carol sue carlson, md march 28, 2008 herpes zoster and post-herpetic neuralgia
TRANSCRIPT
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
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