Patient Presentation
A 4.5-year-old male came to clinic for his well child examination and medication followup. His mother reported that he was overall doing well in preschool this year with his teachers “not sending home too many notes,” this year. He had a history of being a difficult child even from infancy with large emotional outbursts, difficulty sleeping, ignoring adults and being a risk-taker. These behaviors had not improved with parent-child interaction therapy and consistent caregiver interventions. Ten months previously he was diagnosed with attention deficit hyperactivity disorder (ADHD) by a psychiatrist and was started on guanfacine. Since then, his most challenging behaviors had improved as had his sleeping. “He gets along with most of the kids, most of the time,” his mother reported. “He can be a bit much and even his sister has to get away from him sometimes. The teachers at school say it is the same there. He isn’t malicious or mean, he just isn’t great at reading other people’s emotions and is a little, let’s say too enthusiastic at times. I love that about him but Dad and I need a break sometimes too,” she explained.

The pertinent physical exam showed a smiling male asking lots of questions. His growth parameters were 50%. His physical examination was unremarkable.

The diagnosis of a healthy male with ADHD treated effectively was made. The mother stated that she felt she knew how to handle him and didn’t think he would benefit by restarting behavioral therapy at this time. She would continue to see the psychiatrist as well.

Discussion
Attention deficit/hyperactivity disorder (ADHD) is a common problem with potentially 2.5% of children affected. Preschool children normally have less regulation than older children. Those with ADHD can have exaggerated behaviors which can cause additional problems including difficult caregiver-child interactions, impaired peer interactions, problems with learning and potential for expulsion from childcare/school facilities.

The differential diagnosis for ADHD is very broad and an inattention problem may not be ADHD. A review can be found here. For young children, normal variations in behavior are common. Parent and other caregiver expectations, and tolerance for those behaviors can be mismatched. Also parental skills for managing challenging behaviors may need to be learned or supported.

Guanfacine is an imidazole derivate acting as a selective central α 2-adrenergic receptor agonist. It theoretically acts by modulating the pre-frontal cortex and therefore improves attention and decreases impulsivity and irritability. It has short-acting and long-acting variations. Overdose can potentially cause central nervous system depression with bradycardia and hypotension; extended-release medications have long half-lives and therefore the side-effects can persist for days.

Learning Point
Once a young child has been diagnosed with ADHD then the first treatment option is behavioral interventions and support, along with monitoring. For children where this treatment is not enough, then stimulant medication usually with methylphenidate is the next step. If the child has concurrent symptoms of oppositional behavior or severe irritability, then an alpha adrenergic is the first line medication treatment instead. If the child is unresponsive to stimulants or cannot tolerate the side effects then an α adrenergic medication such as guanfacine is recommended.

In the first study reporting medication response and treatment side-effects for ADHD for preschool children seen in behavioral-developmental clinics, 497 children with a mean age of 62 months and 82% males were studied. Medications prescribed were methylphenidate (57.5% – mainly short-acting), amphetamines (7.2%), guanfacine (31.6% mainly short-acting) and clonidine (3.6%). In their study, preschool children had improvement with both drug classes. For “associated with improvement” stimulants were 78% while α adrenergic medication were 66%, and for “very much improved”, stimulants were 38% and α adrenergic medications were 25%. The side effect profiles were also different. Patients using stimulants reported moodiness/irritability (50%), appetite suppression (38%), disrupted behavior (22%) and sleep difficulties (21%), and stomachaches 13%, and repetitive behaviors (11%). Patients using α adrenergic medication reported daytime sleepiness (38%), moodiness/irritability (29%), disruptive behavior (28%), and sleep difficulties (11%). Children prescribed α adrenergic medications were more likely to continue to use the medications longer than those using stimulants.

Guanfacine is also used as an additional medication to help control ADHD symptoms in some older children and adolescents who are not controlled with stimulants alone.

Questions for Further Discussion
1. What medications do you use for young children with ADHD? Why?
2. What are indications for referral to a psychiatrist or psychologist?
3. How is the diagnosis of ADHD made in young children?

Related Cases

Disease: Attention Deficit Disorder with Hyperactivity | Child Behavior Disorders

Symptom/Presentation: Attention Deficit Disorder/ Overactivity

Specialty: Developmental Disabilities | General Pediatrics

Age: Preschooler

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: Guanfacine and ADHD.

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.

Childress A, Hoo-Cardiel A, Lang P. Evaluation of the current data on guanfacine extended release for the treatment of ADHD in children and adolescents. Expert Opinion on Pharmacotherapy. 2020;21(4):417-426. doi:10.1080/14656566.2019.1706480

Froehlich TE. Comparison of Medication Treatments for Preschool Children With ADHD: A First Step Toward Addressing a Critical Gap. JAMA. 2021;325(20):2049. doi:10.1001/jama.2021.5603

Harstad E, Shults J, Barbaresi W, et al. α 2 -Adrenergic Agonists or Stimulants for Preschool-Age Children With Attention-Deficit/Hyperactivity Disorder. JAMA. 2021;325(20):2067. doi:10.1001/jama.2021.6118

Peters E, Hodgson SE, Elliott R, Greene SL. Guanfacine exposure in paediatric and adolescent patients: A multicentre retrospective review. Emergency Medicine Australasia. 2025;37(2):e70018. doi:10.1111/1742-6723.70018

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

Patient Presentation
A 4-year-old female came to the emergency room with a history of increased seizures for the past several days. She was a former premature infant with hypoxic-ischemic encephalopathy who had known intermittent seizures that were usually treated with levetiracetam. She had been more tired, cranky and had had 3 seizures in 3 days. She did not need rescue medication, and had had her usual post-ictal somnolence for about 1-2 hours each time. Her parents thought she was worsening overall and brought her to the emergency room. She had fallen during a playground game 5 days previously and hit her head on the cement. She was not able to participate in school for the rest of the day but did go to school for the rest of the week. Her medications had not recently changed and her parents were adamant that she had received her regular dosing on schedule and had not seen any evidence of medication poisoning.

The review of systems was negative for fever, diarrhea, rashes and upper respiratory symptoms. She did complain that her head hurt and the lights in the emergency room hurt her eyes and these were new symptoms per the parents.

The pertinent physical exam her heart rate was 62 beats/minute, blood pressure was 115/60, respiratory rate of 24. Her Glascow coma scale was 15 but she appeared very tired. She would become cranky easily during the examination, especially the eye examination which could not be completed. Her overall examination was normal and there were no specific focal findings on neurological examination.

The work-up included the usual laboratory evaluation and urine for toxicology. The radiologic evaluation of computed tomography revealed a brainstem mass. Magnetic resonance imaging was most consistent with glioma. The patient’s clinical course showed that stereotactic biopsy was planned for further evaluation of the mass. The diagnosis of pediatric-type diffuse high-grade glioma was eventually made and radiation was started. Chemotherapy was also being considered.

Figure 150 – Sagittal T1 MRI without contrast of the brain (above left) shows a large mass expanding the entire brainstem. Axial T2 (above right) and axial FLAIR (below left) MRI show the mass to be somewhat heterogenous and the mass has multiple foci of enhancement on the axial T1 MRI with contrast (below right).

Discussion
Brain tumors, even those with favorable prognoses, have the potential for causing morbidity and mortality within a short-time because of their obvious space-occupying capacity within the closed space of the skull. Secondary brain tumors, those due to metastases from distant location cancers, are the most common brain tumors.

Risk factors for gliomas include age and exposure to ionizing radiation. “Cellular phone use is not associated with increased risk of gliomas.” Hereditary risk factors for gliomas are well known for some genetic mutations. Family history is positive for 5% of glioma patients without a known tumor predisposition syndrome such as the following:

• Neurofibromatosis type 1 – especially pilocytic astrocytoma (Grade 1)
• Neurofibromatosis type 2 – especially spinal ependymoma
• Tuberous sclerosis complex – subependymal giant cell astrocytoma
• Li-Fraumeni syndrome – several cancers including IDH-wild-type- high-grade astrocytic gliomas or IDH-mutant astrocytomas
• Lynch syndrome – IDH-mutant astrocytomas

Presentation usually is due to evaluation for focal neurological deficits, seizures, and increasing/non-resolving symptoms such as headache. They can also be an incidental finding such as neuroimaging after head trauma, or may be found due to screening for patients with hereditary cancer syndromes. Magnetic resonance imaging or Positron emission tomography (PET) scans are usually the imaging of choice. Treatment is primary surgical if the tumor is amenable. Radiation and chemotherapy can be options in some cases. Management of other problems such as cerebral edema by use of dexamethasone, anti-epileptics, and multi-disciplinary management with physical therapy, speech therapy, occupational therapy, social work and psychology can also be important for overall functioning. Quality of life can be dramatically altered even with a “treatable” glioma. Patients have increased risk of mental health issues such as depression and anxiety, fatigue, and continued seizures. Survivors can also have neurocognitive impairment (including cognition, attention, processing speed, and working memory), psychosocial problems and overall lower socioeconomic status.

Learning Point
Of primary brain tumors in adults and children, 30% are caused by gliomas and 80% of malignant brain tumors are caused by gliomas. Overall central nervous system (CNS) tumors have an incidence of 24.83/100,000 population, occurring in females more than males and also more in non-Hispanic populations. The highest incidence is Europe.

Overall the most common brain tumors for adults and children are:

• Meningiomas – 40.8%
• Pituitary tumors – 17.2%
• Glioblastoma – 14.2%
• Nerve sheath tumors – 8.3%
• Diffuse and anaplastic astrocytoma – 3.1%
• Ependymal tumors – 1.5%
• Olidgodendrogliomas and oligoastrocytic tumors 1.3%

The World Health Organization (WHO) 5 major grouping of gliomas are:

• Pediatric-type diffuse low-grade glioma – most common pediatric brain tumor, accounting for 30% of all pediatric brain tumors
• Pediatric-type diffuse high-grade glioma
• Adult-type diffuse glioma – 90% of gliomas overall in adults and children
• Circumscribed astrocytic glioma
• Ependymal tumors

Adult-type gliomas can be found in the pediatric age group and pediatric-type gliomas can be found in the adult age group, especially in the “cross-over” years of young adulthood.

Grading of gliomas

• Grade 1
  • Slow-growing, well-demarcated, usually amenable to surgery, favorable prognosis
  • Example: pilocytic astrocytoma
• Grade 2
  • Slow-growing, have invasive growth so not amenable to complete resection
  • Example: diffuse astrocytoma and oligodendrogliomas
• Grade 3
  • Rapidly growing, aggressive growth
  • Example: anaplastic astrocytomas and oligodendrogliomas
• Grade 4
  • Rapidly growing, highly aggressive, poor prognosis
  • Example: glioblastoma, IDH wild type, pediatric-type high grade

Overall prognosis depends on the group, grade, specific molecular subtypes and location.

Questions for Further Discussion
1. What are the components of Cushing’s triad?
2. What is the scoring system for the Glascow Coma Scale? A review can be found here
3. What is in the differential diagnosis for first time seizures?

Related Cases

Disease: Glioma | Childhood Brain Tumors

Symptom/Presentation: Fatigue | Seizures

Specialty: Neurology / Neurosurgery | Oncology | Radiology / Nuclear Medicine / Radiation Oncology

Age: Preschooler

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: Childhood Brain Tumors

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.

Sait SF, Giantini-Larsen AM, Tringale KR, Souweidane MM, Karajannis MA. Treatment of pediatric low-grade gliomas. Curr Neurol Neurosci Rep. 2023;23(4):185-199. doi:10.1007/s11910-023-01257-3

Wu J, Heidelberg RE, Gajjar A. Adolescents and Young Adults with Cancer. J Clin Oncol. 2024;42(6):686-695. doi:10.1200/JCO.23.01747

Fangusaro J, Jones DT, Packer RJ, et al. Pediatric low-grade glioma: State-of-the-art and ongoing challenges. Neuro Oncol. 2023;26(1):25-37. doi:10.1093/neuonc/noad195

Weller M, Wen PY, Chang SM, et al. Glioma. Nat Rev Dis Primers. 2024;10(1):33. doi:10.1038/s41572-024-00516-y

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

Patient Presentation
A 9-year-old male came to clinic for his health maintenance examination. He was overall healthy and there were no parental concerns. The past medical history found him to be fully immunized including seasonal vaccines.

The pertinent physical exam revealed him to have normal vital signs and growth parameters that were 10-50%. His examination was normal.

The diagnosis of a healthy male was made. His mother consented to all vaccines but asked why the HPV vaccine was being done at this age as her older daughter had it at 11-12 years. “In our community the vaccine rate was relatively poor. Not in our clinic but in the community. So we as a practice are following the recommendation to start vaccinating at age 9 years. We had a good rate before but now our rates are even higher so we are happy with the results. For some families who might be hesitant it also gives them a little bit more time to learn about the cancers it prevents and become more comfortable with getting the vaccine. Families like it that we can give it with other vaccines too like flu shots,” he responded.

Discussion
Human papilloma virus (HPV) is a circular, double-stranded DNA-virus that is the most common sexually-transmitted infection in the US and in many places world-wide. Diseases range from genital warts to respiratory papillomatosis to cancer. Cancer locations include skin, oropharyngeal, vulvar, vaginal, cervical, anal and penile cancers. It is estimated that HPV infection is associated with ~125,000 cases of cancer annually in the US.

HPV vaccine was initially approved in 2006 in the US with a quadrivalent vaccine. In 2016 a nonavalent vaccine was approved and is the only HPV vaccine currently approved in the US. The vaccine is recommended for ages to be given at 9-14 years with catchup vaccination routinely done up to 26 years, and potentially as late as 45 years of age with shared decision making between patients and health care providers.

Serotypes included are 6 and 11 (rarely carcinogenic but associated with 90% of anogenital warts and recurrent respiratory papillomatosis), 16 and 18 (associated with 70% of cervical cancers, 16 is associated with 95% of HPV-related oropharyngeal cancers), and 31, 33, 45 and 52 (associated with an additional 20% of cervical cancers). HPV prophylactic vaccines work by blocking entry of the virus into cells, presumably by antibody neutralization.

Learning Point
HPV vaccines are highly efficacious with mild side effects. It is estimated that up to 90% of HPV-related cancers are prevented especially cervical cancer. “Studies have […] demonstrated that earlier administration of the vaccines results in greater immunogenicity and long-lasting protection.” Greater effectiveness “”[…] is likely due to administration of these prophylactic vaccines prior to natural exposure to HPV from sexual activity rather than a biological mechanism independent of natural exposure.” It is estimated that up to 60% of adolescents have their sexual debut by age 18 years. It is also estimated that that “most sexually active women and men will become infected with HPV at least once in their lifetime.” Administration at early ages can lead to greater completion of the vaccine series as well.

Older adolescents and adults do have robust antibody responses that are higher than natural infection which likely gives substantial protection against HPV.

Some studies have also reported herd immunity protection effects as well. As the HPV vaccine has been efficacious, especially against cervical cancer, oropharyngeal cancers still are increasing and are now the main type of HPV-related immunity.

HPV vaccines for treatment (as opposed to prophylaxis) are also being developed designed to induce cellular immunity against established infections and potentially prevent continuation to cancer.

Questions for Further Discussion
1. What are treatments for respiratory papillomatosis? A review can be found here
2. What are treatments for genital warts? A review can be found here
3. What are some methods for counseling families who may be vaccine hesitant? A review can be found here

Related Cases

Disease: HPV | Sexually Transmitted Diseases | Childhood Immunization

Symptom/Presentation: Health Maintenance and Disease Prevention

Specialty: General Pediatrics | Infectious Diseases

Age: School Ager

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: HPV and Vaccines.

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.

Ellingson MK, Sheikha H, Nyhan K, Oliveira CR, Niccolai LM. Human papillomavirus vaccine effectiveness by age at vaccination: A systematic review. Hum Vaccin Immunother. 19(2):2239085. doi:10.1080/21645515.2023.2239085

Skolnik JM, Morrow MP. Vaccines for HPV-associated diseases. Molecular Aspects of Medicine. 2023;94:101224. doi:10.1016/j.mam.2023.101224

Escoffery C, Petagna C, Agnone C, et al. A systematic review of interventions to promote HPV vaccination globally. BMC Public Health. 2023;23(1):1262. doi:10.1186/s12889-023-15876-5

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

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