“Pins and needles”

1. “Pins and needles” ECHO / WITS PAEDIATRIC HIV CLINICS

2. PatientTM • 14 years and 11 months on presentation at HIV Clinic on 14/7/2009 • Referred from Dermatology clinic where treated for hypertrophic shingles X 4 episodes • Mother HIV negative in second pregnancy

3. Complaints • Weakness • Short of breath • Cough • Dysphagia • No TB contacts/previous TB • Missed 3mths school due to illness

4. On Examination • 32.25kg (59% EWFA) • Extensive hyperpigmented nodules right arm, lesions resolving • Oro-oesophageal thrush • No clubbing • Shotty lymphadenopthy axillae • Rest of examination findings non-contributary • Chest Xray- Bilateral infiltrates, some breakdown

5. Assessment • Almost 15 year old girl • WHO IV – 59% EWFA - Oesophageal candidiasis - Pulmonary TB - Resolving hypertrophic Zoster

6. Blood tests • Severe immunocompromise: • CD4 7 (1.08%) • HIV RNA (Viral load) 140 000 • ALT 20 • FBC essentially normal, normocytic anemia

7. Treatment • Started on Rifafour at 1st visit after sputum and Bactec ® taken • Oral fluconazole • Preparation for ART

8. 2 weeks later…. • Still very ill • Weight loss • Started ART (3TC/D4T/EFV) at appropriate doses

9. Progress….. • Seemed to be doing well on TB treatment and ART • Gained weight • Beginning of October started complaining of painful lower legs- burning, pins and needles type pain • Hyperaesthesia to touch, level to just below knee… “stocking” distribution • Absent ankle reflexes

10. Assessment-Peripheralneuropathy • What could be causing this? • HIV • INH • D4T

11. Onfurtherenquiry……. • Seemed as if “pins and needles” present prior to starting TB treatment or ART • Further management • D4T changed to ABC • Pyridoxine added • Unfortunately missed follow up

12. Sensory Neuropathies associated with HIV

13. Two main types of HIV associated sensory neuropathy • Distal sensory polyneuropathy • Antiretroviral toxic neuropathy • Clinically indistinguishable • Usually discussed in combination as many think that antiretroviral toxcity may “unmask” an existing silent distal sensory polyneuropathy

14. Prevalence • In USA around 30% in hospitalised (advanced) patients • Much lower if CD4 count > 200 cells/µl (3%) • Malawi, Beadles et al 35% of patients • Thailand, Sthininamsuwan et al 6-20% • Nigeria, Isezuo et al Nil recorded • Paucity of Paediatric data….up to 35% of children in 2000

15. Risk factors • Age • Nutritional deficiencies • Alcohol • High HIV viral set point • Low CD4 count

16. Clinical features • Pain or uncomfortable sensations • Timing of onset and ART may help with distinguishing between the two • Bilateral, symmetrical symptoms • Gradual onset- aching, burning, painful numbness • Mostly soles, worse at night or after walking • Hyperalgesia

17. Clinical features cont…. • Weakness rare • Usually confined to intrinsic foot muscles • No fasciculations • Ankle reflexes often absent/reduced • Nerve conduction velocities axonal, length dependant sensory polyneuropathy • Quantitative sensory testing: impairment of thresholds for heat, pain and cooling (usually research tool)

18. Distal sensory polyneuropathy- Pathophysiology • Sensory fibre degeneration with little regeneration • Large myelinated and unmyelinated • Same symptoms as diabetes, alchoholism and amyloidosis • Skin-punch biopsies show epidermal denervation

19. Pathophysiology of antiretroviral toxicities • “Deadly D’s” –dideoxynucleosides;d4T;ddI;ddC • d4T currently part of 1st line regimen in SA • Alternatives eg Abacavir far more expensive (about 10X) • Mitochondrial toxicity underlies pathogenesis • Often increased serum lactate and reduced acetyl carnitine

20. Pathophysiology continued • Inhibition of gamma DNA polymerase • Reduction in copy numbers of mtDNA • Resulting metabolic abnormalities • Usually takes a few months to develop • Mitochondrial toxicity may also cause pancreatitis, lactic acidosis, hepatic steatosis, lipodystrophy • May be dose dependant

21. Treatment • In ART-toxic neuropathy change offending agent eg. d4t to ABC/ TDF in older children • d4T dose in adults reduced to a max of 30mg • Usually improve within 3 months • Add pyridoxine to all TB treatment in HIV infected children • Dose: < 5 years 12.5 mg/day • > 5 years 25 mg

22. Treatment continued… • Tricyclic antidepressants (placebo controlled trials show modest benefit) • Anticonvulsants- lamotrigine showed large benefit in 2 trials • High dose capsaicum or lidocaine have yielded positive results • HD Co-enzymeQ worsened pain • Acupuncture not effective

23. Treatment….. • Narcotics- transdermal fentanyl, morphine, oxycodone preparations for severe neuropathies • Regenerative strategies with recombinant human nerve growth factor- trials showed moderate effect • Further research needed

24. Patient TM • All risk factors for HIV sensory neuropathy • Likely distal sensory neuropathy • BUT complicated by INH and d4T • Late detection of problem • Need increased awareness • Likely often missed in children

25. References • McArthur J et al. Neurological complications of HIV Infection. Lancet Neurol 2005;4 • Beadles W et al. Neuropathy In HIV-positive patients at an ART clinic in Lilongwe, Malawi. Tropical Doctor 2009;39 • Isezuo SA et al. Clinical neuropathy in HIV/AIDS:an eight year review of hospitalised patients in Sokoto, North Western Nigeria. Tropical Doctor. 2009;39 • Sithinamsuwan P et al. Frequency and Characteristics of HIV associated sensory neuropathy Among HIV patients in Bangkok, Thailand. JAIDS 2008; 49