When Is the Clinical Nadir for Guillain-Barré Syndrome?

Patient Presentation
A 6-year-old female came to clinic with a 3 day history of abnormal gait. Her mother said she seemed to be walking funny and was having more problems going up stairs.
She said she felt a little unbalanced but denied any vertigo. She also denied any pain, fever, chills, nausea, emesis, diarrhea, cough, rhinorrhea, rashes, vision changes or breathing problems. The mother said she was able to do other things but seemed a little more tired. The past medical history showed she was treated as an outpatient for community acquired pneumonia 1 month previously. She was otherwise well and was completely immunized. The family history showed no neurological diseases but there was thyroid disease and diabetes on both sides of the family. The review of systems was otherwise normal. There was no travel history and no known tick bites.

The pertinent physical exam showed a well-appearing child. Her vital signs were normal without tachycardia, blood pressure changes or fever. Her growth parameters were normal. Heart and lungs were normal. Her neurological examination showed normal mentation. Cranial nerves III-XII were normal. She had normal strength and deep tendon reflexes in her upper extremities. In her lower extremities she was able to lift her legs against gravity but not against pressure. Ankle reflexes could not be obtained and knee reflexes were decreased bilaterally. She said her legs felt a little funny but there was no discernable level where she had changed sensation in her legs. She was able to sit without support. She had a slightly halting gait and a positive Gower sign. No skin changes were noted. She had good peripheral pulses. The laboratory evaluation in the clinic showed a normal respiratory peak flow.

The diagnosis of an acute onset of lower extremity weakness and areflexia was made. Guillian-Barré syndrome was considered the most likely cause as the patient was afebrile and had recent community acquired pneumonia. After discussion with a pediatric neurologist, the patient was transferred to a regional children’s hospital where her clinical course showed she underwent several tests including neuroimaging which showed no spinal cord anomalies and a lumbar puncture that had increased protein and 8 lymphocytes. The patient had ascending paralysis of the lower extremities over the next 2 days up to her hips and was treated with intravenous gamma globulin. The patient improved slowly and was monitored closely and never had any respiratory compromise. She was discharged on day 10 to a local relative’s home and she was monitored daily for the next few days. Her symptoms continued to improve and by 6 weeks the family denied any problems and her examination was normal.

Discussion
Guillian-Barré syndrome (GBS) is an acquired, acute, inflammatory, demyelinating polyneuropathy. It is the most common cause of acute and subacute flaccid paralysis in children.
GBS causes about 0.4-1.3 cases per 100,000 persons/year in children. It can occur in any age group and the incidence increases among all age groups until a peak in the 50s. Both genders are affected and there may be a slight increase in males.

GBS usually occurs 2-4 weeks after a prodromonal gastroenteritis or respiratory illness. It is most often associated with Campylobacter jejunae, Haemophilus infuenza, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus. There are some possible associations with GBS and influenza A vaccination but it has not been associated with other vaccines. GBS causes autoantibody production against Schwann cells of the neuron and the axon itself. There is an increase in anti-ganglioside antibodies which can be specifically identified in about 50% of children. Surgery may also trigger antibody production.

Classically GBS is a symmetric, progressive ascending muscle weakness and/or paralysis usually first occurring in the legs and then ascending to the upper extremities usually over days to weeks. Areflexia or diminished deep tendon reflexes are early signs (usually first week) if the patient comes to attention. Reflexes can be preserved in some patients though. Sensory changes including pain or paraesthesia can be a first sign in up to 50% of children. The pain can be poorly localized or vocalized because of the children’s age and development. Patients can appear to be ataxic but with further examination this is due to muscle weakness and sensory changes, not actual ataxia. Patients are afebrile.

There are a number of variations of GBS. The classic form is acute inflammatory demyelinating polyneuropathy (ADIP) and ADIP is about 75% of cases especially in the US and Europe. Acute motor axonal neuropathy (AMAN) is similar but has no sensory defects and has more fulminant motor defects. Miller-Fisher syndrome is another variant that has ataxia, ophthalmoplegia and areflexia without peripheral weakness. The other variations have different sensory deficit profiles.

The differential diagnosis of paralysis is large, but important ones for GBS as they are treatable include botulism (which is a descending paralysis), acute spinal cord problems such as cord compression or transverse myelitis (usually has a spinal cord level on examination), and tick paralysis (which improves after the tick is removed). Diagnosis is clinical but elevated cerebrospinal fluid protein without an elevated cell count, usually < 10 cells/mm3 and all or most are lymphocytes, is the most common profile.

Treatment is supportive. The nutrition, respiratory support, rehabilitation and psychosocial needs of the patient need to be met. Patients are usually monitored in the hospital especially for the risk of respiratory failure. Immunoglobulin (IVIG) is felt to bind the autoantibiodies and downregulate antibody production. IVIG helps to improve ambulation and decrease hospital stays. Dosing is usually a total dose of 2 g/kg that is divided over 2-5 days. Plasmapheresis decreases the levels of autoantibodies that are circulating and may also decrease cytokines. It can be performed in patients > 10 kg but obviously has additional problems of being more invasive than IVIG. Both IVIG and plasmapheresis have not shown differences in long term outcomes.

Learning Point
The clinical nadir when symptoms are the worst is usually around 2 weeks after symptoms begin and most patients begin improving after that. Most have signficant improvement by 4 months and most have full recovery. Patients with classic AIDP or AMAN usually recover more quickly than other variations. Some still have problems including fatigue and sensory issues long term. It is uncommon but GBS can occur more than once.

Questions for Further Discussion
1. What are indications for referral to a neurologist?
2. What are potential radiologic imaging studies which may help with the diagnosis for GBS?
3. What causes ataxia? Click here for a differential diagnosis.
4. What causes muscle weakness with and without hypotonia Click here for a differential diagnosis.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Guillian-Barre Syndrome

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Rosen BA. Guillain-Barre syndrome. Pediatr Rev. 2012 Apr;33(4):164-70.

Ryan MM. Pediatric Guillain-Barre syndrome. Curr Opin Pediatr. 2013 Dec;25(6):689-93.

Roodbol J, de Wit MC, Aarsen FK, Catsman-Berrevoets CE, Jacobs BC. Long-term outcome of Guillain-Barre syndrome in children. J Peripher Nerv Syst. 2014 Jun;19(2):121-6.

Sudulagunta SR, et. al.. Guillain-Barre syndrome: clinical profile and management. Ger Med Sci. 2015 Sep 21;13:Doc16..

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Are the Complications and Treatment for Lymphedema?

Patient Presentation
A 10-year-old female came to clinic for her health maintenance examination. She was a survivor of childhood leukemia and it was 3 years after her last chemotherapy. She was followed by her oncologist and did not have any obvious side effects of her treatment other than some mild lymphedema. It had begun about 15 months after a lymph node biopsy in her left inguinal area and was relatively mild. She was using a compression garment most days and was followed by the pediatric surgeons. She was current on all of her immunizations. The review of systems was negative.

The pertinent physical exam showed a healthy female with normal vital signs and growth parameters were 50-75%. She had no obvious lymphadenopathy, masses or hepatosplenomegaly. She had well-healed scars in her upper right chest from a port placement, and a scar in her left inguinal area. Her left foot and calf were mildly enlarged compared to her right (3 cm difference in calf size) with a symmetric outline of the anatomical structures. There was no pitting edema and pulses were strong and symmetric. The rest of her examination was normal.

The diagnosis of a healthy girl who was a cancer survivor with mild lymphedema was made. The pediatrician reiterated that it was important to continue to use the compression garments all or most of the time to help with the lymphedema. He also reminded the girl to make sure she wore shoes to protect her feet.

Discussion
Lymphedema occurs because of abnormal development or damage to the lymphatic structures. It is a chronic often progressive swelling of tissues starting distally and advancing more proximally. Extremities are the most common sites followed by genitalia. Fluid accumulation in the interstitial, superficial spaces causes adipose deposition and fibrosis. This causes the lymphedematous tissue to then enlarge. Edema is pitting early on and later is non-pitting.

Causes of lymphedema can be primary (~1%) or secondary (~99%). Primary lymphedema has been associated with several genetic mutations. Milroy disease is a primary lower extremity lymphedema that occurs in infants with a positive family history or who have a positive mutation for VEGFR3. Familial lymphedema with onset in the adolescent age group is called Meige disease and its mutation is not known at this time.

Secondary lymphedema is most common after trauma (e.g. penetrating trauma, lymph node excision, radiation) or infectious disease (especially the round worms of Filarioidea family).

The term “lymphedema” is often generically used for causes of extremity overgrowth or misdiagnosed for other vascular anomalies. For a review of overgrowth syndromes click here. A review of lymphatic malformations can also be found here.

In addition to history and physical examination, genetic studies can be done and lymphoscintigraphy is considered the standard for lymphatic function evaluation.

Learning Point
Complications of lymphedema include an increased risk of infections, skin changes (often thickening) and potentially but rarely malignancy. Patients with lymphedema do not have skin ulceration but do have an increased risk of skin infections often with Streptococcus species.

Lymphedema can’t be cured but can be treated. Treatment is conservative if at all possible. The affected area should have good skin hygiene of washing/drying and moisturizing to help prevent infections. Protective clothing is also helpful, especially wearing long pants/sleeves and foot wear or gloves. Compression garments (usually custom made) are a main treatment modality and can help to reduce the extremity volume and help to slow the disease progression. Patients need enough garments so they can be laundered regularly and they need to be replaced when worn (usually every 6 months). Other compression treatments can be offered including using pneumatic pumps. Regular exercise to maintain conditioning and normal body mass also helps treatment. Muscle contraction is the primary way that lymph fluid is transported centrally to the body. Elevation of the extremity when non weight bearing and when convenient to the patient can also help. Specific massage techniques from a trained professional can also provide some relief but can be time consuming and expensive.

Surgical treatments are used when the lymphedema is causing significant morbidity. They include lipectomy to remove adipose tissue and skin/subcutaneous resections. Microsurgical techniques can also be used to help reconstruct or reconnect lymphatic drainage.

Questions for Further Discussion
1. How is lymphedema different than generalized edema?
2. What are complications of cancer treatment that survivors need to be monitored for?
3. What are indications for surgical consultations?

Related Cases

    Symptom/Presentation: Edema

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Lymphedema

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Schook CC, Mulliken JB, Fishman SJ, Alomari AI, Grant FD, Greene AK. Differential diagnosis of lower extremity enlargement in pediatric patients referred with a diagnosis of lymphedema. Plast Reconstr Surg. 2011 Apr;127(4):1571-81.

Blatt J, Powell CM, Burkhart CN, Stavas J, Aylsworth AS. Genetics of hemangiomas, vascular malformations, and primary lymphedema. J Pediatr Hematol Oncol. 2014 Nov;36(8):587-93.

Maclellan RA, Greene AK. Lymphedema. Semin Pediatr Surg. 2014 Aug;23(4):191-7.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Look What I Got On Summer Vacation – Giardia!

Patient Presentation
A 6-year-old male came to clinic with 5 days of diarrhea. They were loose watery stools occurring several times a day without blood or mucous. He denied abdominal pain or emesis but said sometimes he felt a little nauseous. He had recently been on vacation in the northern United States to visit his grandparents who lived on a farm with various animals and crops. He also had been swimming in 2 different lakes and had been to a family reunion potlock dinner during the past 2 weeks. He was drinking well and was urinating normally. The family wasn’t sure but maybe a cousin also had diarrhea. He had no recent antibiotic exposure. He was previously healthy and his review of systems revealed he had no fever, chills, or muscle aches.

The pertinent physical exam showed a well-appearing male in no distress. His vital signs were normal and his growth parameters were 25-50% for age. His mucous membranes were moist and he had good skin turgor. His abdominal examination showed slightly hyperactive bowel sounds. He had no abdominal tenderness, hepatosplenomegaly or masses. Genitourinary examination was normal as was his anus.

The diagnosis of diarrhea with significant exposure to potential infectious disease pathogens was made. As the patient was well hydrated, the family was counseled about prolonged diarrhea and recommendations for fluid intake and diet. A laboratory evaluation of stool studies for common bacterial pathogens along with stool for ova and parasites, Giardia and Clostridium difficile was made. The stool was positive for giardia and he was treated with Flagyl®. The diarrhea improved and repeated cultures were negative. The cousin had diarrhea but his resolved and he was not tested.

Discussion
People often don’t think that developed countries have parasitic diseases but this is not true. The major parasitic infections endemic in the United States can be thought of as:

  • Intestinal parasitic infections
    • Seen throughout the US but especially in the northern states during the summer
    • Often occur through recreational water use
    • Cryptosprodiosis, Dientamoebiasis and Giardiasis are the most common.
  • Neglected tropical diseases
    • Seen especially in the southern states (especially Texas) and are linked to extreme poverty
    • Chagas disease, Cutaneous Leishmaniasis, Toxocariasis, and Toxoplasmosis are the most common.

Learning Point
Giardia intestinalis (also known as Giardia lambia or Giardia duodenalis) is considered a zoonotic disease sometimes known as Beaver Fever. It was one of the first organisms Antonie van Leewenhoek saw under the microscope. It is a flagllated protozoan found globally that usually affects the cells in the duodenum and jejunum. It is most commonly found in children ages 1-9 years old. The number of cases is slightly decreasing in last few years in the U.S. with about 16-19,000 cases depending on the year. Cases cluster often in the northern states in the summer. Contaminated water and fecal-oral contamination of the cysts spread the disease. The cysts are difficult to kill as they are chlorine tolerant. Cysts can be killed by boiling water for more than 1 minute, or using a filter with an absolute pore size of 1 micron or smaller to remove the cysts. Incubation is 9-15 days.

The disease can be asymptomatic, have mild to severe diarrhea. Other symptoms can include anorexia, bloating, abdominal pain and cramping and explosive diarrhea. Unfortunately about 50% of patients may not clear the organisms and have chronic disease which may include anorexia, malabsorption, diarrhea and weight loss which can last years. Giardia should be considered when diarrhea lasts more than 3 days in the appropriate setting. Routine ova and parasite tests may not test for Giardia so specific testing should be ordered. Testing is by direct fluorescent antibody testing of the stool. Giardia is not continually shed and therefore 3 negative stool tests from different days are considered the standard for a negative test. Treatment is usually with nitroimidazole compounds such as metronidazole (Flagyl®), ornidazole, secnidazole or tinidazole. Other treatments are available to try if there is initial treatment failure.

Questions for Further Discussion
1. For what indications do you consider testing for stool pathogens?
2. When do you consider testing for Clostridium difficile?
3. What is in the differential diagnosis of diarrhea? Click here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Giardia Infections and Parasitic Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Muhsen K, Levine MM. A systematic review and meta-analysis of the association between Giardia lamblia and endemic pediatric diarrhea in developing countries. Clin Infect Dis. 2012 Dec;55 Suppl 4:S271-93.

Barry MA, Weatherhead JE, Hotez PJ, Woc-Colburn L. Childhood parasitic infections endemic to the United States. Pediatr Clin North Am. 2013 Apr;60(2):471-85.

Painter JE, Gargano JW, Collier SA, Yoder JS; Centers for Disease Control and Prevention. Giardiasis surveillance — United States, 2011-2012. MMWR Suppl. 2015 May 1;64(3):15-25.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital