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12 Articles in Volume 9, Issue #1
Atypical Herpetic Reactivation and Chronic Pediatric Pain
Blending Prescription Pain Treatments with Alternative Medicine
Cervical Disc Disease with Referred Pain to TMJ
Deep Cervical Muscle Dysfunction and Head/Neck/Face Pain–Part 1
In My Opinion
Laser Therapy: Treating Shoulder Pain in Hemiplegic and Spinal Cord Injured Patients
Pain Management in the Elderly
Personality Disorders in Migraineurs
Surgical Implants for Pain Management
Treating Shoulder Pain in Hemiplegic and Spinal Cord Injured Patients
Trigger Point Ablation and TMJ Syndrome
What a Decade of the Mind Affords the Decade of Pain Control and Research

Atypical Herpetic Reactivation and Chronic Pediatric Pain

A report of three unexplained, severely-disabling pediatric cases—in otherwise healthy children—successfully treated with long term anti-viral therapy.

Medically unexplained chronic pain (i.e. pain persisting for more than three months) is a common problem in patients.1,2 Three cases of otherwise healthy children (two females aged 13 and 15 and one male aged 10) with medically unexplained, severely disabling pain are presented in the following sections. In all three cases, patients had severe, disabling pain of more than one year’s duration, and thorough medical evaluations were negative. Prior to developing pain syndromes, these patients were healthy children and free of medical co-morbidities or any other apparent contributing psychosocial factors. These young patients were referred to an outpatient Rehabilitation Medicine setting by their pediatrician and/or other pediatric sub-specialists. All had previous extensive medical evaluations that had not identified the cause of their chronic pain syndromes.

All three children had very high IgG titers to at least one of the herpetic viruses and had a history of childhood chicken pox and had never received vaccination to varicella. A classic vesicular outbreak in a radicular distribution was not present in any of these children. Atypical herpetic presentations have been noted before in the literature.3-9 A presumed diagnosis of herpetic reactivation was based on an extensive negative medical workup and the presence of significantly elevated IgG antibody titers to HSV I and/or varicella zoster.

Case 1

A 13 year-old female was referred for evaluation of severe burning pain of 1.2 years duration in the neck and back areas rendering her increasingly immobile and unable to participate in normal activities of daily living. She was in good health prior to injuring her left knee 14 months earlier. Within two to three weeks of the left knee injury, she developed flu-like symptoms and more severe left knee pain and swelling. Her pain symptoms gradually generalized to include pain in the neck, upper extremities, low back, and lower extremities and she developed generalized fatigue. She developed painful vesicles in the mouth and oropharynx which interfered with eating and resulted in anorexia, severe weight loss, and hospitalization.

Prior to referral, she had been evaluated and treated by multiple medical specialties including rheumatology, orthopedic surgery, dermatology, psychiatry, psychology, and physical medicine.

The prior workup included:

 

 

 

  • palpable anterior cervical lymph nodes
  •  

     

     

     

    Prior treatment included a two week course of acyclovir that had not altered the symptoms (her mother could not recall dosage or frequency of administration.)

    On initial physiatry examination at 14 months post injury, this patient had diffuse tightness and tenderness in the muscles of the neck, shoulders, low back and hips with multiple foci of muscle contraction. She was able to stand and briefly walk in an abnormal gait pattern due to guarding from pain. She spent her day lying in bed, sitting in a comfortable chair, or being pushed in a manual wheelchair by her mother. Her neurological exam was normal with respect to reflexes and motor strength but she had severe hyperalgesia to pinprick over the skin of the neck, back, upper and lower extremities.

    Also present were:

     

    Given the negative medical work up, the presence of herpetic-appearing vesicles in the throat coupled with hyperalgesia, painful rash, and enlarged lymph nodes, a diagnosis of herpetic reactivation was postulated. IgM and IgG viral antibody titers for varicella zoster, herpes simplex 1 and 2 were measured. IgG to varicella zoster was elevated (see Table 1). The patient was started on acyclovir 400mg 3 times per day. There was mild to moderate improvement at this dosage. After three to four weeks of treatment, the dosage was increased to 400mg of acyclovir five times per day.

    After eight weeks of treatment, the oropharyngeal pain and vesicles and the erythematous rash over the left buttock and thigh had resolved. The patient had been able to resume eating and her weight had normalized. She continued to have pain in the neck, back and extremities, which was improving slowly.

    After approximately eight weeks of treatment with anti-viral medication, a four-week inpatient acute rehabilitation program was initiated. The inpatient treatment program was followed by eight weeks of outpatient physical therapy. By the end of the course of outpatient physical therapy, this patient was cautiously ambulating without assistive devices. She continued to slowly improve and re-mained on 400mg acyclovir five times per day.

    The last time she was evaluated, at twelve months after initiation of anti-viral therapy, the patient’s pain had significantly improved. She was eating normally, walking without assistive devices and able to return to school. The patient and her family moved and she was lost to follow-up.

    Case 2

    A 15 year-old female was referred for evaluation of progressively increasing musculoskeletal pain of several years duration involving the neck, back, chest wall, and upper and lower extremities. She described frequent rashes accompanied by itching or burning sensations over the arms and thighs. There was no history of trauma or other known precipitating causes for this pain. She had been quite active in sports, participating in softball and basketball until six months prior to her physiatry evaluation, when all sports activity ceased due to pain.

    “All three children had very high IgG titers to at least one of the herpetic viruses and had a history of childhood chicken pox and had never received vaccination to varicella.”

    She had recurrent ear infections and sore throats, leading to a tonsillectomy at age 8, placement of bilateral myringotomy tubes at age 9, and adenoidectomy at age 10. Frequent bouts of nausea, vo-miting, and abdominal pain over two years’ time led to cholecystectomy at age 13 without relief of her symptoms. She was using an inhaler daily for seasonal and environmental allergies.

    A complete cardiac workup for chest pain and cardiac palpitations was negative.

    She was being treated for possible mild ADHD and depression without psychiatric medication. Over the course of her illness, she had been seen and evaluated by multiple medical specialties including gynecology, orthopedic surgery, dermatology, gastroenterology, allergy, pediatric cardiology, and a pediatric developmental specialist. Although previously active in several sports, she had not participated for the six months prior to her referral due to increasing neck, back, and upper extremity pain.

    On initial physical examination there was:

     

     

    IgG and IgM antibody titers were measured (See Table 1). IgG to Herpes Simplex 1 was extraordinarily elevated, varicella was extremely elevated, and Epstein-Barr IgG titer was mildly elevated.

    During the initial four to six weeks of treatment with acyclovir (400mg 4-5 times per day), the rash over the upper extremities, shoulders, and face improved. After approximately two months on acyclovir, her dermatologist changed to valacyclovir (500mg 2 times per day) in response to an outbreak of herpetic lesions around the right side of her mouth. By the end of three months of antiviral therapy the rashes over the shoulders and upper extremities had resolved. Symptoms of muscle soreness, pain, and fatigue improved sufficiently for her to begin an aerobic reconditioning program.

    Approximately eight months after initiation of antiviral therapy, she developed a fever and dehydration and was briefly hospitalized. Repeat IgG and IgM viral antibody titers were drawn shortly after discharge (See Table 1). Epstein-Barr virus IgM viral antibody titer had become mildly elevated, and Epstein-Barr IgG viral antibody titer was significantly more elevated than previously. Both varicella zoster and HSVI IgG viral antibody titers were lower than previously but remained significantly elevated. Cytomegalovirus viral antibody titers remained negative.

    Patient remained on valacyclovir 500mg BID and continued to improve. At one year of antiviral therapy, antibody titers had decreased (See Table 1) and valacyclovir was discontinued. Approximately 1.5 years later, she experienced an acute flare up of pain and fatigue. Valacyclovir (500mg 2 times per day) was restarted for three months with a similar improvement in her level of pain and functioning.

    Table 1. Time of Antiviral Titer Testing Relative to Start of Antiviral Treatment
      Cytomegalovirus Epstein-Barr Varicella zoster Herpes simplex 1 Herpes simplex II
      IgM* IgG* IgM* IgG* IgM* IgG* IgM* IgG* IgM* IgG*
    Case 1
      prior to treatment N/A N/A N/A N/A normal 2.49 normal normal normal normal
    Case 2
      prior to treatment normal normal normal 1.32 normal 8.4 normal 35.2 normal normal
       at 8 mos. normal normal 1.34 9.43 normal 7.8 normal 16.4 normal normal
       at 12 mos normal normal 0.39 6.55 normal 6.4 normal 14.4 normal normal
    Case 3
      prior to treatment normal normal normal normal normal 9.6 normal normal normal normal
       at 14 mos. N/A N/A N/A N/A normal 6.4 N/A N/A normal normal
    N/A – test not done
    *Normal < 0.9
    HSV II was measured at the outset and was less than 0.9 in all three patients

    Case 3

    A 10 year-old male was referred for evaluation of diffuse musculoskeletal pain of two years duration involving the shoulders, back and hips. The patient had undergone extensive evaluation by a pediatric neurologist—including ruling out infectious, nutritional, metabolic and endocrine perpetuating factors for myofascial pain—but no underlying cause for his severe chronic disabling pain syndrome was determined. A bone scan done when the pain initially presented showed increased uptake in the left hip and pelvic area. Follow-up MRI scan of the hip and pelvis was consistent with eosinophilic granuloma. Needle and open biopsies of the area failed to retrieve a specimen consistent with that diagnosis, and a repeat bone scan performed 21 months after the initial bone scan was negative. A diagnosis of fibromyalgia syndrome was made and he was started on medication (amitriptyline 25mg at night) for sleep disturbance by his pediatric neurologist. This medication was not helpful.

    Two years following onset of pain, initial physiatry evaluation showed:

     

    Initially, the diagnosis of herpetic reactivation was not considered. Physiatrist pursued symptomatic treatment of presumed myofascial pain syndrome of undetermined etiology.

    Approximately one month after initial physiatry examination, the patient developed nausea, low-grade fever, and left chest wall pain. Chest x-ray, thyroid study, CBC and chemistry profile were all normal. Over the next several months, he developed progressive hip pain (worse at night and worse on the right side). He was treated symptomatically with Zanaflex (4mg at bedtime) for muscle spasm and pain, Neurontin (300mg 2 times per day and at bedtime) for pain, and Vistaril (25mg at bedtime) for sleep. In spite of these medications, his pain gradually worsened. Although range of motion in the lumbar spine and hips remained normal, his pain significantly increased when walking and standing. He became wheelchair bound for long distances and unable to attend school.

    Approximately four months after initial evaluation, IgG titers for herpetic viruses were obtained (See Table 1). Only the varicella titer was significantly elevated. As the only finding following an exhaustive medical work up, the titer result prompted the diagnosis of probable varicella reactivation. The patient was started on acyclovir (400mg 5 times per day). He was also continued on his other pain and sleep medications. After five weeks of antiviral medication, the patient no longer required the use of the wheelchair for mobility. After 12 weeks of treatment with anti-viral therapy, he was able to return to school.

    He ran out of acyclovir and stopped taking the medication for approximately three weeks. He developed an acute relapse of his pain including hyperesthesia in the skin over the thighs and hips. He again required a wheelchair for mobility.

    He was restarted on acyclovir (400mg 5 times per day), and referred to an outpatient physical therapy and pool therapy program. After approximately six weeks of outpatient physical therapy and continued anti-viral medication, he was able to resume normal activities for his age. A second set of IgG and IgM serum convalescent viral antibody titers for varicella-zoster were drawn fourteen months after the initial set of antibody titers (See Table 1). IgG varicella-zoster serum viral antibody titer had decreased but was still elevated.

    During a four year follow up, the patient continued to require acyclovir in order to maintain independence in mobility and activities of daily living typical for his age, and to suppress severe neuropathic pain. Whenever the antiviral medication was decreased or stopped, he consistently developed a relapse of his severe pain.

    Discussion

    All three pediatric patients presented with severely disabling, medically unexplained chronic pain. After long-term anti-viral therapy, all three patients experienced decreased pain, regained normal ambulation, and resumed normal functioning in activities of daily living. Cases 1 and 2 presented with rashes and Case 3 presented without rashes. The classic skin vesicles associated with shingles were not present and the rashes did not follow the classic radicular pattern of herpes zoster outbreak. Painful vesicles were noted in the oropharynx of one patient and erythema was noted in the oropharynx of the other two patients. The findings suggest herpetic reactivation may be a contributing etiologic factor in the chronic pain experienced by these three children.

    IgG convalescent serum viral antibody titers were significantly elevated for at least one of the herpetic viruses in all three cases. Two patients had elevated titers to varicella only; the third had elevated titers to both varicella and HSVI. All three patients responded well to antiviral medications. The only known efficacy of these medications is against herpetic viruses.

    It is known that cutaneous eruptions or rashes caused by herpes simplex one and two and herpes varicella zoster are not always vesicular in presentation and often look like other common dermatoses.4,9 Case reports describe pain from reactivated varicella (herpes) zoster viral infections with or without rashes (“sine herpetica”).5-8 Reports also note chronic herpetic reactivation with burning pain and itching but without a rash (herpes “sine herpete”).3 Some reports have found long-term use of antiviral medication effective in reduction of symptoms and improvement in daily functioning, but no large scale trials have been done.6-8

    Summary

    Three pediatric cases of medically unexplained, severely disabling chronic pain were referred after having had thorough, negative medical workups. All three were successfully treated with a long-term moderate dose of oral antiviral medication (acyclovir/valacyclovir) known to be effective only against herpetic viruses. Elevated IgG titers to herpes virus were seen in all three children and these titers declined with antiviral therapy. All three children had a significant improvement in pain/ function in response to long-term antiviral medication.

    There were many confounding issues in these cases, including a lack of consistency in types of workups performed on these children. However, the common pattern that was emerging among these cases presented a new potential etiology for the treating physician to consider. The physician cautiously instituted antiviral therapy with the first patient. After the first patient’s positive response to antiviral therapy, he began to treat more aggressively. Therefore, the latter cases received higher dosages of antiviral medication. In addition, one patient had very high titers to EBV and another patient had a flu-like prodrome at the onset of her chronic pain syndrome. This raises the possibility of other viruses, in addition to herpes, contributing to the chronic pain syndrome.

    A thorough, prospective, double blinded study, with IgG levels drawn before, during and after treatment would be the logical next step in exploration of atypical herpetic reactivation as a possible contributing etiology for some cases of unexplained chronic pain.

    Acknowledgement

    This material is the result of work supported with resources and the use of facilities at the W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina.

    • negative cervical spine xrays
    • negative ANA
    • mildly elevated antibody titers to CMV (2.36)
    • mildly elevated Epstein-Barr titers (dilution of 1:40)
      • palpable anterior cervical lymph nodes,
      • erythema and vesicles in the oropharynx,
      • • mild, subtle, papular erythematous rash over the left buttock and thigh.
      • diffuse muscle soreness and tenderness of neck, back, chest wall, and upper and lower extremities
      • subtle popular-type rash was noted over the proximal arms
      • erythema and some mild exudates of the oropharynx
      • • anterior cervical lymphadenopathy bilaterally
      • diffuse muscle soreness and tenderness of neck, back, chest wall, and upper and lower extremities;
      • normal neurological exam with respect to reflexes, motor strength, and balance;
      • diffuse tightness and tenderness with occasional foci of muscle contraction in the muscles of the neck, shoulders, low back, and hips;
      • mild increased erythema in oropharynx, without evidence of vesicles or exudates;
      • mild hypertrophy of the tonsils;
      • a few enlarged cervical lymph nodes.
    Last updated on: January 5, 2012
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