Carol Sue Carlson, MDMarch 28 , 2008

Herpes Zoster and Post-Herpetic Neuralgia

Zoster (AKA “Shingles”)

Case – MR

53 yo ♂C5 Tetraplegic 2o to Spinal Cord InfarctPMHx: NonHodgkins Lymphoma s/p

Chemo/RT on Decadron po

c/o burning, achy pain in posterior neck ~36-48 hrs later rash

Dx: CN V3 Herpes ZosterPain!!

PCA, Acyclovir, Amitryptiline, Oxcarbazepine, Pregabalin, Duloxetine, Capsaicin, Lidoderm 5% patch, Methadone, Hydrocortisone Cream, Triamcinolone Cream

Case – MR

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Varicella-Zoster Virus

Varicella Zoster Virus

Varicella Zoster Virus

Varicella “Chicken Pox”

Zoster “Shingles”

Varicella Zoster Virus – Pathogenesis

Viral Latency Limited # of Proteins

Expressed

Emergence from Latency Not Well-Understood

Reactivation Spreads w/in Ganglion Multiple Sensory

Neurons Infection of Skin

Varicella Zoster Virus – Pathogenesis

Acute Zoster Pathogenesis

1st - Hemorrhagic Inflammation Peripheral Nerve Dorsal Root DRG Spinal Cord Leptomeninges

Nociceptor Activation Poorly Localized Pain “Pre-Herpetic

Neuralgia” Nociceptor

Sensitization Clinical Ramifications

Acute Zoster Pathogenesis

2nd - Fibrosis DRG Nerve Root Peripheral Nerve

Autopsy Results Similar +/- PHN

Zoster Pathogenesis

Pain of Acute Herpetic Neuralgia (1) Inflammation 2o to

Movement of Virus (2) Hyperexcitability

of Dorsal Horn Neurons Spontaneous Activity Exaggerated

Responses

Allodynia, Hyperalgesia Interneuron Spread

Normal Post-Zoster

Intercostal Nerve Histology

Zoster Pathogenesis – Reactivation

DRG and Dorsal Horn Intense Inflammation Hemorrhagic Necrosis of Nerve Cells Neuronal Loss Fibrosis

Zoster Pathogenesis

Neurotransmitters: Substance P

Transmission Serotonin, NE

Inhibition

Therapeutic Implications

Studies No Difference Side to

Side

Zoster – Cell Mediated Immunity

Cell-Mediated Immune Responses Control Viral Latency Limit Potential for Re-activation ↓ Skin Reactivity to VZV by 40 yo Severely ↓ by 60 yo

↑ Rates of Herpes Zoster In: Older Individuals Lymphoproliferative Malignancies

BUT No ↑ Rates of Zoster or Protracted Varicella In: Children w/ Hypogammaglobulinemia

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Zoster Epidemiology

Cumulative Lifetime Incidence 10-20% of Population

Older Age Groups 30% > 55 yo Incidence ↑ w/Age

1 per 1000 in Pts < 20 yo 5-10X Greater in Pts > 80 yo ***Highest Incidence after 6th decade***

♂ = ♀

Zoster Epidemiology

Immunocompromised at ↑↑↑ Risk Age Disease Chemotherapy

Several Times More Common in Pts w/ Ca, HIV, Transplant Recipients

Zoster Epidemiology

Zoster Epidemiology

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Zoster – Natural History and Infectivity

Zoster – Natural History

75% have Prodromal PainGrouped Vesicles or Bullae w/in 3-4 daysCrusting in 7-10 Days

No Longer InfectiousScarring, Hypo- or HyperpigmentationRecurrence is Rare

Zoster Rash

Zoster – Natural History

PAIN – Most Common Sx Deep, “Burning”, “Throbbing”, “Stabbing”

Dermatomal Thoracic, CN V, Cervical – Most Common Zoster Keratitis, Zoster Ophthalmicus (CN V1)

Systemic Sx – Rare (<20%)Most Cases – Self-Limited BUT:

Can Interfere w/ Sleep, Appetite, Sexual Fnxn Psychosocial Dysfunction

Zoster Dermatomal Distribution

Zoster – Infectivity

Immunocompetent Host Via: Direct Contact w/ Lesion

Contact Precautions Recommended in Hosp. Pts Until Lesions Crust

VZV Naïve Pts Exposed to Zoster At Risk to Develop 1o Varicella NOT Zoster

Zoster – Infectivity

Immunocompromised Pt w/ Either: (1) Disseminated HZ (2) Local HZ in Pt at Risk for Dissemination

Hospitalized, Strict Isolation Rx ~ Varicella (in which Airborne Spread is Possible)

Herpes Zoster

Herpes Zoster

Herpes Zoster

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Zoster Complications

POSTHERPETIC NEURALGIA ***Most Common*** (10-15%)

OcularNeurologic

Motor Neuropathies – 2nd most common (2-3%) CN palsies Meningitis Myelitis Encephalitis

Bacterial SuperinfectionRamsey-Hunt Syndrome

Zoster Ophthalmicus

Zoster – Motor Paresis

Zoster – Motor Paresis

Zoster – Motor Paresis

Zoster – Bacterial Superinfection

Ramsey-Hunt Syndrome

Zoster Complications – Immunosuppressed

Includes: HIV-infected pts Transplant Recipients Hematologic Malignancies

↑↑↑ Risk for Severe Complications Cutaneous Dissemination Visceral Involvement

Pneumonitis, Hepatitis, Pancreatitis, Meningo-encephalitis

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Uncomplicated Herpes Zoster Treatment

Antiviral Therapy Goals:

(1) Promote Rapid Healing

(2) ↓ Severity and Duration of Pain

(3) ↓ Incidence and Severity of PHN

Prompt Use of Anti-Virals ↓ Duration of Pain by ½ ↓ Overall Incidence of PHN

Acyclovir

Oral Acyclovir 800 mg 5X/day Excellent Safety Profile Mainstay of Rx BUT:

Poor Bioavailability Frequent Dosing

Within 48-72 Hrs of Rash Onset Accelerates Resolution of Pain (Esp. in Pts > 50 yo) 1 Meta-Analysis – Sig. ↓ in PHN at 6 months by 46%

Archives of Internal Medicine Vol 157 Apr 28, 1997, pp 909-911

Acyclovir with Corticosteroids

Rx of Uncomplicated Acute HZStudy:

ACV 800 mg po 5X/day X 21 days + Prednisone X 21 days

ACV + Placebo Prednisone + Placebo 2 Placebos

ACV + Prednisone: Less Time to Crusting, Healing, Sleep, Return to Prior

Activity Faster Resolution Acute Neuralgia Earlier D/C of Analgesics

Drawbacks

Valacyclovir

Valacyclovir 1000 mg po tid X 7-14 days vs. ACV Accelerated Resolution of Pain

38 days vs. 51 days

↓ Duration of PHNSimilar Adverse Events

Anti-Viral Recommendations

Initiate w/in 72 hrs Esp. in Pts > 50 yo In Pts < 50 yo, Consider Risk Factors for Developing

PHN

Valacyclovir 1000 mg po tid X 7 days More Rapid Resolution Acute Neuritis Shorter Duration of PHN Lower Pill Burden Improved Compliance BUT ↑ $$$

Higher Cost than ACV

Anti-Viral Recommendations

Steroids Have Only Been Studied w/ ACV Moderate Acceleration of Healing and Resolution of

Pain No Effect on PHN ↑ Adverse Effects w/ Steroids May ↑ Risk of Bacterial Superinfection

Recommend Prednisone 40 mg Taper over 7-10 days ONLY in Pts:

(1) w/ Severe Sx at Onset (2) w/o Specific Contraindication

Last Dose Should Coincide w/ End of Anti-Viral Rx

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Zoster – Prevention

Major Precipitant for Zoster Reactivation?Decline in Cell-Mediated Immunity!

Elderly Population Immunosuppressed Pts

Subclinical VZV Infection Enhanced VZV Cell-Mediated Immunity!

Prevention in Immunosuppressed Hosts? ACV – ↓ Re-Activation in Hematopoietic Cell Transplant Recipients

Varicella Vaccine Concerns

(1) ↑ Risk of Vaccine-Assoc. Zoster Esp. in Immunocompromised Children

(2) ↑ Zoster in General Population ↓ Circulation Wild-Type Virus ↓ in Cell-Mediated Immunity

Neither Concern Has Been Proven Correct

Varicella Vaccine in Older Adults

2 Clinical Trials in Older Pts (55-87 yo)↑ CMI to VZV after Immunization

↑ Freq. of VZV-Specific T-cells 1 in 68,000 1 in 40,000

Similar ratio to 35-40 yo!

Zoster Vaccine

Randomized, Double-Blind Placebo-Controlled Trial

38,546 Pts, 60 yo or OlderGoal: Determine if Vaccine Would:

↓ Incidence and Severity of Zoster and PHN

Results: (1) ↓ Incidence of Zoster by 51% (2) ↓ Incidence of PHN by 67% (3) Those Who Developed Zoster:

Sig. Shorter Duration of Pain and Discomfort

New England Journal of Medicine June 2, 2005, Vol 352 No 22, pp 2271-2282

Zoster Vaccine

Zoster Vaccine

Do Not Use In: Pregnant ♀ Pts w/ hx/o Anaphylactic Rxn to Gelatin or Neomycin

NOT Advised In: Pts w/ 1o or Acquired Immunodeficiencies

AIDS Leukemia Lymphoma Malignancies of Bone Marrow or Lymphatic System Pts on Immunosuppressive Therapies

NOT for Rx of Zoster or PHN

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Post-Herpetic Neuralgia

Acute Herpetic Neuralgia Pain Preceding or Accompanying Rash

Up to 30 Days from Onset

Subacute Herpetic Neuralgia Pain Persisting Beyond Healing of Rash

Resolves w/in 4 mos of Onset

Post-Herpetic Neuralgia Pain Persisting Beyond 4 mos from Initial Onset of

Rash

Post-Herpetic Neuralgia – Epidemiology

Incidence ↑ w/ Advanced Age Rare in Children Pts < 60 yo – Risk is < 2%

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

PHN Risk Factors

Older Age Assoc w/ ↑ Severity and Persistence of Sx

Greater Acute PainGreater Rash Severity♀ SexPresence of a ProdromeRisk is NOT ↑ in Immunocompromised

Individuals

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

PHN – Clinical Manifestations

Pain Acute Zoster – Sharp, Stabbing PHN – Burning

Allodynia > 90% of pts

Anesthesia Deficits of Thermal, Tactile, Pinprick, Vibration Beyond Dermatomal Margins

PHN

(1) Allodynia

(2) Cutaneous Scarring

(3) ↓ Sensation to Pinprick, Cold, Touch

PHN

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

PHN – Pathogenesis Theories

(1) Sensitized Nociceptors “ABC syndrome”

(2) “Sensitization-like” Characteristics(3) Neuroma Formation(4) Central Hypersensitivity

~ “Trickle” Current(5) ABNL “Epileptiform” Activity in Spinal

Neurons

MULTIDETERMINATE!Therapeutic Implications

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Prevention of PHN

(1) Rx of Acute Zoster(2) VaccineOR:

Very Early Rx w/ Preventive Pain Medicines ie: TCAs, Anticonvulsants

Epidural Steroid Injections w/ Anesthetics No Benefit

Recommendation: Low-dose TCA w/in 2 days Rash Onset, X 90 days Gabapentin (If Limited By S/E)

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Treatment of PHN

AntidepressantsAnalgesicsCapsaicinTopical LidocaineAnticonvulsantsIntrathecal CorticosteroidsNMDA Receptor AntagonistsCryotherapySurgery

PHN – Tricyclic Antidepressants

Effective for PHNMainstay of RxInhibit Re-uptake of NE and Serotonin

↑ Inhibition of Nociceptive Signals

Study Amitriptyline vs. Lorazepam vs. Placebo Sig. More Effective for Moderate Pain Relief Sig. Correlation Btwn:

Serum Amitriptyline levels & Degree of Pain Relief

PHN – Tricyclic Antidepressants

Sig. Side Effects Esp. Sedation, Dry Mouth, Orthostatic Hypotension

Nortriptyline vs. Amitriptyline Nortriptyline Better Tolerated but Similar Analgesic

ActionMay be a Lag of Up To 3 Weeks

Neurology (51) October 1998 pp1166-1171

PHN – Analgesics

ASA, NSAIDs – Limited ValueOpioids

Randomized, Double-Blind, Placebo-Controlled, Crossover

Opioid vs. Tricyclic vs. Placebo – 8 weeks eachConclusions:

Opioids and TCAs Better than Placebo Trend toward Opioids but Not Statistically Sig. No Appreciable Effect on Cognition Noted w/ Opioids

Tramadol More Effective than Placebo

Neurology (59) October 2002, pp1015-1021; Pain 104 (2003) pp 323-331

PHN – Capsaicin

Alkaloid Derivative from Seeds of Plants

(1) Enhances Substance P Release from C-fibers

(2) Prevents Re-accumulation of Substance P

PHN – Capsaicin

Topical Application Burning, Stinging, Erythema Intolerable in ~ 1/3 of Pts

Appears to be Effective for PHN Moderate Relief when Applied QID 21% ↓ in Pain Score (vs. 6% w/ placebo)

True Blinding is Impossible

Pain 33 (1988) pp 333-340

PHN – Topical Lidocaine

Meta-analysis (2007) 2 Small Trials Pain Relief Modestly

Greater than PlaceboRecommendations:

Insufficient Evidence to Recommend as 1st Line Agent

May be Useful as Adjunctive Rx

Cochrane Database for Systemic Reviews. 4,2007

PHN – Anticonvulsants

Esp. Useful in Lancinating Component of Pain ie: CN V Neuralgia

Commonly Used Anticonvulsants Phenytoin Carbamazepine Gabapentin Pregabalin

PHN – Gabapentin

2 Studies1o Outcome

Statistically Sig. ↓ in Pain Score vs. Placebo

2o Outcome ↓ Sleep Interference Improved Mood, QOL

Side Effects Somnolence, Dizziness

**Most Common** Peripheral Edema, Infection

Pain 94 (2001) pp 215-224; JAMA December 2, 1998 Vol 280, No 21, pp 1837-1842

PHN – Pregabalin

Structural Analog of GABA (~Gabapentin)Results:

Improvement in Sleep, ↓ in Pain 150 mg to 600 mg po QD

Side Effects Dizziness, Somnolence, Dry Mouth Peripheral Edema, Weight Gain

Schedule V Controlled Substance – EuphoriaIf d/c Taper Over 1 wk

2o to Withdrawal Sx

Pain 109 (2004) pp 26-35; Neurology 60, April 2003, pp 1274-1283

PHN – Intrathecal Steroids

Study of 277 pts w/ intractable PHN for 1 yr+ Intrathecal Methylprednisolone + Lidocaine 1X/wk X

4 wks Intrathecal Lidocaine 1x/wk X 4 wks No Rx

Regional Anesthesia and Pain Medicine, Vol 24, No 4, July-August 1999, pp 287-293

PHN – Intrathecal Steroids

Results: (1) >90% of pts in Steroid Group Had:

Good/Excellent Pain Relief at 4 wks, 1 yr, 2 yrs (vs. 6% in Lidocaine Group, 4% in No Rx Group)

(2) Allodynia – ↓ by > 70% in Steroid Group (Lidocaine – ↓ by 25%)

(3) ↓ Need for Diclofenac in Steroid Group

Potential for Serious Neurologic Side Effects Adhesive Arachnoiditis Meningitis

Regional Anesthesia and Pain Medicine, Vol 24, No 4, July-August 1999, pp 287-293

PHN – NMDA Receptor Antagonists

Animal Data Excitatory AA NTs – Role in Maintenance of Chronic

Pain

NMDA Antagonists Relieve Neuropathic Pain IV Ketamine

Modest Pain Relief At Doses Sedation, Dysphoria, Dissociative Episodes

Dextromethorphan No Better than Placebo in PHN S/E – Ataxia, Sedation

Neurology 48, May 1997, pp1212-1218

PHN Treatment Recommendations

Tricyclic Antidepressants Amitriptyline Nortriptyline

“Strong” Opioids Methadone Morphine Tramadol

Anticonvulsants Pregabalin Gabapentin

Topicals Lidocaine 5% Patch Capsaicin

Intrathecal Methylprednisolone

PHN Treatment

Limitations to Rx of PHN

Overview

(1)Herpes Zoster Pathogenesis Epidemiology Natural History and

Infectivity Complications Treatment Prevention

(2) PostHerpetic Neuralgia Epidemiology Risk Factors Clinical Manifestations Pathogenesis Prevention Treatment

(3) EMG studies

Herpes Zoster of Head and Limbs

158 Consecutive Cases, Head and LimbsResults:

> ½ Sensory Axonal Neuropathy w/ NL or Only Slightly ↓ SNAP CV

> 1/3 Motor Fiber Involvement 19% Clinically – Segmental Motor Paresis 17% Subclinical – by EMG

55% Improvement in Segmental Motor Paresis 2.5% Sensorimotor Axonal PN

Severity of Peripheral Fiber Axonal Damage ↑ w/ Age

Archives of Physical Medicine and Rehabilitation, Vol 83, September 2002, pp. 1215-1220

Herpes Zoster of Head and Limbs

Electrophysiological Findings +/- PHN

23 Pts w/ PHN, 64 Pts w/o PHNAll Pts had ↓ SNAP Amplitude

Assoc w/ NL or Only Slightly ↓ CV

No Correlation Btwn Severity of Axonopathy & PHN So – PHN Not 2o to Damage of Lg Diameter Sensory Fibers

10% had Segmental Paresis Additional 17% had EMG Evidence of Axonal Motor Damage

No Sig. Diff. in EP Findings of Pts w/ or w/o PHN

Electroencephalography an Clinical Neurophysiology 101 (1996) pp 185-191

Electroencephalography and Clinical Neurophysiology, 101 (1996) 185-191

Electrophysiological Findings +/- PHN

Segmental Zoster Paresis of Limbs

Report of 3 Cases and Literature Review (1) PSW and Fibs in 40-50% of Cutaneous

Zoster Subclinical Motor Involvement – Not Uncommon

(2) Weakness Commonly Occurs w/in 2 wks of Rash

(3) Proximal Weakness More Common Older Age May Be a Risk Factor

(4) Motor Paresis – ↑ Freq. of Assoc w/ Malignant DzNCS: ↓ SNAP and CMAP AmplitudesAntiviral Rx May Be Assoc w/ ↓ Incidence of HZ Paresis

The Neurologist, Vol 13, Number 5, September 2007, pp 313-317

Effects of Acyclovir

Goal: Eval. Efficacy of ACV in: ↓ Incidence of: PHN, Motor Paresis, Peripheral Nerve

DamageNo Difference in Incidence of PHNACV Group:

Sig. ↓ in Clinically Evident Motor Paresis & ABNL EMGs

Un-Rx Group: More Freq. ABNL in SNCS, MNCS, H-Reflex, Blink

ReflexACV May Be Assoc w/:

↓ Sensory Axonopathy, ↓ Motor Paresis BUT No Effect on PHN

European Neurology, 1996;36:288-292

Motor Involvement in Acute HZ

40 Pts w/ Acute HZ

EMG ABNL in 53% – Fibs, PSWs In 62% EMG Findings were Subclinical

Widespread ABNL Not Confined to Segment Invaded by Rash

7 Pts had Motor Paresis

Muscle and Nerve, November 1997, pp 1433-1438

Conduction Block of VZV Neuropathy

Case Report: 64 yo ♀ w/ CML Acute HZ in R C6-C7 Dermatome Weakness in RUE – Not Confined to C6-C7

NCS: CB and CV Slowing in R Median Nerve in Forearm CB in R Radial Nerve Btwn Cubitus and Brachial

PlexusEMG: Spontaneous Activity in R TricepsMRI: Extensive Lesions in Connective Tissue around FF Tendons

& Muscles Along Median Nerve

Improvement in CBs & MMT of APB w/ Prednisone

Neurology, October 2003 (61) pp 1153-1154

Conduction Block of VZV Neuropathy

Conduction Block in Forearm

29 yo ♂ w/ Left FA Numbness, Left Hand Weakness 9 Days After Onset Severe 1o Attack Varicella

PE: (+) Weakness Left APB, OP, 1st/2nd Lumb L MCN nerve – Sensory Branch Hypesthesia No Atrophy, DTRs +2

MNCS: L Median (FA) – Partial CB (↓ CV, Absent F-wave) Elbow Mixed Median Nerve – ↓ on L (15.2 μV vs. 33.9 μV)

SNCS: L Sensory Branch MCN – Absent, NL on R

EMG: ↓ Interference Pattern L APB, (+) Fascics in APB

J Neurol Neurosurg Psychiatry 2005;76:1604-1605

Conduction Block in Forearm

Explanation?

(1) Median & Sensory MCN Share Cervical Roots → Lateral Cord

(2) Close Anatomical Proximity in Arm 2o to Anatomical Variations Direct Spread of Virus Between Nerves

(3) Indirect Spread from Purely Sensory MCN via Spinal Cord

J Neurol Neurosurg Psychiatry 2005;76:1604-1605

Thank You!

Thank You!