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Carol Sue Carlson, MD March 28, 2008 Herpes Zoster and Post-Herpetic Neuralgia.

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Presentation on theme: "Carol Sue Carlson, MD March 28, 2008 Herpes Zoster and Post-Herpetic Neuralgia."— Presentation transcript:

1 Carol Sue Carlson, MD March 28, 2008 Herpes Zoster and Post-Herpetic Neuralgia

2 Zoster (AKA “Shingles”)

3 Case – MR 53 yo ♂ C5 Tetraplegic 2 o to Spinal Cord Infarct PMHx: NonHodgkins Lymphoma s/p Chemo/RT  on Decadron po c/o burning, achy pain in posterior neck  ~36-48 hrs later  rash Dx: CN V 3 Herpes Zoster Pain!!  PCA, Acyclovir, Amitryptiline, Oxcarbazepine, Pregabalin, Duloxetine, Capsaicin, Lidoderm 5% patch, Methadone, Hydrocortisone Cream, Triamcinolone Cream

4 Case – MR

5 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

6 Varicella-Zoster Virus

7 Varicella Zoster Virus  Varicella  “Chicken Pox”  Zoster  “Shingles”

8 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

9 Varicella Zoster Virus – Pathogenesis

10 Acute Zoster Pathogenesis 1 st - Hemorrhagic Inflammation  Peripheral Nerve  Dorsal Root  DRG  Spinal Cord  Leptomeninges Nociceptor Activation  Poorly Localized Pain  “Pre-Herpetic Neuralgia”  Nociceptor Sensitization  Clinical Ramifications

11 Acute Zoster Pathogenesis 2 nd - Fibrosis  DRG  Nerve Root  Peripheral Nerve Autopsy Results  Similar +/- PHN

12 Zoster Pathogenesis Pain of Acute Herpetic Neuralgia  (1) Inflammation 2 o to Movement of Virus  (2) Hyperexcitability of Dorsal Horn Neurons  Spontaneous Activity  Exaggerated Responses Allodynia, Hyperalgesia  Interneuron Spread

13 Normal Post-Zoster Intercostal Nerve Histology

14 Zoster Pathogenesis – Reactivation DRG and Dorsal Horn  Intense Inflammation  Hemorrhagic Necrosis of Nerve Cells  Neuronal Loss  Fibrosis

15 Zoster Pathogenesis Neurotransmitters:  Substance P  Transmission  Serotonin, NE  Inhibition Therapeutic Implications Studies  No Difference Side to Side

16 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

17

18 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

19 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 6 th decade*** ♂ = ♀

20 Zoster Epidemiology Immunocompromised at ↑↑↑ Risk  Age  Disease  Chemotherapy Several Times More Common in Pts w/ Ca, HIV, Transplant Recipients

21 Zoster Epidemiology

22

23 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

24 Zoster – Natural History and Infectivity

25 Zoster – Natural History 75% have Prodromal Pain Grouped Vesicles or Bullae w/in 3-4 days Crusting in 7-10 Days  No Longer Infectious Scarring, Hypo- or Hyperpigmentation Recurrence is Rare

26 Zoster Rash

27 Zoster – Natural History PAIN – Most Common Sx  Deep, “Burning”, “Throbbing”, “Stabbing” Dermatomal  Thoracic, CN V, Cervical – Most Common  Zoster Keratitis, Zoster Ophthalmicus (CN V 1 ) Systemic Sx – Rare (<20%) Most Cases – Self-Limited BUT:  Can Interfere w/ Sleep, Appetite, Sexual Fnxn  Psychosocial Dysfunction

28 Zoster Dermatomal Distribution

29 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 1 o Varicella NOT Zoster

30 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)

31 Herpes Zoster

32

33

34 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

35 Zoster Complications POSTHERPETIC NEURALGIA  ***Most Common*** (10-15%) Ocular Neurologic  Motor Neuropathies – 2 nd most common (2-3%)  CN palsies  Meningitis  Myelitis  Encephalitis Bacterial Superinfection Ramsey-Hunt Syndrome

36 Zoster Ophthalmicus

37 Zoster – Motor Paresis

38

39

40 Zoster – Bacterial Superinfection

41 Ramsey-Hunt Syndrome

42 Zoster Complications – Immunosuppressed Includes:  HIV-infected pts  Transplant Recipients  Hematologic Malignancies ↑↑↑ Risk for Severe Complications  Cutaneous Dissemination  Visceral Involvement  Pneumonitis, Hepatitis, Pancreatitis, Meningo-encephalitis

43 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

44 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

45 Acyclovir Oral Acyclovir 800 mg 5X/day  Excellent Safety Profile  Mainstay of Rx BUT:  Poor Bioavailability  Frequent Dosing Within 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

46 Acyclovir with Corticosteroids Rx of Uncomplicated Acute HZ Study:  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

47 Valacyclovir Valacyclovir 1000 mg po tid X 7-14 days vs. ACV  Accelerated Resolution of Pain  38 days vs. 51 days  ↓ D uration of PHN Similar Adverse Events

48 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

49 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

50 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

51 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

52 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

53 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 yo!

54 Zoster Vaccine Randomized, Double-Blind Placebo-Controlled Trial 38,546 Pts, 60 yo or Older Goal: 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

55 Zoster Vaccine

56 Do Not Use In:  Pregnant ♀  Pts w/ hx/o Anaphylactic Rxn to Gelatin or Neomycin NOT Advised In:  Pts w/ 1 o or Acquired Immunodeficiencies  AIDS  Leukemia  Lymphoma  Malignancies of Bone Marrow or Lymphatic System  Pts on Immunosuppressive Therapies NOT for Rx of Zoster or PHN

57 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

58 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

59 Post-Herpetic Neuralgia – Epidemiology Incidence ↑ w/ Advanced Age  Rare in Children  Pts < 60 yo – Risk is < 2%

60 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

61 PHN Risk Factors Older Age  Assoc w/ ↑ Severity and Persistence of Sx Greater Acute Pain Greater Rash Severity ♀ Sex Presence of a Prodrome Risk is NOT ↑ in Immunocompromised Individuals

62 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

63 PHN – Clinical Manifestations Pain  Acute Zoster – Sharp, Stabbing  PHN – Burning Allodynia  > 90% of pts Anesthesia  Deficits of Thermal, Tactile, Pinprick, Vibration  Beyond Dermatomal Margins

64 PHN (1) Allodynia (2) Cutaneous Scarring (3) ↓ Sensation to Pinprick, Cold, Touch

65 PHN

66 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

67 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

68 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

69 Prevention of PHN (1) Rx of Acute Zoster (2) Vaccine OR:  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)

70 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

71 Treatment of PHN Antidepressants Analgesics Capsaicin Topical Lidocaine Anticonvulsants Intrathecal Corticosteroids NMDA Receptor Antagonists Cryotherapy Surgery

72

73 PHN – Tricyclic Antidepressants Effective for PHN Mainstay of Rx Inhibit 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

74 PHN – Tricyclic Antidepressants Sig. Side Effects  Esp. Sedation, Dry Mouth, Orthostatic Hypotension Nortriptyline vs. Amitriptyline  Nortriptyline Better Tolerated but Similar Analgesic Action May be a Lag of Up To 3 Weeks Neurology (51) October 1998 pp

75 PHN – Analgesics ASA, NSAIDs – Limited Value Opioids  Randomized, Double-Blind, Placebo-Controlled, Crossover  Opioid vs. Tricyclic vs. Placebo – 8 weeks each Conclusions:  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, pp ; Pain 104 (2003) pp

76 PHN – Capsaicin Alkaloid Derivative from Seeds of Plants (1) Enhances Substance P Release from C-fibers (2) Prevents Re-accumulation of Substance P

77 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

78 PHN – Topical Lidocaine Meta-analysis (2007)  2 Small Trials  Pain Relief Modestly Greater than Placebo Recommendations:  Insufficient Evidence to Recommend as 1 st Line Agent May be Useful as Adjunctive Rx Cochrane Database for Systemic Reviews. 4,2007

79 PHN – Anticonvulsants Esp. Useful in Lancinating Component of Pain  ie: CN V Neuralgia Commonly Used Anticonvulsants  Phenytoin  Carbamazepine  Gabapentin  Pregabalin

80 PHN – Gabapentin 2 Studies 1 o Outcome  Statistically Sig. ↓ in Pain Score vs. Placebo 2 o Outcome  ↓ Sleep Interference  Improved Mood, QOL Side Effects  Somnolence, Dizziness  **Most Common**  Peripheral Edema, Infection Pain 94 (2001) pp ; JAMA December 2, 1998 Vol 280, No 21, pp

81 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 – Euphoria If d/c  Taper Over 1 wk  2 o to Withdrawal Sx Pain 109 (2004) pp 26-35; Neurology 60, April 2003, pp

82 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

83 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

84 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, pp

85 PHN Treatment Recommendations Tricyclic Antidepressants  Amitriptyline  Nortriptyline “Strong” Opioids  Methadone  Morphine  Tramadol Anticonvulsants  Pregabalin  Gabapentin Topicals  Lidocaine 5% Patch  Capsaicin Intrathecal Methylprednisolone

86 PHN Treatment

87 Limitations to Rx of PHN

88 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

89 Herpes Zoster of Head and Limbs 158 Consecutive Cases, Head and Limbs Results:  > 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

90 Herpes Zoster of Head and Limbs

91 Electrophysiological Findings +/- PHN 23 Pts w/ PHN, 64 Pts w/o PHN All Pts had ↓ SNAP Amplitude  Assoc w/ NL or Only Slightly ↓ CV No Correlation Btwn Severity of Axonopathy & PHN  So – PHN Not 2 o 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 Electroencephalography and Clinical Neurophysiology, 101 (1996)

92 Electrophysiological Findings +/- PHN

93 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 Dz NCS: ↓ SNAP and CMAP Amplitudes Antiviral Rx May Be Assoc w/ ↓ Incidence of HZ Paresis The Neurologist, Vol 13, Number 5, September 2007, pp

94 Effects of Acyclovir Goal: Eval. Efficacy of ACV in:  ↓ Incidence of: PHN, Motor Paresis, Peripheral Nerve Damage No Difference in Incidence of PHN ACV Group:  Sig. ↓ in Clinically Evident Motor Paresis & ABNL EMGs Un-Rx Group:  More Freq. ABNL in SNCS, MNCS, H-Reflex, Blink Reflex ACV May Be Assoc w/:  ↓ Sensory Axonopathy, ↓ Motor Paresis BUT No Effect on PHN European Neurology, 1996;36:

95 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

96 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 Plexus EMG: Spontaneous Activity in R Triceps MRI: 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

97 Conduction Block of VZV Neuropathy

98 Conduction Block in Forearm 29 yo ♂ w/ Left FA Numbness, Left Hand Weakness  9 Days After Onset Severe 1 o Attack Varicella PE: (+) Weakness Left APB, OP, 1 st /2 nd 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 μV ) SNCS: L Sensory Branch MCN – Absent, NL on R EMG: ↓ Interference Pattern L APB, (+) Fascics in APB J Neurol Neurosurg Psychiatry 2005;76:

99 Conduction Block in Forearm Explanation?  (1) Median & Sensory MCN Share Cervical Roots → Lateral Cord  (2) Close Anatomical Proximity in Arm 2 o 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:

100 Thank You!

101


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