Brenda Banwell, MD
A previously healthy 16-year-old girl presents with a 1-month history of increasing sleepiness. Over the last week, she has fallen asleep even while eating, causing her family to fear that she will choke. Once asleep, she is almost impossible to wake up.
She also reports being increasingly hungry, eating things she never previously liked and eating at all hours of the day or evening. She has gained 40 pounds. Her one other complaint is that she has frequent hiccups, which can last for hours.
Discussion: The medical diagnoses to consider in the patient with changing sleep patterns include disorders of sleep such as narcolepsy, or abnormality of the sleep center in the brain. Our patient also presents with hyperphagia (abnormally increased appetite). Hyperphagia is a disorder of satiety (the feeling of being full), which is regulated by an area of the brain called the diencephalon. Finally, our patient also complains of frequent hiccups. While hiccups are most commonly due to irritation of the diaphragm muscle in the brainstem, they can also occur due to disorders of the brainstem.
On examination, the optic nerves were abnormal, with pallor of the temporal aspect of the nerves, and reduced vision in her right eye. She reports that two years previously she had an episode of pain with eye movement followed by difficulty seeing colors in the right eye and loss of normal vision. Her symptoms lasted several weeks and improved incompletely. She did not see a doctor for the symptoms. Examination also reveals that our patient has increased reflexes in her legs and some leg stiffness. MRI scans of the brain and spine (see Figure 1) reveal abnormal areas of inflammation in the brain stem and midbrain, the areas of the brain that are involved in sleep regulation, the hunger center, and the region of the brain that can cause hiccups, and she has a long extensive area of inflammation in the spinal cord.
A: Diencephalic and midbrain lesions; B: Thalamic lesions; C: Lesion in the brainstem surrounding the 4th ventricle
The combination of optic nerve abnormalities, spinal cord abnormalities, and abnormal inflammation in specific areas of the brain stem led to a diagnosis of neuromyelitis optica (NMO). The diagnosis was confirmed by the presence of antibodies that react against aquaporin 4 (or “NMO IgG”).
NMO is a serious immune disorder in which the immune system attacks certain area key areas of the optic nerves, brain, and spinal cord. NMO is a rare disease, with onset in both childhood and in adulthood. NMO appears to be more common in Asian countries, but is being recognized more in multiple world regions. The disease is an acquired autoimmune disease and may occur is isolation or in patients who have other autoimmune diseases such as lupus, Sjogren’s syndrome, or thyroid disease. Treatment with immuno-suppressant medications is essential. Untreated, patients experience recurrent attacks of impairment of the optic nerves, brain, or spine, which can lead to blindness, paralysis, and even death.
NMO is one of a now increasingly recognized group of immune disorders affecting the central nervous system. The classic autoimmune disease of the central nervous system is multiple sclerosis (MS). MS shares several clinical features of NMO, but the two diseases have different biologies and require different treatment strategies. The goal of treatment for NMO and MS is to control abnormal immune activity, without eliminating normal immune control of infection.
Treatments for NMO include corticosteroids, Imuran, and rituximab. Treatments for MS include corticosteroids (only at the time of an attack), interferon-beta, and glatiramer acetate. Newer treatments are on the horizon for both MS and NMO, and treatment trials for children with these diseases will be launched in the near future. Our 16-year-old-patient is now doing well on oral prednisone 10 mg per day and on 6 monthly courses of rituximab.
Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology. 2003;60(5):848-853.
Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489.
Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology. 2008;70(5):344-352.
Cree B. Neuromyelitis optica: diagnosis, pathogenesis, and treatment. Curr Neurol Neurosci Rep. 2008;8(5):427-433.
Dale RC, Brilot F, Banwell B. Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol. 2009;22(3):233-240.
Jennifer McGuire, MD
A 17-year-old male presents for medical evaluation of new academic and attention problems at school. He attends a local public high school where he is in the 11th grade, and has previously been an A and B student. Over the course of this academic year, teachers have begun to note worsening attention in class, disinhibited behavior, and a drop in grades. His family and friends also note poor attention and new working memory problems. There are no significant social or financial stressors, no new alcohol or substance abuse, and he does not endorse symptoms of depression.
His past medical history is remarkable for HIV infection, acquired via sexual contact at the age of 14. He has received regular routine HIV-related care and screening since he was diagnosed, although he has thus far chosen not to start antiretroviral therapy (ART). His nadir CD4 count was 100 around the time of diagnosis; his current CD4 count is 360. His current viral load set point is around 100,000. The remainder of his medical history and review of systems is normal.
On neurologic examination, you note difficulties engaging in conversation and attentional deficits with serial 7s (serial subtractions of seven from 100) and spelling backwards and forwards. He also demonstrates non-specific executive dysfunction. The remainder of his neurologic and general medical examination is normal.
You obtain a gadolinium-enhanced MRI of his brain, which is normal. You subsequently refer him to CHOP Neuropsychology for formal neurocognitive evaluation. There, he demonstrates deficits in attention and executive function domains of more than 1 SD for ageand demographically matched normal values, and functional surveys demonstrate his daily life is affected by these deficits.
Discussion: The diagnosis is mild neurocognitive disorder (MND), a subset of HIV-associated neurocognitive disorder (HAND) (See Table 1). HAND is a common and devastating complication of HIV infection, affecting up to 52% of HIV-infected adults in the combined ART era. Clinical risk factors include low CD4 nadir count and high viral load. The prevalence in adolescents with behaviorally acquired disease is less well described, but may be as high as 65%. The diagnosis of HAND is difficult to make in the clinical setting because it is based on lengthy and costly batteries of neurocognitive testing. However, efficient identification of affected individuals is imperative: In addition to worsening medication adherence, HAND independently predicts non-central nervous system (CNS) morbidity and overall mortality.
Asymptomatic Neurocognitive Impairment (70% of HAND)
Mild Neurocognitive Disorder (25% of HAND)
HIV-Associated Dementia (5% of HAND)
*Impairments must not be explained by comorbid conditions, and individual may not meet criteria for delirium or dementia
Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799.
HIV invades the nervous system early in infection via infected monocytes and lymphocytes that migrate across the blood-brain barrier (BBB). Infected monocytes then differentiate into macrophages that support low-level viral replication, infect neighboring astrocytes and microglia, and release soluble cytokines/chemokines. These soluble mediators cause a diffuse immune dysregulation, increased BBB permeability, and elevated parenchymal concentrations of excitatory neurotransmitters and neurotoxins, which ultimately result in neuronal and white matter damage. Congenital HIV infection has a different pathophysiology and clinical course compared to classical HAND and is not discussed here.
Blood testing for HAND is not currently available. Instead, the diagnosis rests on clinical neurocognitive testing and exclusion of other known causes of cognitive impairment. Neuroimaging is an important component of diagnosis to exclude CNS opportunistic processes. MRI may also demonstrate cortical and subcortical atrophy and confluent signal abnormalities in the deep white matter.
Research is currently underway to identify plasma, CSF, and neuroimaging biomarkers of HAND to help recognize affected and at-risk youth. Starting ART in affected individuals improves cognition in those most severely affected, but milder forms of HAND are persistent despite adequate therapy. Trials for adjunctive pharmacologic therapies and cognitive rehabilitation are underway.
McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67(6):699-714.
Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL. HIVassociated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharm. 2010;5(3):294-309.
Nichols S, Bethel J, Garvie B, Patton D, Thornton S, Kapogiannis B, Ren W, Li T. Neurocognitive functioning in antiretroviral therapy-naïve youth with behaviorally acquired HIV. Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, GA. March 2013.
Katherine S. Taub, MD
An 8-year-old female with tuberous sclerosis complex (TSC) presents for a follow-up appointment with daily seizures despite treatment with two antiepileptic drugs (AEDs). At 7 months of age, she developed infantile spasms consisting of flexor extensor spasms with increased irritability and developmental regression. On examination she had hypomelanotic macules. An MRI of the brain showed classic features of TSC including cortical tubers and subependymal nodules. Her infantile spasms responded quickly to vigabatrin. At 18 months of age she developed partial seizures involving eye deviation to the right and right arm tonic clonic seizures. Unfortunately, despite treatment with multiple AEDs over 7 years, she continues to have 5 seizures per day that have her sent home from school frequently and hinder her from going to sleepovers. Her parents are concerned with her sleepiness related to her high dose of AEDs and her increasing seizure frequency; they want to discuss the next treatment options.
Discussion: Tuberous sclerosis is an inherited neurocutaneous disorder with abnormal growths in multiple organs including the brain, heart, lung, eye, and kidney. This abnormal growth results from a mutation in either the TSC1 or TSC2 gene, which code for hamartin and tuberin, proteins involved in a cascade that regulates cell growth. Genetic testing for TSC1 and TSC2 is available, but diagnosis is based on clinical manifestations of the disease. Based on the diagnostic criteria for tuberous sclerosis complex, a patient has TSC if he or she has 2 major features or 1 major feature with 2 minor features. A possible diagnosis is made if the patient has either 1 major feature, 1 major and 1 minor, or >2 minor features (see Table 2).
| Major Criteria
• Facial angiofibromas or forehead plaque
• Nontraumatic ungual or periungal fibroma hypomelanotic macules (>3)
• Shagreen patch (connective tissue nevus)
• Cortical tuber
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Multiple retinal nodular hamartomas
• Cardiac rhabdomyoma (single or multiple) lymphangiomyomatosis
• Renal angiomyolipoma
• Multiple randomly distributed dental enamel pits
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white-matter “migration tracts”
• Gingival fibromas
• Retinal achromic patch
• Nonrenal hamartoma
• “Confetti” skin lesions
• Multiple renal cysts
Adopted from Roach ES. J Child Neurology. 1998
The hypomelanotic macules are often present at birth and become more apparent as a child gets older. A Wood’s lamp aids in identifying these macules. Angiofibromas appear in preschool age and may progress into teenage years along the nasolabial folds as raised erythematous lesions. Shagreen patches also appear in teenagers as a flesh-colored raised lesion commonly seen on the lower flank and back. Ungual fibromas are flesh-colored lesions of the nail.
A formal ophthalmologic exam with a dilated fundoscopic examination is recommended for patients newly diagnosed with TSC to assess for retinal hamartomas, which are commonly asymptomatic but may cause visual impairment. Patients are also advised to have a renal ultrasound, which detects renal angiomyolipomas. Angiomyolipomas may cause increased blood pressure and kidney failure. There is a risk for angiomyolipomas to bleed and evolve into renal cell carcinoma. Cardiac rhabdomyomas may be detected on fetal ultrasounds or are first diagnosed by echo to evaluate a cardiac murmur. They may cause cardiac arrhythmias or obstruction of blood flow.
Cardiac rhabdomyomas shrink in size with time and thus cause fewer complications as a child gets older. Lymphangioleiomyomatosis presents in adolescent and young adult females presenting with shortness of breath, hemoptysis, and pneumothorax. Subependymal nodules are abnormal growths of the subependymal lining of the ventricles.
Subependymal nodules may grow into subependymal giant cell tumors (see Figure 2A). These nodules can cause obstruction of cerebral spinal fluid, especially at the foramen of Monro, resulting in increased intracranial pressure. Treatment includes surgical resection or everolimus, an immunosuppressant that inhibits the mTOR pathway. Tubers are cortical dysplasias that, unlike subpendymal nodules, do not grow (see Figure 2B). However, the abnormal brain tissue around the tuber is epileptic. The total number of cortical tubers does not correlate with the severity of disease. For example, our patient has a small tuber burden but has medicationresistant epilepsy.
A: Subependymal giant cell tumor; B: Tubers
Crino P, et al. The tuberous sclerosis complex. NEJM. 2006;355(13):1345-1356.
Through the TSC Clinic at The Children’s Hospital of Philadelphia, we offered our patient alternative treatments for her seizures including the ketogenic diet (KD) and epilepsy surgery. The TSC Clinic works closely with CHOP’s KD team of neurologists and nutritionists. The TSC Clinic collaborates with CHOP’s Pediatric Regional Epilepsy Program and neurosurgeons to assess if a patient is a surgical candidate. We also discuss new research assessing the efficacy of everolimus in treating seizures in TSC patients.
The TSC Clinic was devised to coordinate the multidisciplinary care provided by the cardiologists, nephrologists, neurogeneticists, dermatologists, developmental pediatricians, and social workers involved in caring for our TSC patients. We also strive to provide compassionate care and support to family members involved in the lives of their children with TSC.
Crino P, et al. The tuberous sclerosis complex. NEJM. 2006;355(13):1345-1356.
Krueger DA, et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80(6):574- 580.
Roach ES, et al. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19(9):643-649.
To refer a patient to the Division of Neurology or one of its specialty programs, call 215-590-1719. Specialty programs include Neuromuscular Program, Pediatric Regional Epilepsy Program, Pediatric Multiple Sclerosis Clinic, Pediatric Stroke Program, Friedreich’s Ataxia Program, Neurogenetics Clinic, Movement Disorder Clinic, and the Multidisciplinary Headache Clinic.
For more information, go to www.chop.edu/neurology.
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