Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort

doi:10.4236/wja.2012.23035

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World Journal of AIDS, 2012, 2, 265-269

doi:10.4236/wja.2012.23035 Published Online September 2012 (http://www.SciRP.org/journal/wja) 1

Autonomic Neuropathy in HIV: A Case Report and

Review of Potential Symptoms in an Advanced-Stage, HIV

Cohort

Jessica Robinson-Papp, Kathryn J. Elliott, Maria Pizzirusso, Susan Morgello

Department of Neurology, Mount Sinai School of Medicine, New York, USA.

Email: jessica.rob[email protected]

Received July 19th, 2012; revised August 19th, 2012; accepted August 27th, 2012

ABSTRACT

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

Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort

266

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

Cohort

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.

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

Cohorta.

N 168

HIV-DSP 40%

Age, years 52 (47, 57)

Gender

Female 55%

Male 45%

Ethnicity

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

Autonomic Neuropathy in HIV: A Case Report and Review of Potential Symptoms in an Advanced-Stage, HIV Cohort

268

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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