Painful HIV-associated sensory neuropathy

Peter Kamerman

16th World Congress on Pain, Yokohama, Japan, 2016

Major neurological complications of HIV infection

Central nervous system

HIV-associated neurocognitive disorders (HAND)

Myelopathy

Peripheral nervous system

HIV-associated sensory neuropathy (HIV-SN)

Inflammatory demyelinating polyneuropathies

Polyradiculopathy

Mononeuritis multiplex

Ferrari et al., 2006; Pardo et al., 2001; Power et al., 2009

Global prevalence of HIV-SN (adults): 30-60%

For review: Kamerman et al., 2012a

Global prevalence of HIV-SN (children): 13-38%

Araujo et al., 2000; Esteban et al., 2009; Peters et al., 2014; Benjamin et al., manuscript in preparation; Floeter et al., 1997

Typical clinical features

SIGNS

Reduced:

Pin-prick sensitivity

Vibration sense

Reflexes

Temperature sense

SYMPTOMS

Pain

Numbness

Paraesthesias

Bouhassira et al., 1999; Tagliati et al., 1999; Martin et al., 2003; Wadley et al., 2011; Freeman et al., 2014; Phillips et al., 2014

Pathogenesis

Pathogenesis of HIV-SN

For review: Kamerman et al., 2012a and 2012b

Dorsal root ganglion Axon and peripheral terminalSpinal cord

HIV Neurotoxic antiretroviral drugs

(d4T, ddI, ddC)

Macrophage infiltration from the skin to the DRG

Goullée & Price, unpublished

Pardo et al. Journal of the Peripheral Nervous System 6:21–27 (2001)

25

athy. Selective degeneration of gracile tract in patientswith sensory neuropathy, characterized by loss of ax-ons and myelin sheaths in the cervical and upper tho-racic cord, described and suggested a “dying-back” de-generation process of DRG neurons

(Dal Pan et al.,1994; Rance et al., 1988; Scaravilli et al., 1992).

Otherstudies have shown a frequent presence of peripheralneuropathy in patients with vacuolar myelopathy

(Brew,1994; Dal Pan et al., 1994; Grafe and Wiley, 1989; Tanand Guiloff, 1998).

Epidermal nerve fiber pathology

The recent introduction of epidermal nerve fiberanalysis by immunocytochemical techniques using thepanaxonal marker PGP 9.5 (protein gene product 9.5), aneuronal ubiquitin hydrolase, has contributed to the in-vestigation of PNS disorders. This technique allows thestudy of epidermal innervation by small-caliber C andA

!

nerve fibers

(Holland et al., 1997; McCarthy et al.,1995).

Studies of skin biopsies of patients with HIV-associated sensory neuropathy developing during treat-ment with didanosine or zalcitabine showed reductionin the number of epidermal fibers in distal areas of thelower extremities with an inverse correlation betweenneuropathic pain intensity and epidermal nerve fiberdensity

(Polydefkis M, 2000).

In some of these pa-tients, there was an increase in the frequency of fibervaricosities and fragmentation in the dermis likely to berepresentative of degenerating fibers and absence ofPGP 9.5 fibers in the epidermis (Fig. 3). There were alsofewer epidermal fibers in HIV-seropositive patients with-out clinical evidence of neuropathy than in seronegativecontrols. This finding suggests that HIV infection may beassociated with the loss of cutaneous innervation evenbefore the onset of sensory symptomatology

(McCarthyet al., 1995).

A recent clinical trial that evaluated the useof nerve growth factor in the treatment of HIV-associ-ated sensory neuropathy used epidermal nerve fiberdensity analysis as a secondary therapeutic outcome

(McArthur et al., 2000).

Figure 2. Dorsal root ganglia pathology in HIV neuropathy ischaracterized by foci of macrophage-lymphocytic infiltration(A) and Nagoette nodules (B). Infiltration by activated mac-rophages is demonstrated by immunostaining with anti-CD68

antibodies (C) (bar 50 "m).

Figure 3. Skin biopsy from a normal control (A) and an HIVpatient with DSP (B). Note the decreased number of epider-mal fibers and varicosity formation (B) (bar 50 "m).

50µm

Pardo et al., 2001

been shown in DSP, but the reduction is more modestthan the distal axonal loss [28]. Furthermore, selectivedegeneration of the gracile tracts in patients with DSP,characterized by loss of axons and myelin sheaths in thecervical and upper thoracic cord, has been described[29]. This finding represents degeneration within thecentrally directed extensions of the sensory neurons,and is the central nervous system’s counterpart of thedying back process seen in the peripheral nerve.

Immunopathological studies in DSP have shown pro-minent macrophage activation with the local release ofproinflammatory cytokines in areas of axonal degenera-tion (Fig. 2). Moreover, there has been consistentdemonstration of increased frequency of Nageottenodules. Nageotte nodules are compact areas of pro-liferation of satellite cells that frequently accompanyDRG neuronal loss from any cause. DRG inflamma-tory infiltrates are seen (Fig. 3) comprised mainly oflymphocytes and activated macrophages, with conco-mitant immunostaining for pro-inflammatory cytokinessuch as tumor necrosis factor (TNF)-Æ, interferon-ªand interleukin-6 [30–32].

What causes the multifocal macrophage activation inperipheral nerves and DRG in DSP? The answer is notyet known, and there are two complementary and notnecessarily mutually exclusive hypotheses. In one theo-ry, it is postulated that a mild degree of distal axonaldegeneration occurs because of nutritional deficiencies,alcohol exposure, substance abuse [33] or other non-specific factors. As in other types of Wallerian-likedegeneration, macrophages would then be recruitedinto the affected nerves. However, in HIV infection,these macrophage responses to the axonal degenerationare ‘hyperactive’, resulting in multifocal inflammationin the nerve and DRG. In the second theory, circulat-ing activated monocytes and pro-inflammatory cyto-kines enter DRG and peripheral nerves in excessive

Fig. 1. Skin biopsy from a normal control (a) and a HIV patient with DSP (b). Note the decreased number of epidermal nervefibers and formation of nerve fiber swellings (b) (bar, 50 !m).

Fig. 2. Macrophage infiltration of peripheral nerve as ob-served by immunocytochemistry with anti-CD68 antibodies(a) Cross section. (b) Longitudinal section. (Bar, 50 !m.)Reproduced with permission from [26].

AIDS 2002, Vol 16 No 162108

50µm

Pardo et al., 2001

Spin

al

cord

Skin

DRG Nerve trunk Skin

Dorsal root ganglion Axon and peripheral terminal

Spearman's rho = −0.68, p = 0.050

2

4

6

8

10

12

14

0 2 4 6 8 10

Epidermal macrophage count (cells/mm)

Epide

rmal

nerv

e fib

re d

ensit

y (fib

res/m

m)

Healthy controlsHIV neuropathy

Typical clinical features

SIGNS

Reduced:

Pin-prick sensitivity

Vibration sense

Reflexes

Temperature sense

SYMPTOMS

PainNumbness

Paraesthesias

Bouhassira et al., 1999; Tagliati et al., 1999; Martin et al., 2003; Wadley et al., 2011; Freeman et al., 2014; Phillips et al., 2014

Pain is a common symptom of HIV-SN

Sadosky et al., 2008

HIV-SN is a major cause of chronic pain

Primary source of painPainful peripheral neuropathy 45-48%

Low back pain 22-28%

Arthralgia 6-13%

Koeppe et al., 2010

o Participants:324 HIV-positive out-patients with a diagnosis of chronic pain.

The impact of painful HIV-SN

Having pain is associated withbeing unemployed

↑ depression and anxiety

↑ severity of depressive symptoms

↑ sleep disturbance

↓ independence

↓ social functioning

Ellis et al., 2010; Phillips et al., 2014

Painful HIV-SN in children

Benjamin et al., manuscript in preparation

o Participants:- 135 HIV-infected children- 50% female- Age: 7 (3 - 11) years - CD4: 1184 (927-1440) cells/ml- All exposed to stavudine (d4T)

o SN diagnostic criteria: Bilaterally reduced / absent ankle reflexes OR vibration sense

0

5

10

15

20

HIV-SN SymptomaticHIV-SN

PainfulHIV-SN

Mea

n (9

5% C

I) pr

eval

ence

(%)

Low rates of symptomatic HIV-SNin children

Symptoms are typically moderate to severe

Phillips et al., 2014

Intensity ratingSevere (7-10)

Moderate (4-6)

Mild (0-3)

o Participants:21 patients with painful HIV-SN

o Assessment: Neuropathic Pain Symptom Inventory (NPSI)

Risk of painful HIV-SN

Risks for developing painful HIV-SN

Malvar et al., 2015

493 pain-free

HIV+Median follow-up: 24 months

(IQR: 12-42; 1961 visits)

Assessment at each visito Pain: Yes / Noo Signs: Bilaterally reduced / absent pin-prick OR vibration sense OR ankle reflexes.

Incidence of painful HIV-SN

Malvar et al., 2015

Risks for developing painful HIV-SN

Malvar et al., 2015

Risks for having painful HIV-SN

Pillay et al., under review

Assessment:o Pain: Yes / Noo Signs:

Bilaterally reduced / absent pin-prick sensation ORvibration sense ORankle reflexes.

n = 129 painfulHIV-SN

n = 72pain-freeHIV-SN

• anxiety / depression• total pain burden

Risks for having painful HIV-SN

Pillay et al., under review

Depression and anxiety

Painful HIV-SN (n = 129)

Non-painful HIV-SN (n = 72)

1 tile = 1%

I am not depressed or anxious

I am moderately depressed or anxiousI am extremely depressed or anxious

Risks for having painful HIV-SN

Pillay et al., under review

Percent with other pain sitesPainful HIV-SN (n = 129)

Non-painful HIV-SN (n = 72)

1 tile = 1%

No

Yes

Pain intensity at other sites

Painful HIV-SN (n = 129)

Non-painful HIV-SN (n = 18)

1 tile = 1%

Mild pain

Moderate pain

Severe pain

Cause or effect: reduced cortical volume?

Keltner et al., 2014

Prop

ortio

n w

ith p

ainf

ul H

IV-S

N

0.6

0.4

0.3

0.2

0.1

0.0

0.5

Q1 Q2 Q3 Q4Quartiles of adjusted log cortical volume loss

o Participants:241 patients HIV-SN from 5 study centres in the USA (CHARTER)

Pharmacological management

Treatment: there is a lack of evidence

Finnerup et al., 2015

“Pain due to HIV-related painful polyneuropathy…seems more refractory [to treatment] than other types of pain in our meta-analysis.”

“This difference might be due to large placebo responses in HIV-related neuropathy trials”

Large placebo response

Cepeda et al., 2012

Large placebo response?

Pillay et al., 2015

What is being used to manage the pain?

* Median (IQR) amitriptyline dose: 25 (25-75) mg/day | APAP: Paracetamol

o Participants:130 adults with painful HIV-SN

o SN diagnostic criteria: Bilaterally reduced / absent ankle reflexes OR vibration

Summary

Acknowledgments

University of the WitwatersrandAntonia WadleyZané LombardPrinisha PillayLiesl HendryAsma Shaikh

Burnet Institute, MelbourneKate Cherry

University of Western AustraliaPatricia PriceHayley GoulléeConstance Chew

Funding• National Research Foundation,

South Africa• South African Medical Research

Council• International Association for the

Study of Pain• University of the Witwatersrand

…and• The Honey Badger