Part 1: Basics of PHN, theories on its etiopathogenesis. 

 

Background: 

Post herpetic neuralgia (PHN) is a chronic pain syndrome that persists beyond 4-6 weeks or in some definitions up to 90 days after a shingles episode [1]. Shingles or Herpes Zoster(HZ) is caused by varicella Zoster Virus reactivation (VZV). VZV is the same virus that causes chicken-pox. After primary infection ie. Chicken pox usually in childhood the VZV virus travels from the skin retrogradely (backwards) to the spinal ganglion. The virus lays dormant for decades until conditions are favorable for reactivation. Risk factors for reactivation seem to be waning of cell mediated immunity (t-cell) with age, immunosuppression, stress, UV, leukemia and cancer chemotherapy among others. As chickenpox rashes can appear all over the skin and even over the mucosal surfaces both sensory and autonomic ganglia can become infected and can subsequently reactivate. Usually HZ reactivation is confined to one dermatome although in immunosuppressed patients multiple dermatomes  can be affected, a condition called disseminated zoster.

Unfortunately, the incidence of HZ is increasing with an estimated more than 1 million cases of HZ per year in the US alone. Moreover, the incidence of PHN varies anywhere from 10-50% which gives an indication to the immensity of this problem [2]. Shingles vaccination can reduce the burden of HZ and as a corollary PHN.

The pain of PHN can be constant or intermittent and greatly affects the quality of life for the sufferers. The pain can be dermatomal – usually characterized by burning, searing, poking pain or allodynia in the dermatome involved by Zoster which may partially respond to topical therapy or sclerotomal - which is a deep pain gnawing, tearing or ripping pain that does not respond to topical therapy. Some patients have a combination of dermatomal and sclerotomal pain.

Unfortunately, most first line medical therapy such as amitriptyline, gabapentin/pregabalin, opiates, carbamazepine are only partially effective in controlling pain in most patients. Interventional therapies such as spinal cord stimulator, ganglion block or RF ablations have been done with some success [1]. Despite these options a majority of patients have persistent pain for years without adequate pain management options.

 

Etiopathogenesis of PHN and personal experience:

There are two current competing theories, although not necessarily mutually exclusive, regarding the etiology of PHN

1) Post HZ scarring and inflammation that alters neural conduction (without active viral replication) or

2) PHN patients have persistent VZV replication that is not controlled and results in ongoing inflammation in the spinal ganglia resulting in the pain syndrome.

Classical teaching and current treatments are geared towards the first hypothesis despite accumulation of evidence suggesting ongoing VZV replication.

Evidence from multiple studies show that persistent viral replication is seen in PHN patients - treatment with appropriate dose of antivirals show reduction in pain, evidence of viral ganglionitis in PHN patients, detectable virus and inflammatory cells in spinal ganglia/csf , studies from zoster sine herpete (where there is no detectable rash but viral reactivation causes pain), presence of salivary VZV DNA in PHN patients which is absent in HZ recovered patients without PHN and lastly detection of interferon signature indicating viral replication from polymorphonuclear leukocytes (PMNs)[3–7].

My own personal experience with this condition suggests that atleast in some cases ongoing viral replication (despite absence of active rash) is the etiology for this condition. I had complete relief from pain after starting treatment dose of valacyclovir (Vala)1g three times a day. This came from an old paper from late Prof.Gilden’s group where they used acyclovir iv infusion followed by oral Vala for PHN patients[3] . Even though this was an uncontrolled study upto 58% of patients reported improvement in the pain score by atleast 2 points which is clinically significant.

 

 

 

 

References: 

1.        Post-herpetic Neuralgia: A Systematic Review of Current Interventional Pain Management Strategies - PMC. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061658/. Accessed 2 January 2023.

2.        Cohen JI. Herpes Zoster. N Engl J Med 2013; 369:255–263.

3.        Quan D, Hammack BN, Kittelson J, Gilden DH. Improvement of Postherpetic Neuralgia After Treatment With Intravenous Acyclovir Followed by Oral Valacyclovir. Arch Neurol 2006; 63:940–942.

4.        Haanpää M, Dastidar P, Weinberg A, et al. CSF and MRI findings in patients with acute herpes zoster. Neurology 1998; 51:1405–1411.

5.        Gershon AA. The History and Mystery of VZV in Saliva. J Infect Dis 2011; 204:815–816.

6.        Sutherland JP, Steain M, Buckland ME, et al. Persistence of a T Cell Infiltrate in Human Ganglia Years After Herpes Zoster and During Post-herpetic Neuralgia. Front Microbiol 2019; 10. Available at: https://www.frontiersin.org/articles/10.3389/fmicb.2019.02117. Accessed 21 December 2022.

7.        Chen Y-C, Figliozzi RW, Hsia SV. Pilot Analyses of Interferon Subtype Expression Profiles in Patients with Herpes Zoster or Postherpetic Neuralgia. Viral Immunol 2021; 34:437–447.