PERIPHERAL NERVE DISEASE IN HIV INFECTED SUBJECTS 2006

1
PERIPHERAL NERVE DISEASE IN HIV- INFECTED
SUBJECTS2006

• AN AFRICAN PERSPECTIVE
• Jens Mielke

2
Overview - 2004

• Epidemiology
• Classification
• Pathology and neurophysiology
• Clinical characteristics
• Investigations
• (Management)
• (Prognosis)

3
INTRODUCTION - 2006

• New research findings
• New perspectives
• Ongoing questions

4
Classification

• Distal Symmetrical polyneuropathy (DSP)
• Idiopathic
• Associated with neurotoxic drugs
• Associated with vitamin B12 deficiency
• Inflammatory demyelinating polyneuropathy
• Mononeuropathy (multiplex)
• Progressive polyradiculopathy
• Autonomic neuropathy

5
Distal symmetric polyneuropathy
Not on ARVs
6
Clinical and subclinical neuropathy in patients
with human immunodeficiency virus receiving
antiretroviral therapy Villelabeitia-Jaureguizar
K

• Spanish
• Incidence of symptomatic and subclinical PN in
  108 patients on ddI, lamivudine and efavirenz 2
  years
• 1.85 symptomatic, (but prevalence 66
  subclinical on EMG study)

7
HIV neuropathy natural history cohort study
assessment measures and risk factors Simpson DM
ACTG A 5117

• 101 subjects, 49 d-drug ARVs, mean CD4 169
• 62 PN, 35 (10/28) developed during study
• ARV use not associated with worsening of TNS
• No correlation PN and lactate or mtDNA content
• study nurses misclassified ankle and distal
  vibratory sensation compared with neurologists.
  Nonphysician correct ankle reflexes 53/101 (52)

8
Antiretroviral use and other risks for
HIV-associated neuropathies in aninternational
cohort C.L. Cherry

• 63 PN
• Symptomatic strongly associated with ddI or d4T
• Vibratory threshold best discriminator for sPN
• Neuropathy prevalence similar Baltimore and
  Melbourne

9
Skin biopsy a predictor of transition to
symptomatic HIV neuropathy?A longitudinal study
D.N. Herrmann

• Measures of small sensory fibres (leg epidermal
  nerve fibre density, cooling and heat pain
  thresholds) seem to be associated with transition
  to symptomatic HIV-associated distal sensory
  neuropathy 6 to 12 months later

10
Toxic neuropathy from ARVs

• NRTIs zalcitabine (ddC), stavudine (d4T) and
  didanosine (ddI).
• onset 1 week to 6 months, typically more acute
  than the onset of DSP, and pain may be more
  prominent
• Symptomatic improvement weeks to months in about
  two-thirds of patients after discontinuation,
  often preceded by initial period worsening
  symptoms.

11
Toxic neuropathy from ARVs

• Often these two conditions are
  indistinguishable. The failure of at least
  one-third of cases of TNA to improve upon
  cessation of the precipitating NRTI increases the
  difficulty of distinguishing TNA from DSP.
• Estimated 15-30
• Mechanism inhibition of mtDNA polymerase

12
Incidence rates of TNA/100 person years in 1116
patients, receiving one of five antiretroviral
regimens and followed by the Johns Hopkins AIDS
Service.
13
Toxic neuropathy from ARVs

• serum lactate levels have been found to help
  distinguish between nucleoside induced neuropathy
  and HIV neuropathy with a specificity and
  sensitivity of 90.
• mitochondrial DNA in peripheral blood mononuclear
  cells quantification single-tube duplex
  real-time DNA-nucleic acid sequence-based
  amplification assay.

14
Toxic neuropathy from ARVs

• A small open label study using l-acetyl carnitine
  demonstrated improvement in the symptoms of
  neuropathy induced by NRTIs, providing support
  for mitochondrial toxicity as a mechanism for
  NRTI induced neuropathy

15
Protease InhibitorMediated Neurotoxicity
Jacqueline A. Pettersen,

• 101/ 221 PN (37 ARV PN) 1998-2004
• HIV-infected DRG cultures exposed to indinavir or
  didanosine showed significant neuronal atrophy,
  neurite retraction, and process loss, compared
  with controls. Indinavir was selectively
  cytotoxic to DRG macrophages compared with other
  ARVs

16
HIV associated neuromuscular weakness syndrome

• Motor weakness days to weeks, hyperlactaemia,
  nausea / vomiting, hepatomegaly
• Variable presentation progressive sensorimotor
  polyneuropathy to myopathy
• 13 mortality

17
Diffuse infiltrative lymphocytosis syndrome

• Persistent CD8 lymphocytosis
• Visceral infiltration salivary glands, lungs,
  kidneys, GIT, nerves.
• Acute or subacute painful multifocal symmetrical
  neuropathy (axonal)
• Angiocentric CD8 infiltrates and p24 expression
• Treatment ARVs /- steroids

18
Inflammatory Demyelinating Polyneuropathy

• Guillain Barre syndrome (AIDP) and chronic
  inflammatory demyelinating polyneuropathy (CIDP)
• GBS acutely (up to four weeks) progressive
  generalised weakness with areflexia and mild
  sensory impairment
• CIDP longer course, monophasic or relapsing
• Often seen in asymptomatic HIV

19
Inflammatory Demyelinating Polyneuropathy

• No controlled treatment trials
• Response similar to HIV- (but anecdotally related
  to degree of immune suppression)
• CIDP oral corticosteroids. AIDP and relapses
  CIDP role of IV immunoglobulins / plasma
  exchange.

20
Multiple Mononeuropathy

• Rare Multifocal sensory complaints in the
  distribution of cutaneous nerves, mixed nerves
  and roots.
• Asymmetrical distribution, preserved reflexes
• Two syndromes limited in those with CD4 200,
  extensive in others with concomitant CMV
  infection
• Nerve biopsy may be necessary (immune suppression
  vs specific Rx e.g. ganciclovir)

21
Progressive Polyradiculopathy

• Frequent CMV association (also VZV infection,
  neurosyphilis and leptomeningeal lymphoma )
• Rapid progression
• Lower extremity and sacral parasthesiae
• Paraparesis, areflexia, ascending sensory loss
  (occasional thoracic level) and urinary retention
• Cauda equina pain
• Onset to deaths - six weeks
• CSF WBC ? (polymorphs), protein ?, glucose ?

22
(No Transcript)