No specific diagnostic evaluation
had been performed because the symptoms were pre-
sumed to be medication related. Current CD4+ count was
257 cells/mm3 and HIV-1 viral load was undetectable,
CD4+ nadir was 164 cells/mm3 at the time of initial HIV
diagnosis. She had mild hypertension, but no other active
medical co-morbidities, and did not use alcohol or other
substances. Over the course of one year the patient de-
veloped worsening pain in her feet, for which she was
referred to the neurology clinic. Neurologic examination
revealed hyperalgesia and allodynia in the soles of both
feet and decreased pinprick sensation up to the distal calf
bilaterally, and was otherwise normal. Nerve conduction
studies and electromyography were normal. Laboratory
testing revealed no evidence of diabetes mellitus, hypo-
thyroidism, vitamin B12 deficiency, or monoclonal
gammopathy. A presumptive diagnosis of small fiber
neuropathy was made and the patient was started on a
low dose of gabapentin (100 mg PO TID) because of the
history of difficulty tolerating medications. She devel-
oped lower extremity edema and dizziness. Gabapentin
was discontinued and duloxetine 20 mg daily was started.
The patient developed intolerable nausea and dizziness.
Duloxetine was discontinued and nortiptyline 10 mg QHS
was started, with hydrocodone-acetaminophen 5 - 500
mg once a day in the afternoon. She developed marked
constipation, but this was resolved with oral senna and
docusate. Due to the difficulty in treating her, additional
testing was pursued to confirm the diagnosis of small
fiber neuropathy. An au tonomic r ef lex scr een was ch o sen
over skin biopsy because it is a non-invasive measure of
small fiber function. Testing included the quantitative
sudomotor axon reflex test (QSART), heart rate response
to deep breathing (HRDB), Valsalva maneuver (VM) and
tilt table testing. [5] All measures were abnormal indi-
cating moderately severe autonomic neuropathy involv-
ing sudomotor, sympathetic and parasympathetic systems.
During the tilt table she exhibited ortho static hypo tension,
without adequate compensatory tachycardia and was
nearly syncopal (see Figure 1). In light of these results,
further inquiry was made for possible autonomic symp-
toms that could have been overlooked, and her records
over the past 3 years were reviewed. Chart review con-
firmed intolerance to multiple medications with symp-
toms of dizziness or nausea and vomiting, as well as un-
controllable diarrhea in response to darunavir and teno-
fovir/emtricitabine two years prior to her neurologic
presentation. Earlier that year, she had been diagnosed
with “dyspepsia” and started on esomeprazole. Current
symptoms elicited by interview and administration of the
Autonomic Symptoms Profile [6], a validated question-
naire, included: lightheadedness, dry mouth, changes in
sweating, nausea and bloating after a small meal, urinary
urgency with stress incontinence, and light sensitivity.
Following the diagnosis of autonomic neuropathy, the
patient was educated on its signs and symptoms and its
relationship to DSP. Subsequent symptomatic medica-
tions were initiated at the lowest possible doses with
close follow-up for worsen ing of orthostatic hypotension
or nausea. Although her neuropathic pain symptoms re-
mained difficult to treat, understanding the underlying
autonomic neuropathy provided the patient some reas-
surance and enhanced her acceptance of medication trials.
If a tolerable neuropathic pain treatment cannot be found,
the next step in management will be the addition of an-
cillary treatments specifically directed at side effects
such as lower extremity compression stockings to combat
venous pooling and edema, reduction of antihyperten-
sives to reduce orthostatic hypotension, and addition of
prokinetic agents to enhance gastric motility and reduce
nausea and vomitin g.
3. Potentially Autonomic Symptoms:
Prevalence in an Advanced Stage, HIV
The Manhattan HIV Brain Bank (MHBB) is an ongoing,
Figure 1. Data from a tilt table test reveals orthostatic hy-
potension, without adequate compensatory tachycardia, in a
patient presenting with painful HIV-associated distal sym-
metric polyneuropathy. The patient was upright in the time
period between the triangles (minutes 5 - 7). This was one of
four autonomic reflex tests performed. All were abnormal,
confirming the presence of autonomic neuropath y.
Copyright © 2012 SciRes. WJA
Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort 267
prospective nervous system study of participants with
long-standing HIV, as described previously. [7] All par-
ticipants seen between 1/1/2009 and 11/15/2011 were
reviewed for signs of HIV-DSP and potential symptoms
of autonomic dysfunction. There were 168 complete,
distinct records. Each visit consisted of a structured
medical history including review of antiretrovirals and
co-morbid illnesses relevant to DSP (e.g. diabetes melli-
tus); measurement of CD4+ count and HIV-1 viral load;
and a comprehensive neurological examination perfor med
by an attending neurologist. A diagnosis of symptomatic
DSP was assigned if a participant reported paresthesias,
dysesthesias or numbness in a distal distribution and dis-
played at least two of the following three signs: dimin-
ished sense of vibration at both gr eat toes, bilateral distal
decreased sensation to pin prick in both lower extremities,
and ankle reflexes absent or diminished as compared to
the knees. An extensive review of systems was per-
formed as part of the general neuromedical assessment
and contained the following potentially autonomic symp-
toms: syncope or fainting, urinary incontinence, fecal
incontinence, diarrhea, changes in appetite, changes in
sleep and pupillary abnormalities.
The great majority (94%) of participants were receiv-
ing antiretroviral therapy including: nucleoside reverse
transcriptase inhibitors (87%), non-nucleoside reverse
transcriptase inhibitors (31%), protease inhibitors (61%),
entry inhibitors (4%) and integrase inhibitors (21%).
Sixty-seven participants (40%) had HIV-DSP (see Table
1). Many other neurologic conditions were also observed.
Seventy-eight percent of participants had at least mild
cognitive impairment detected on neuropsychological
testing. Fifty-three percent had a neurologic diagnosis
other than HIV-DSP or neurocog nitive impairment. The se
included cerebrovascular disease, cranial nerve abnor-
malities, Parkinsonism, tremor, visual impairment, her-
pes zoster, and radiculopathy. These disorders were typi-
cally medically managed according to standard of care,
although specific data about surgical interventions was
not collected in a standardized fashion.
Potentially autonomic symptoms were common, with
136 (81%) participants experiencing at least one symp-
tom, 38 (23%) experiencing two, and 55 (33%) experi-
encing three or more. The presence of one or more of the
above symptoms was associated with HIV-DSP in a
Chi-square analysis (χ2(1) = 7.4, p = 0.007). Among par-
ticipants with one or more of these symptoms, 45% had
HIV-DSP compared to 19% among the remaining par-
ticipants. The presence of one or more of these symp-
toms was also associated with longer duration of HIV
infection: 19 years (IQR 15.21) vs 16 years (IQR 12.19)
(Wilcoxon rank-sum (n1 = 136, n2 = 31) = 1955, p =
0.007); but not with: age, gender, ethnicity, current
CD4+ count, a detectable HIV viral load, the use of an
Table 1. Characteristics of Manhattan HIV Brain Bank
N 168
Age, years 52 (47, 57)
Female 55%
Male 45%
White 18%
African-American/Black 50%
Hispanic/Latino 30%
Other 2%
HIV duration, years 19 (14, 21)
Log (VL, copies/ml) 1.7 (1.7, 3.0)
CD4+ (cells/mm3) 397 (195, 616)
Prescribed ART 93%
Symptom prevalence
Syncope 11%
Urinary incontinence 30%
Fecal incontinence 14%
Diarrhea 22%
Changes in sleep 57%
Changes in appetite 50%
Pupil changes 14%
aValues are median (interquartile range), unless indicated as a per-
centage. Abb reviation s: HIV-DSP = HI V-associat ed distal symmetric
polyneuropathy; VL = viral load; AR T = antiretroviral treatment.
tiretrovirals (in general or by class), or a diagnosis of
diabetes mellitus (all p-values > 0.1 in Chi-square or the
Wilcoxon rank sum test as appropriate). The association
between the presence of one or more potentially auto-
nomic symptoms and both duration of HIV infection (OR
= 1.1; 95%CI: 1.0, 1.2; p = 0.01) and HIV-DSP (OR =
3.7; 95%CI: 1.3, 10.1; p = 0.01) was maintained in a
multivariate logistic regression model adjusting for age,
antiretroviral use and diabetes mellitus.
4. Discussion
This report describes a commonly encountered clinical
scenario, distal neuropathic pain due to HIV-DSP. There
is a high level of awareness in the HIV community about
the prevalence of HIV-DSP and its signs and symptoms.
However there is very little awareness that HIV-DSP
may be accompanied by autonomic neuropathy, as ex-
emplified by our case report. This patient had symptoms
that were fairly typical of autonomic dysfunction, but
remained undiagnosed, perhaps because her symptoms
Copyright © 2012 SciRes. WJA
Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort
were relatively mild until exacerbated by medication. In
her case, the development of painful HIV-DSP finally led
to the diagnosis of her autonomic neuropathy.
It is unknown what proportion of patients with HIV-
DSP have autonomic neuropathy, although recent studies
have documented an association between autonomic
neuropathy and HIV [8-10] and studies from early in the
HIV epidemic suggested that autonomic neuropathy was
in fact quite common [11,12]. In our review of partici-
pants in the MHBB, potentially autonomic symptoms
were found far more frequently in participants with
symptomatic HIV-DSP than those without. Without for-
mal autonomic testing it is impossible to say whether or
not these symptoms were truly due to autonomic neu-
ropathy. However the symptoms were not associated
with current disease severity as measured by CD4+ count
and HIV-1 viral load, suggesting that they were not read-
ily explained by HIV alone. Similarly, the lack of asso-
ciation with antiretrovirals suggests that these symptoms
cannot be explained by toxicity alone.
Raising awareness about the symptoms of autonomic
neuropathy is complicated by the diverse and non-spe-
cific nature of autonomic symptoms, and the difficulty in
proving that any g iven symptom is autonomic. The com-
plexity of assessing autonomic symptoms is illustrated by
the Autonomic Symptom Profile (ASP), the most exten-
sively used measure of autonomic symptoms [6]. The
ASP contains 169 items which query a wide variety of
symptoms including: positional and situational dizziness
and syncope; skin changes including color changes (due
to vasomotor instability) and changes in sweat output;
dry eyes and mouth; gastrointestinal symptoms such as
nausea, vomiting or bloating (particularly after eating),
diarrhea or constipation; urinary incontinence or hesi-
tancy; sexual dysfunction; sensitivity to light or blurry
vision (due to dysfunction of pupillary constriction); and
sleep disturbance. Even patients with florid autonomic
failure do not typically experience all of these sympto ms
and patients with milder disease may have only one or
two, which may make appreciation of an underlying
autonomic disorder particularly challenging.
In the case of our patient, autonomic neuropathy likely
predated her HIV-DSP symptoms and could have ac-
counted for the numerous side effects she experienced
from antiretrovirals. This would have been important
information for her care providers that might have altered
their prescribing strategy and led to exposure to fewer
antiretrovirals and greater attention to providing symp-
tomatic relief. Further research is needed to determine
the prevalence of autonomic neuropathy in HIV and its
relationship to HIV-DSP.
5. Acknowledgements
The authors thank the staff and participants of the Man-
hattan HIV Brain Bank. Dr. Robinson-Papp receives
funding from NINDS (K23NS066789) and Dr. Morgello
receives funding from NIMH and NINDS (U01MH-
083501, R24MH59724).
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Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort
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