Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study

Abstract

HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n=28), of whom 75% (n=21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.

Keywords: Anxiety; Catastrophizing; Depression; Diagnosis; HIV-SN; IENFD; Pain; Phenotyping; QST; Quality of life; Triglycerides.

Fig. 1

Dot plot of z-score QST parameters in the healthy control, HIV–No SN and HIV-SN groups for Mechanical QST parameters (A) and Thermal QST parameters (B). ^∗Kruskal-Wallis, Dunn’s post hoc 1-way analysis of variance: ^∗P < .05; NS, P > .05. QST, quantitative sensory testing; HIV-SN, HIV sensory neuropathy; HIV–No SN, no HIV sensory neuropathy; NS, not significant.

Fig. 2

Loss and gain of sensory function. Comparison of participants in the HIV-SN group, HIV–No SN group, and healthy controls who have QST values outside the 95% confidence interval of the DFNS reference database. The y-axis shows the percentage of patients in each group (HIV-SN n = 38, HIV–No SN n = 28, healthy controls n = 36), with ‘gain’ of sensory function plotted upwards and ‘loss’ of sensory function plotted downwards. HIV-SN, HIV sensory neuropathy; HIV–No SN, no HIV sensory neuropathy; QST, quantitative sensory testing; HIV–No SN, no HIV sensory neuropathy. Chi squared test of association: ^∗P < 0.05, ^∗∗P < 0.01 comparison to Healthy controls; ^†P < 0.05, ^††P < 0.01 comparison to HIV-No SN.

Fig. 3

Pain intensity response curves for suprathreshold heat stimuli in healthy control subjects (n = 36), HIV–No SN group (n = 38), and HIV-SN (n = 28) group. Data are presented as mean (SD). No statistically significant difference was present between groups. VAS, visual analogue scale; HIV-SN, HIV sensory neuropathy; HIV–No SN, no HIV sensory neuropathy.

Fig. 4

Two representative skin biopsy samples of HIV-infected participants. (A) Participant from HIV-SN peripheral neuropathy group demonstrating complete absence of small unmyelinated sensory nerve fibres reaching epidermis. Subepidermal dermal plexus fibres are present (blue arrow) as identified by pan neuronal marker PGP 9.5. (B) Participant from HIV–No SN group with normal counts of small unmyelinated nerve fibres (black arrows) reaching epidermis beyond dermal epidermal junction (red dotted line), and positive dermal plexus staining (blue arrows). Original magnification, 40×. Scale bar = 50 μm. HIV-SN, HIV sensory neuropathy; HIV–No SN, no HIV sensory neuropathy.

Fig. 5

Distribution of NPSI descriptors in the painful HIV-SN population divided by categories of severity. NPSI, Neuropathic Pain Symptom Inventory; HIV-SN, HIV sensory neuropathy.