What Are Some Risk Factors for Cerebral Palsy?

Patient Presentation
A 5-year-old male came to clinic with increased spasticity for 2 days. He had underlying cerebral palsy and was wheelchair bound and non-verbal. His mother stated that he had not been crying or tearing but had increased spasticity and couldn’t seem to get comfortable. He had some rhinorrhea, but no cough, fever or rash. He had normal urination and had not had any hard stools using her normal bowel regimen. His mother said that when she bathed him she didn’t see any skin lesions or break down. His seizure pattern was also unchanged.

The past medical history showed he was a former 32-week premature infant who had a complicated neonatal intensive care stay. He was followed by multiple specialties including neurology, developmental disabilities, gastroenterology, and orthopaedics and he received comprehensive therapy services at school and in the community. The review of systems was not contributory.

The pertinent physical exam showed him posturing more than normal during the visit but there were times when he relaxed. His vital signs were normal, but a new weight was not obtained. His oxygen saturation was 97% on room air. HEENT showed clear rhinorrhea and a reddened pharynx without exudate but with palatal and peritonsilar vesicles. His ears were normal. Lungs, heart and abdomen were normal. His palms and soles had several 2-3 mm vesicles. There were no other lesions noted. His neurological examination showed increased spasticity in all extremities, but again he could relax at times. He was non-verbal but possibly reacted more during his HEENT examination.

The diagnosis of hand, foot and mouth disease was made. “It looks like he is having hand, foot and mouth infection. For some kids they don’t have many symptoms and for others they can have a lot. Maybe his mouth is bothering him more than we realize or he just plain doesn’t feel good. Why don’t we try to give him some ibuprofen on a schedule and see what happens. He doesn’t seem to be a lot more affected like he’s not having more seizures or doesn’t seem to have a second infection like an ear infection,” the pediatrician discussed. “Okay. He’s had an orthopaedic appointment to watch his hips and a wheel-chair fitting appointment in 2 days, so I could come back then if he’s not getting better,” the mother replied.

The term, cerebral palsy, or CP has gone through many iterations with the first description in 1861 by W.J. Little who described it as “The condition of spastic rigidity of the limbs of newborn children.” The most recent definition is from Rosenbaun et al. in 2007 which states it is “a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behaviour, by epilepsy, and by secondary musculoskeletal problems.”

The incidence is about 2-3/1000 live births in high income countries but higher in low income countries. CP can be a severe motor problem for children and adults with up to 40% of patients unable to walk independently.

CP is really a clinical diagnosis with help from neuroimaging. It basically includes using history, some standardized physical examination ratings (i.e. Prechtl General Movement Assessment and Hammersmith Infant Neurological Examination), and cranial ultrasound or MRI which may show findings consistent with the history and physical examination such as intraventricular hemorrhage, cerebral or cerebellar hemorrhage, posthemorrhagic ventricular dilatation, or cystic periventricular leukomalacia. Diagnosis can be made within the first 6 months but this is usually in infants who have more problems. Patients are usually diagnosed after a year when the clinical trajectory of the patient and their individual problems are more consistent. This does not mean that a patient and family should wait for a diagnosis of CP to receive developmental surveillance and treatment if there are risk factors or concerns about the patient.

Any motoric area can be affected and subtypes are named for the area affected and how it is affected. For example, with predominantly the lower limbs (diplegia), the arm and leg on one side (hemiplegia) or all of the body (quadriplegia), and/or spasticity, dystonia (the two most common movement disorders with CP) and or dyskinesia.

The patient’s abnormal movements vary by the patient and the age. Patients with CP have a wide variety of comorbid problems, with the percentages given from high-income countries.

  • Chronic pain – 75%
  • Intellectual disability – 49%
  • Unable to walk independently – 40%
  • Epilepsy – 35%
  • Hip subluxation – 28%
  • Bladder control problems – 24%
  • Non-verbal – 23%
  • Sleep problems, pathological – 23%
  • Sialorrhea – 22%
  • Blind, functionally – 11%
  • Feeding tube requirement – 6%
  • Hearing impairment, severe 4%

Treatment includes managing the overall patient’s health, preventive services, specific services for their problems and early intervention services. Early intervention services are multidisciplinary services that focus on assisting the patient in all developmental areas including potentially physical therapy, occupational therapy, speech therapy, social interactions and cognitive interactions. Data more strongly supports benefits in cognition but less so for motor development. Other needs may include:

  • Spasticity and dystonia – physical therapy, occupational therapy, splinting, medications (i.e. Baclofen, Botulinum toxin A, Clonidine, Diazepam, Gabapentin), or neurosurgical interventions (i.e. selective dorsal rhizotomy, deep brain stimulation)
  • Hip dysplacement is common and needs ongoing screening particularly if the child is less mobile or immobile
  • Feeding and nutrition – difficulty swallowing, aspiration and drooling can be major problems for patients
  • Pain – this is common because of constipation, hip dislocation, spasticity and dystonia
  • Sleep disturbance – often because of other problems listed above, and may require behavioral interventions and medication

Learning Point
CP’s cause is not entirely known but appears to be multifactorial especially with accumulations of potential insults. Gestational age is a strong factor. Unfortunately for many of the risk factors, there are no easy or obvious treatments or preventive practices for them.

Rick factors for CP include:

  • Pregnancy
    • Genetics – higher risk in siblings particularly twins
    • Fetal growth restriction
    • Infections
    • Maternal obesity
    • Multiple births
    • Preeclapsia
    • Prolonged labor
    • Socioeconomic status, lower
  • Perinatal
    • Prematurity – 14.6% in gestation age 22-27 weeks, 6.2% in 28-31 weeks, 0.7% in 32-36 weeks, 0.11% in term infants
    • Post-maturity
    • Low birth weight
    • Small for gestational age
    • Birth defects
    • Birth complications – fetal bradycardia, low Apgar score, delayed time to first breath, breech position are some risk factors
    • Chorioamnionitis
    • Infection/inflammation
    • Kernicterus
    • Seizures
    • Stroke, perinatal
    • Abnormal neuroimaging findings
    • Post natal corticosteroid use
    • Early surgery
    • Mechanical ventilation
  • Protective factors for CP include:
    • Magnesium sulfate treatment for mother during pregnancy
    • Caffeine therapy for the infant
    • Brain or body cooling for the infant

    Questions for Further Discussion
    1. What are indications for referral to a developmental disabilities specialist?
    2. What does non-verbal mean? A review can be found here
    3. What is the classification for intraventricular hemorrhage? A review can be found 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 and the Cochrane Database of Systematic Reviews.

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

    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.

    Little W.J. Transaction of the Obstretrical Society of London. Longmans, Green and Co. 1862: 293-344.

    Spittle AJ, Morgan C, Olsen JE, Novak I, Cheong JLY. Early Diagnosis and Treatment of Cerebral Palsy in Children with a History of Preterm Birth. Clin Perinatol. 2018;45(3):409-420. doi:10.1016/j.clp.2018.05.011

    Graham D, Paget SP, Wimalasundera N. Current thinking in the health care management of children with cerebral palsy. Med J Aust. 2019;210(3):129-135. doi:10.5694/mja2.12106

    Korzeniewski SJ, Slaughter J, Lenski M, Haak P, Paneth N. The complex aetiology of cerebral palsy. Nat Rev Neurol. 2018;14(9):528-543. doi:10.1038/s41582-018-0043-6

    Lins LAB, Watkins CJ, Shore BJ. Natural History of Spastic Hip Disease. J Pediatr Orthop. 2019;39(Issue 6, Supplement 1 Suppl 1):S33-S37. doi:10.1097/BPO.0000000000001347

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa

  • What Causes Neutropenia?

    Patient Presentation
    A 4-month-old female came to the emergency room with fever, poor feeding, fussiness and strong smelling urine. She had not been feeding well for 36 hours, with a decreasing number of diapers and increasing foul-smelling urine. The fever began about 18 hours previously and had ranged from 99.8°F to 102.3°F. Acetaminophen helped but the fever returned. She was crying more, and could be consoled but she appeared overall ill. She had 2 episodes of emesis just before coming to the emergency room but no diarrhea. Her parents denied any cough, rhinorrhea, or rashes other than her eczema.

    The past medical history showed a term-infant born without complications who had received appropriate preventative care including vaccinations. She had been diagnosed with atopic dermatitis 2 week previously. The family history was positive for heart disease and diarrhea. They denied any kidney disease or immune problems. The review of systems was otherwise negative.

    The pertinent physical exam revealed a tired and fussy infant who would calm with some effort. Her vital signs had a fever of 102.6° with tachycardia to 114 beats/min, respiratory rate of 26/min and an oxygen saturation of 100%. Her weight was down 250 grams from her visit 2 weeks ago, which was at the 50%. Her capillary refill was 2-3 seconds, with slightly dry mucous membranes. Her fontanelle was normal. Her skin showed dry reddened areas in the flexural areas and behind her ears, and general xerosis of her trunk and cheeks. Her examination was otherwise well. Her diaper smelled foul.

    The laboratory evaluation showed a catheterized urinalysis of 1.025 specific gravity, many white blood cells, some red blood cells with positive nitrites and leukocyte esterase. Her complete blood count showed a hemoglobin of 10.6 x 1000/mm2, white blood cell count of 5.2 x 1000/mm2 with only 1350 neutrophils. Her platelets were 360 x 1000/mm2. The rest of her complete blood count was normal as a complete metabolic profile. Her C-reactive protein was elevated at 2.7 mg/dl.

    The diagnosis of a urinary tract infection and potential bacteremia was made. She was admitted for intravenous fluids, antibiotics and monitoring. The patient’s clinical course showed that she improved with treatment and was discharged at 48 hours. The blood culture was negative. Her urine culture grew Escherichia coli that was pansensitive to antibiotics and she was sent home on oral antibiotics. An ultrasound of her kidneys was normal before discharge. Her complete blood count still showed mild neutropenia at 1475 at discharge. Her C-reactive protein had decreased to 1.8 mg/dl. At her one week followup appointment her neutropenia and complete blood count were normal. At her one year well-child examination, her complete blood count was normal and she had not had any other urinary tract infections.

    Neuropenia is defined as a neutrophil count < 1500/µL. It is classified as mild from 1000-1500/µL, moderate from 500-1000/µL, and severe if < 500/µL.

    It is not uncommonly seen in the setting of acute self-limited infections, and with re-testing returns to normal. It is also not uncommon at certain ages, such as perinatally, especially in premature infants (up to 6%) . It is also common in certain ethnic groups particularly African American or Arabic populations where up to 10% of the children may have mild neutropenia which does not cause clinical disease. The overall prevalence and incidence are not known but some studies estimate it at 2 per million persons.

    Neutropenia can be thought of as an acute problem due to rapid neutrophil use or destruction, or decreased production of neutrophils. Chronic neutropenia is due to decreased production or splenic sequestration.

    Neutropenia can also be thought of as a primary or intrinsic problem due to primary myeloid cell production or an intrinsic defects. Secondary or acquired causes of neutropenia are usually due to infections, immune response, bone marrow infiltration or drugs.

    Clinical signs or symptoms of potential neutropenia include fever, oral ulcers, upper airway infections (e.g. otitis media, pharyngitis, sinusitis), respiratory (e.g. pneumonias) or perianal infections. Skin infections like cellulitis, paronychia, or furunculosis may also indicate neutropenia. Bacteremia or sepsis are also potential clinical indications. Recurrent or complicated infections or infections with unusual organisms may indicate neutropenia. Other systems can also be affected.

    Treatment depends on the underlying cause with antibiotics, general support, discontinuation of potential iatrogenic causes, and granulocyte stimulating medications if appropriate.

    Learning Point
    The differential diagnosis of neutropenia includes:

    • Age or ethnic-related
      • Premature infant
      • Newborn infant
      • African American or Arabic ethnicity
    • Infection
    • Congenital or hereditary neutropenia
      • ELANE mutations
        • Cyclic neutropenia – generally 21 day cycles between normal and abnormal neutrophil counts
        • Severe congenital neutropenia
      • Non-syndromic
        • Autosomal dominant severe congenital neutropenia
          • Kostman syndrome
        • Autosomal recessive severe congential neutropenia
          • Wiskott Aldrich syndrome
        • X-linked neutropenia
      • Other syndromic
        • G6PC3 deficiency
        • Barth syndrome
        • Cohen syndrome
      • Bone marrow insufficiency
        • Dyskeratosis congenital
        • GATA2 deficiency
        • Fanconi anemia
      • Combined immunodeficiency
        • XHIGMS
        • WHIM syndrome
        • Reticular dysgenesis
      • Metabolic disease
        • Glycogen storage disease 1b
        • Isovaleric acidemia
        • Methylmalonic acidemia
        • Propionic acidemia
      • Oculocutaneous hypopigmentation
        • Chediak-Higashi syndrome
        • Griscell syndrome type 2
        • Hermansky Pudlak syndrome type 2
        • p14 deficiency
      • Pancreatic insufficiency
        • Schwachman-Diamond syndrome
        • Pearson marrow syndrome
    • Drug related
      • Antibiotics
      • Alcohol
      • Chemotherapy
    • Immune mediated
      • Neonatal alloimmune – transplacental transfer of maternal antibodies to paternal antigen
      • Neonatal isoimmune neutropenia – transplacental transfer of existing maternal IgG antibodies
      • Autoimmune – probably triggered by viral infections or environmental antigens
      • AIDS
    • Myelodysplasia
      • Bone marrow infiltration or replacement
        • Leukemias
        • Dysgammaglobulinemia
    • Other
      • Folate or Vitamin B12 deficiency
      • Hypersplenism or splenic sequestration

    Questions for Further Discussion
    1. What are common presentations for primary immunodeficiencies? A review can be found here

    2. What are different fever patterns and what are their potential problems? A review can be found here

    3. What is in the differential diagnosis of lymphocytosis? A review can be found here
    4. What are potential complications of acute pyelonephritis? A review can be found here
    5. How do you treat fever and neutropenia due to chemotherapy?

    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 and the Cochrane Database of Systematic Reviews.

    Information prescriptions for patients can be found at MedlinePlus for these topics: Urinary Tract Infections, Blood Disorders and Immune System and Disorders.

    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.

    Neutropenia – Hematology and Oncology. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/hematology-and-oncology/leukopenias/neutropenia?query=neutropenia. Accessed December 3, 2019.

    Dale DC. How I manage children with neutropenia. Br J Haematol. 2017;178(3):351-363. doi:10.1111/bjh.14677

    Kebudi R, Kizilocak H. Febrile Neutropenia in Children with Cancer: Approach to Diagnosis and Treatment. Curr Pediatr Rev. 2018;14:204-209.

    Spoor J, Farajifard H, Rezaei N. Congenital neutropenia and primary immunodeficiency diseases. Crit Rev Oncol Hematol. 2019;133:149-162. doi:10.1016/j.critrevonc.2018.10.003

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa

    What Safety Guidance Should Farm Families Be Aware Of?

    Patient Presentation
    A 6-year-old male and a 9-year-old male came to clinic with their mother for their health supervision visits. The boys both had attention deficit disorder (with hyperactivity and inattention) and were using stimulant medication without side effects. Their mother reported they were doing well in school. The 9-year-old reported that the medicine “helped my brain stay calmer.” The social history showed that the parents were a firefighter and a nurse who also ran a farm with animal stock and crops.

    The pertinent physical exam showed healthy boys with growth parameters in the 10-50% for the 6-year-old and 25-50% for the 9-year-old. Their examinations were normal.

    The diagnosis of healthy boys with attention deficit disorder was made.
    When discussing anticipatory guidance the pediatrician asked about safety rules they had for the farm. The mother asked the 6 year old, “When you’re outside, where can you play?” He said, “I have to stay on the grass, I can’t go in the road.” “And what if you are by the barns with Dad or Grandpa?” she went on. “I can’t go in the barns without them. If I am by the barns and something is moving then I have to put my hand on the barn, the fence or a tree,” he replied. The mother said that the grass was by the house and most of it was fenced off. The driveway separated the house from the barns and they had taught the children if they were in the barn area with adults and a car, tractor, or large animals were moving, then they had to go next to something big and sturdy like the barn itself or a tree. The 9-year-old said, “We can’t be in the barn by ourselves. I’m still too little to be by the steers, but this summer Dad says I can help him with the goats,” the 9-year-old said proudly. “I get to help with the baby goats, though” the 6-year old protested. “Yes but I get to do that AND be with the big goats,” he again said proudly. “We’re pretty strict about the rules. Grandpa wanted to let them drive the golf cart with him. I even vetoed that one. With their ADHD I’m not sure when I am going to let them drive anything with wheels,” the mother said.

    “The agriculture industry is consistently ranked as one of the most hazardous industries in the United States with some of the highest rates of work related injuries and deaths. Agriculture is a unique profession in that children who live on farms are exposed to, and in participate in, the family business of farming. Moreover, children who work on their family farm fall outside the regulation of governmental safety and labor practices….There is often little separation between work areas and play or living areas, thus children living on or visiting a farm may be in close proximity to safety hazards.

    The rates of agriculture-related injuries are decreasing. Children have overall fewer injuries but their injuries are more severe. A study of 0-19 year olds with agricultural-related injuries from 2001-2006 found an annual incidence of ~26,600 injuries. Of these 29% were work-related, 0.32% were fatal (n=84), with falls (35.2%), machinery (3.7%), transportation (14.4%), assaults and self-harm (11.7%), and fire and explosions (0.63%) being the most common causes of injuries. Of the fatalities, machinery (21.4%), fire and explosions (14.2%), transportation (10.7%) and drowning (9.5%) were the most common causes. Boys report more exposure to potential hazards and are injured more than girls.

    Farming is a heterogeneous industry and the activities vary widely. It is important to ask the family the type of farming they engage in when assessing the safety risk factors.

    Potential exposures on a farm include:

    • Tractors, machinery, cars/trucks, small vehicles (e.g. Gator® utility vehicles, all-terrain vehicles, motorcycles, golf carts, snowmobiles etc.).
    • Water hazards – ponds, drainage ditches, water tanks, etc.
    • Falls – buildings, machinery and equipment (e.g. hayloft, silos)
    • Chemicals, petroleum and pesticide product exposures
    • Animal exposures – large animals, domestic animals, wild animals, rodent/insect, etc.
    • Farm product exposure – grain dust, raw milk, product holding areas such as grain bins
    • Recreational activities – horse-back riding, hunting, shooting, archery, snowmobiling, rodeo, fishing, boating, camping
    • Temperature and weather related exposures

    Tractors injuries are the leading cause of trauma on the farm for all age groups. This includes operating or being a passenger on a tractor. Tractors and other farm machinery including lawn mowers are designed for adults. The throttles, gears, pedals, and steering wheels are designed for adults and may be beyond the reach of children and youth (anyone < 19 years old), and they often take more strength to operate properly than a child has. As children are not as tall, they can have a reduced field of view. Children and youth also have poorer executive function and lack experience. Impulse control may not occur until adulthood.

    Learning Point
    Methods to decrease all workplace injuries are the 3 E’s of industrial safety, which are engineering, education and enforcement.

    • Engineering design eliminates or reduces the potential hazard. For example, separation from the hazard such as fencing around the home to make a safe area for children to play in.
      Understanding ergonomic loads on children to determine if, and how, a child or youth can safely perform a specific farm task.

    • Education for both parents and children to understand risks and ways to mitigate them. Various methods can be used including school, organizations, community events and educational materials such as farm safety camps, safety certification programs, etc.
    • Enforcement by both parents and children again can help to mitigate problems. Parental and older sibling modeling of appropriate safety has been shown to decrease injuries.
    • Appropriate supervision is always necessary for children of any age. Supervision includes the adult’s attention (i.e. listening and watching), proximity (within reach or beyond) and supervision continuity over time (intermittent or continuous).

    Risks are increased, as would be expected, when parents are farming, or the child is exposed to equipment or animals. Tractor injuries as noted before carry the highest risk. This includes being the driver or a passenger on a tractor or piece of equipment.

    While many of the usual safety suggestions may seem logical, like any environment, they may be difficult to implement on a consistent basis. A permanent fence around a pond may be easier to implement than locking up every small tool in a workshop every time. Injuries will occur in any workplace or home and children must also be taught basic first aid and how to obtain help if needed. Basics such as good sleep hygiene and appropriate rest periods can have big effects on the decisions adults and children make for their own and others safety.

    Guidance for farm safety includes:

    • Engineering
      • Make sure children know what areas of the farm are unsafe
      • Keep children away from dangerous equipment and water hazards by fencing in play areas
      • Layout workspaces to encourage safety – chemicals and petroleum products locked up in a separate area, workshop with tools can be locked, etc.
      • Safety equipment should be readily available to encourage their use such as fire extinguishers, first aid kits, respirators, etc.
    • Education
      • Check equipment regularly to ensure safety features are working properly
      • Children should not play on equipment, even with adult supervision
      • Monitor changing weather conditions
      • Children < 16 years of age should not operate farm vehicles. Allow youths ages 16 to 18 years to operate farm vehicles on public roads only if they have a motor vehicle license and are graduates of a state-approved tractor and farm vehicle safety training program.
      • Never allow extra riders on tractors, mowers or ATVs, etc.
      • Seat belts should always be used on tractors or any other vehicle
      • Limit young children’s access to large animals
      • Teach children not to run or speak loudly around animals
      • Participate in farm safety events and certificate training programs (e.g. farm vehicle safety, hunter safety, boating safety, etc.)
      • Teach and practice a safety plan for common problems that do occur. For example, what to do when they are near a barn when a tractor drives into the area, or animal is startled, or they find a potentially dangerous tool, or need to get emergency help, etc.
    • Enforcement
      • Children should be adequately supervised at all times
      • Make sure children know how and use all safety equipment properly
        • Use basic safety equipment – seat belts, eye and ear protection, respirators, clothing, etc.
        • Specialized safety equipment should be used appropriately and with additional supervision
      • Children should be properly attired for the work
        • Appropriate clothing that provides comfort while working yet is protective such as closed toed shoes, long sleeve-shirts, pants, hats
        • Hair should be kept short or tied back
        • No loose clothing or hair
      • Encourage children to ask for help when they encounter problems

    Questions for Further Discussion
    1. What professional organizations offer farm safety education and training?
    2. What is the extension? Program information can be found here and a specific example in the State of Iowa can be found here
    3. What diseases are related to livestock exposure?
    4. When can a child mow a lawn? A review can be found 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 and the Cochrane Database of Systematic Reviews.

    Information prescriptions for patients can be found at MedlinePlus for this topic: Farm Health and Safety

    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.

    Rasch H. Down on the farm: Don’t let children fall victim to injuries. AAP News. 2012;33(8):25-25. doi:10.1542/aapnews.2012338-25d

    Zaloshnja E, Miller TR, Lawrence B. Incidence and Cost of Injury Among Youth in Agricultural Settings, United States, 2001-2006. Pediatrics. 2012;129(4):728-734. doi:10.1542/peds.2011-2512

    Schwebel DC, Pickett W. The role of child and adolescent development in the occurrence of agricultural injuries: an illustration using tractor-related injuries. J Agromedicine. 2012;17(2):214-24. doi: 10.1080/1059924X.2012.655120.

    Morrongiello BA, Zdzieborski D, Stewart J. Supervision of children in agricultural settings: implications for injury risk and prevention. J Agromedicine. 2012;17(2):149-62. doi: 10.1080/1059924X.2012.655127.

    Gallagher SS. Characteristics of evaluated childhood agricultural safety interventions. J Agromedicine. 2012;17(2):109-26. doi: 10.1080/1059924X.2012.664033.

    McCallum DM, Murphy S, Reed DB, Claunch DT, Reynolds SJ. What we know about the effectiveness of farm safety day programs and what we need to know. J Rural Health Off J Am Rural Health Assoc Natl Rural Health Care Assoc. 2013;29(1):20-29. doi:10.1111/j.1748-0361.2012.00426.x

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa

    What Are the Different Types of Myasthenia Gravis?

    Patient Presentation
    A 6-year-old male came to clinic for a cough and runny nose for 4 days. He initially had a low grade fever but this had resolved. He continued to cough more at night which was disturbing his sleep. He had no pain. The past medical history was positive for ocular myasthenia gravis that had been diagnosed at age 3. He took pyridostigmine. The review of systems was otherwise negative.

    The pertinent physical exam showed a somewhat tired appearing male, wearing glasses and tilting his head backward. His vital signs were normal without a measured fever. His growth parameters were around the 50th percentile. He had bilateral ptosis, moderate clear rhinorrhea, with normal pharynx and ear examinations. He had coarse upper airway sounds but no wheezing or other adventitial breath sounds on lung examination. He had no rashes. His neurological examination showed no other obvious muscle weakness.

    The diagnosis of an upper respiratory tract infection was made. The physician commented on the ptosis to the family. The mother said that it seemed to get worse with minor infections but then improved. “He always has some droopiness, so this is just part of being sick,” she noted. The physician discussed symptomatic treatment and reiterated signs of respiratory distress with the family. The mother indicated that she was always looking for respiratory distress and knew when to call neurology or go to the emergency room.

    Myasthenia gravis (MG) is a problem of the neuromuscular junction which causes muscle weakness. It can occur in all ages and have a range of symptoms from mild localized disease to mortality-threatening respiratory failure. MG occurs in 1.7-30 cases/million, with a prevalence of 77.7 cases/million. Pediatric patients comprise 10-15% of all patients with MG. In various Asian populations, the juvenile MG can be up to 50% of all of the MG cases. Fluctuations in muscle weakness is a hallmark of the disease.

    As a reminder, “[i]n normal synaptic transmission in the neuromuscular junction, the axon is depolarized and this depolarization travels to the axon terminal. Voltage-gated calcium channels open, leading to acetylcholine containing vesicles to fuse to the cell membrane. Acetylcholine is then released from synaptic vesicles into the synaptic cleft from the axon terminal. The acetylcholine travels across the synaptic cleft to the AChR [acetylcholine receptor] sites where binding causes sodium channels to open, depolarizing the motor end plate of the muscle fiber. Acetylcholinesterase degrades the acetylcholine, and the sodium channels close, allowing repolarization of the muscle fiber.”

    The diagnosis of MG is made by history of fatiguable weakness, clinical examination trying to fatigue muscles such as continuous upward gaze (patients worsen with this activity), physiological testing such as the Tensilon test (which has improved symptoms when the drug is given), electrophysiological testing (worsening with repeated muscle stimulation) and serological testing for antibodies. Treatment varies from none, to acetylcholinesterase inhibitors, immunosuppressive medications, intravenous immunoglobulin and plasmapheresis. Surgical treatment by thymectomy is also used as there appears to be an association with thymomas. Prognosis depends on the type of MG and remissions do occur.

    MG is worsened by “systemic illness, pregnancy, the menstrual cycle, drugs that affect neuromuscular transmission,…, increase temperature, hyperthyroidism or hypothyroidism and emotional upset.”

    Learning Point
    Patients are formally classified by disease severity, but MG has 2 basic forms based on clinical type:

    • Ocular MG
      • Muscles of the eye are preferentially affected in MG and if only ocular muscles are affected it is termed ocular MG (OMG)
      • OMG patients can have ptosis, strabismus or diplopia. Because this is a fatigable muscle disease, patients may have improved symptoms in the morning and worsen throughout the day
      • Patients may complain of difficulty walking not because of affected extremity weakness but because of difficulty seeing where they are walking, particularly with stairs
      • OMG can be unilateral or bilateral
      • Rates of progression to generalized MG are 8-49%. Preadolescents are less likely to progress than adolescents
      • Spontaneous remission with OMG is common
    • Generalized MG
      • Any muscle can be affected
      • Patients will relate various abnormalities in muscular endurance and exercise intolerance
      • Weakness of the respiratory muscles can cause respiratory distress including respiratory failure
      • Patients with bulbar weakness can have problems with chewing or swallowing, which may cause choking including having nasal regurgitation of food
      • Speech can be affected including slurring, quieter voice or having a nasal voice as fatigue worsen even over a day
      • Patients may also have issues with basic hygiene such as toileting, brushing their teeth or washing their hair

    MG has 3 forms based on cause:

    • Transient neonatal MG
      • Cause: Maternal antibodies are transplacentally passed to the newborn
      • Occurs in 5-30% of infants of mothers with MG
      • Presents at or shortly after birth
      • Ocular MG or more generalized weakness may occur – weak cry, poor suck, generalized weakness or respiratory distress
      • Diagnosis is by detecting the antibodies
      • Resolves when antibodies are gone
    • Congenital MG
      • Cause: Functional or structural abnormalities in the proteins involved in the neuromuscular junction
      • Most commonly the AChR proteins and function are affected
      • Mutation specific treatment is important as treatment for one type may worsen another
      • It must be distinguished from myopathies or other neurological conditions
      • Fatigable weakness usually at young age even infancy is the usual presentation
      • Ocular MG or more generalized weakness may occur
    • Juvenile MG
      • Cause: Autoimmune disorder causing dysfunction of the AChR
      • Auto antibodies targeted against various structural proteins, mainly the AChR but also muscle-specific kinase (MuSK)
      • Patients with MuSK antibodies have more severe disease

    Questions for Further Discussion
    1. What causes ptosis? A review can be found here
    2. What causes muscle weakness? A review can be found here
    3. What causes hypotonia? A review can be found here
    4. What causes peripheral neuropathy? A review can be found 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 and the Cochrane Database of Systematic Reviews.

    Information prescriptions for patients can be found at MedlinePlus for these topics: Myasthenia Gravis and Neuromuscular Disorders.

    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.

    Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014;45(2):75-83. doi:10.1055/s-0033-1364181

    Jastrzebska A, Jastrzebski M, Ryniewicz B, Kostera-Pruszczyk A. Treatment outcome in juvenile-onset myasthenia gravis. Muscle Nerve. 2019;59(5):549-554. doi:10.1002/mus.26445

    Peragallo JH. Pediatric Myasthenia Gravis. Semin Pediatr Neurol. 2017;24(2):116-121. doi:10.1016/j.spen.2017.04.003

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa