Aaron Conley. I'm a pediatric physical medicine rehab physician working for St. Luke's Children's. Some of this material was developed with the assistance of previous slides by Dr. Sinner of Gillette Children's and I have no disclosures. The learning objectives today are to identify key features of selected neurodegenerative conditions in pediatrics. This is not an exhaustive lecture, so I'm afraid there's just a selected few. I'm focusing on encephalitis and differentiating between different ideologies and presentations and then kind of ending with reviewing and with a goal of deeper understanding of the distribution and characteristics within pediatric central nervous system tumors. Starting first on multiple sclerosis. Multiple sclerosis is an autoimmune chronic inflammatory disease with the components of demyelination and axonal degeneration. In 2018, there was a review published that said 3-10% of all patients with MS present under the age of 16, with less than 1% being diagnosed under the age of 10, so very rare. Overall, there's a female predominance about 4.5-1, but it's lower in patients with a younger onset, so less than 10 or 12 years old, with an even distribution or even a male predominance in some studies, but not all of those young children, again, less than 10 or 12 years old with presentation. Adults tend to be non-Hispanic whites, but there is a greater racial and ethnic diversity among children. There also can be a history of Epstein-Barr virus infection in pediatric MS. Nearly all children with MS have a relapsing remitting type, about 97, 90, between 96 and 98% of children compared to 84% of adults. They are less likely to develop primary or secondary progressive MS in childhood, so again, relapsing remitting type. The relapse rates are 2-3 times higher in children than adults, and the MRI lesion burden can be higher as well. They frequently present with these kind of multifocal or polyfocal, and common presenting symptoms include sensory deficits, optic neuritis, gait disturbances, and brainstem symptoms. Younger kids are more likely to present with encephalitis and have more common cognitive effects. At time of disease onset, if the child has a progressive initial course, it's a worse prognosis and more predictive of a shorter time to irreversible disability, but again, most patients have this relapsing remitting type at initial diagnosis. Children do tend to accrue motor disability more slowly, and that takes longer to really build up and thought to be related to neuroplasticity, but there is a higher rate of actual sustained axonal damage within the inflammatory lesions, and in fact, pediatric individuals with pediatric onset MS reached secondary progression and disability milestones at ages approximately 10 years younger than adult onset cases. So in review, that's looking at most children are diagnosed with a relapsing remitting course, but since they get it at a younger age, it does seem that they turn into that secondary progressive course earlier than adult onset cases do, and therefore, achieve or hit disability milestones not in a good way at a younger age than those with adult onset cases. The International Pediatric Multiple Sclerosis Study Group updated their guidelines in 2012, and these were published in 2013, and include the following two or more. So one scenario would be two or more non-encephalopathic central nervous system events in different locations 30 days apart or one non-encephalopathic episode with MRI findings and a follow-up with also lesions and demonstrating then time and space, and acute disseminated encephalomyelitis or ADEM followed by a non-encephalopathic attack with MRI lesions disseminated in space, and then patients who are 12 years older, a single non-encephalopathic event, but MRI at that time revealed lesions felt to be consistent with differences in time and space. Diagnostic options include MRI with gadolinium of the brain and spine, and characteristically, there'll be these OVID T2 lesions and flare hyperintensities in the periventricular white matter. Cortical lesions are less common in children than adults. Lumbar puncture for CSF reveals this lymphocytic predominance, normal glucose, and elevated protein. Additional diagnostic blood work can include CBC, CRP, ESR, folate, B12, and TSH. I won't delve too deeply into treatment, but first line can include beta interferon, and then rehab measures or functional status and disability are tracked with the expanded disability status scale, and that ranges from zero, which is a normal neurologic exam, to 10, which is death from multiple sclerosis. There is a caveat within the scale that says it's not appropriate for children who would not expect it to be ambulatory or independent without adult help, which would be our very, very young children. Another scale is the functional system scale, which tracks performance in several different arenas, and that would be pyramidal, cerebellar, brainstem, sensory, bowel and bladder, vision, and then cerebral or mental. As a rehab provider, we can offer tools and assistance in treating spasticity and pain, explore mobility and adaptive equipment support, manage neurogenic bowel and bladder, and then certainly be advocates for young patients who still are going through education, requiring cognitive support, an IEP or individualized education plan, and then certainly try to advocate and be a big proponent for neuropsychologic testing. So here's our question from MS. A 16-year-old girl presents with optic neuritis. She tells you that last year she had difficulty with her writing ability and holding a pen, but she assumed it was because of a long paper she was working on. What type of course is she likely to have related to her new diagnosis of pediatric onset MS? Primary progressive, secondary progressive, or relapsing remitting? So relapsing remitting, 96% to 98% of pediatric onset MS is this relapsing remitting course. And then adults, it's lower, about 84%. I have just a brief mention of neuromyelitis optic. So it's a very rare conditioning, again, a demyelinating process with this polyfocal onset of optic neuritis and transverse myelitis. So optic neuritis presents with unilateral or bilateral blurry vision. It can include a central black spot or acute vision loss. Pain can be present. And then transverse myelitis, or a non-traumatic injury of the spinal cord felt to be autoimmune, is the lesion tends to be complete, or the functional deficit tends to be complete rather than incomplete in this case. The NMO, or neuromyelitis optica, primarily presents in a relapsing course, which was formerly known as devic disease rather than a monophasic event. And it's believed to be a separate entity from multiple sclerosis. The hallmark, besides the optic neuritis and transverse myelitis, you can still have intracranial pathology as brain lesions are more common in pediatric than adult NMO. And on those MRIs, there's this presence of these cloud-like or fluffy enhancements, linear lesions that travel from the brainstem to the spinal cord, and then evidence of PRESS, which is posterior reversible encephalopathy syndrome. Treatment includes high-dose steroids, plasmapheresis, IVIG, and it does have a worse prognosis than MS. We're moving into acute disseminated encephalomyelitis, which I'm going to talk about here first before moving into more encephalitis. So acute disseminated encephalomyelitis, or ADEM, is a get-into-myelinating condition, polyfocal, so multiple areas, and it presents with a rapid onset after prodromal symptoms. So that can be either like a flu-like illness or it generally affects children ages five to eight. One study looked at the Canadian estimate of disease, and they found about 0.2 per 100,000 children, but then a higher incidence rate was reported in San Diego County in their study, looking at 0.4 per 100,000 per year. Symptoms include weakness, loss of vision, numbness, loss of balance, but then can also present to need for intubation because of loss of protective airway function and difficulty related to swelling of the brain. As far as etiology, over half the cases follow a known viral or bacterial infection, and this response is thought to be autoimmune. It's a brief but intense attack of inflammation in the brain and spinal cord, and occasionally the optic nerves, which can damage the myelin. So diagnosing of ADEM with MRI often finds these widespread and multiple changes in the white matter. There can sometimes be lesions in the gray matter or the deep brain as well, and so in some cases over half of the total volume of the white matter can be affected, and these changes are characteristics but not specific for ADEM. So certainly other diagnosis must be considered and other treatments must be explored if ADEM is not the presumed diagnosis initially, certainly. Sometimes a time course can help you too, so over months these changes on MRI should gradually improve and even completely disappear, and the pathology behind that is sleeves of demyelination associated with these inflammatory infiltrates. Lumbar puncture is typically needed, and this is partially to rule out direct infections or other processes that can look like ADEM. So the CSF and ADEM often, when obtained, is found to have a normal opening pressure, normal glucose, moderately elevated cell count, and protein, typically no oligoclonal bands that would be more present in pediatric MS. Criteria like MS was updated in 2012-2013 and includes a first polyfocal clinical CNS event with this presumed inflammatory demyelinating cause, encephalopathy, brain abnormalities consistent with demyelination in the acute phase, and then no new clinical or MRI findings three months or more from the clinical onset. So a rare complication is called acute hemorrhagic leukoencephalitis or AHL, and this occurs with hemorrhaging, vessel necrosis, perivascular exudates, edema, and granulocyte infiltration. It is very rare but can be fatal. Treatment of ADEM, often empiric acyclovir, is started due to suspicion of HSV or herpes simplex virus infection. Steroids, IVIG, plasmapheresis, Generally, IV steroids and then the next line of treatment is IVIG. And then chemotherapy can be used in severe cases or less responsive cases to first line, but generally less toxic therapies are pursued first. So your question, you receive a consult for dystonia management in a seven-year-old boy with ADEM in the pediatric ICU. He was diagnosed three days ago and has had two cycles of IVIG in addition to steroids, but remains ventilated. He is also receiving sedation for agitation. Overnight, he worsens with increased posturing and a sudden loss of brainstem functions. STAT-CT is pending. Though rare, of the following below, you're most concerned for A, Epstein-Barr virus superinfection, steroid-associated myopathy, multiphasic ADEM, acute hemorrhagic leukoencephalitis. So the answer is D, acute hemorrhagic leukoencephalitis. What I didn't put on there was just brainstem herniation and increased intracranial pressure due to swelling because I wanted to focus on acute hemorrhagic leukoencephalitis. And again, this is a rare condition and about 2% can experience a severe decompensation, increased intracranial pressure. Surgical intervention can be warranted, though this condition is often fatal. So moving on to encephalitis, we briefly touched on one avenue of encephalitis in looking at ADEM, but looking at the other pictures and presentations. So inflammation of brain tissue with neurologic dysfunction, typically a flu-like prodrome, and then you start to see changes in behavior or consciousness, headaches, nausea, vomiting. This is thought to be around 10 out of 100,000, but more confident infants. Female to male ratio about 1 to 1, except in autoimmune cases for which girls are at an increased risk. Within the CSF, you see this lymphocytic pleocytosis, normal glucose, elevated protein. And we've already talked a little bit about ADEM. Previously discussed, it has this multifocal presentation. Resemplex virus is characterized often with temporal lobe seizures and overall is the most common etiology of encephalitis not associated with epidemics. Though there are some studies that suggest that ADEM is more common than a viral etiology. Varicose vascular disorder can have an increased incidence with immunosuppression and vasculitis is the major pathology. Especially middle cerebral artery and carotid. An arbovirus infection would be considered in fever and an early abdundant presentation. An EMG can be used if flaccid paralysis is present as well as this can create a poliomyelitis like anterior horn cell disease. And then autoimmune One thing we'll talk about in a minute is this anti-NMDA receptor. Anti-NMDA receptor encephalitis is thought to be immune mediated through targeting of the NR1 receptor. And the California encephalitis project found higher rates of anti-NMDA receptor encephalitis than all viral etiologies in patients less than 30 years old. And it was initially discovered in young women with ovarian teratomas and the ratio of patients in adult pediatrics female to male still remains higher with the female predominance about eight to one. About 37% of patients are under 18 at the age of onset and 19% are less than 12 years of age. HSV is a another confirmed trigger of anti-NMDA receptor encephalitis. Prominent psychiatric symptoms present before neurologic symptoms really become more apparent. So catatonia can be present. Movement disorder tends to be either choreoathetoid, rigidity, Parkinsonism, myoclonus, orophagia, dyskinesias, and then autonomic instability, tachycardia, hypertension, hyperthermia is actually less common in children than adults, but seizures are more common in children. So it can be grouped into three types. Type one would be a classic type seizures, movement disorder, catatonia, agitation, mood behavior changes. Type two is primarily psychiatric and actually has the most favorable trajectory. Type three is primarily catatonic and carries the worst prognosis. Differential diagnosis tends to be quite broad and includes viral, limbic, or perineoplastic, new onset psychosis, neuroleptic malignant syndrome, which can also have rigidity, altered consciousness, hyperthermia, and autonomic instability. Genetic diagnosis is also on the list. And then childhood disintegrative disorder or CCD, which is rapid loss of language skills, cognitive declines, seizures, and autistic features. Diagnosis can include CSF or serum autoantibodies against NMDA type glutamate receptors. MRI can be normal in half of all cases, normal in a third of pediatric cases. When it is abnormal, there's a T2 or flare signal abnormality, typically within the cortical or subcortical regions. And then an abnormal EEG can also occur. Lancet Neurology had a neat pneumonic search for NMDA-RA, which I thought was a great resource. So treatment includes first line IV steroids, IVIG, plasmapheresis, and then with about a 50% response rate, and then proceeding to second line rituximab or cyclophosphamide, about 60% of first line failures do respond to second line treatments. Electroconvulsive therapy or ECT is occasionally used in catatonia. The autonomic instability and consciousness or disorders of consciousness tend to improve first with gradual cognitive recovery. Majority make a good recovery, but some do have functional deficits, specifically cognitive deficits that can be found out later. And certainly there's a role of rehabilitation both in the acute phase and then kind of check-ins if there's any functional deficits or making sure we're advocating for these patients as they continue to learn and transition to older adults. True or false? Autonomic instability related to anti-NMDA receptor encephalitis is more common in children than in adults. The answer is false. Overt neurologic symptoms are more common in kids, and autonomic instability is actually more common in adults. Moving on to our last section, which is pediatric central nervous system tumors. In the U.S., CNS tumors are the most common solid tumors in children. They are the second most common type of childhood cancer following leukemia. It's the leading cause of cancer death in children ages 0 to 14 years old. And their rates of CNS tumor are about 5 to 6 per 100,000 in ages 0 to 14. Higher rates in males. Astrocytomas are the most common brain tumor overall. Our central nervous system tumor overall and medulostoma being the most common malignant brain tumor or number two overall. There are two classification systems for pediatric central nervous system tumors. One is based on tumor histology and the other based on tumor site and morphology. Just in viewing the locations, low-grade astrocytomas make up the largest group of CNS tumors. Medulostoma is the most common malignant brain tumor. More detail briefly, younger children have a higher incidence of tumors of embryonal origin, such as medulostoma or a typical teratoid rhabdoid tumor, which carries a very poor prognosis. Whereas older patients tend to have tumors of glial origin. So medulostoma ranges up to 20% of all pediatric brain tumors. Non-posterior fossa embryonal tumors or formerly called CNS primitive neuroectodermal tumors or PNTs make up less than a third of brain tumors and have a poor prognosis. And then the ATRT is rare. So it only makes up 1 to 2% of all pediatric brain tumors, but in the young children, less than three years old, it makes up 10 to 20% of CNS tumors with a very poor prognosis. Ependymoma is the third most common CNS tumor. Looking at spinal cord tumors, low rates, less than 6% of all CNS tumors, most commonly gliomas, second most common is ependymomas, and it can be classified in three ways based on location, intramedullary, intradural, extramedullary, or extradural. And then genetic disorders also play a role, tuberous sclerosis, neurofibrosis one and two. So NF1 commonly includes optic gliomas and pilocytic astrocytomas. NF2, we think of bilateral vestibular schwannomas or multiple meningiomas. There's also lepharomone, gorlin, and trachome. So looking at distribution by site of CNS tumors, supratentorial brain lesions, cerebrum, ventricle. Infraventorial would be your posterior fossa, your cerebellum, brainstem, pituitary pineal glands, nonspecified sites, cranial nerves. And again, here's spinal cord, less than about 6%. And then meninges would be rare. Clinical mass infestations are often associated with increased intracranial pressure, headache, nausea, vomiting, but can be focal as well. As a rehabilitation provider, we're often meeting the children for the first time in the hospital following their resection. And one of the first decisions is, is there a need for acute inpatient rehabilitation? And this can require coordination and somewhat of a dance around when they are due for chemotherapy, when their radiations due to start, but often there can be an option for early intervention prior to when radiation starts. For late involvement of these patients within our clinics, we can offer cognitive supports for subsequent effects, advocate for neuropsychology, and then certainly be a proponent of their learning and accommodations and their additional management of side effects of seizure medications, on functional and cognitive changes, bowel and bladder, low vision strategies, and then behavior. And then certainly adaptive equipment, pain assessment, fatigue, quality of life, and then kind of working with families that if a palliative care referral would be appropriate, maybe not perhaps for necessarily hospice type initiation, but certainly to look at the the quality of life and symptom management. So your 17-year-old patient you initially saw for neurologic deficits related to a meningioma was lost to follow-up. He returns with new MRI imaging revealing multiple meningiomas. He carries a diagnosis of what disease? Multiple myeloma, neurofibromatosis type 2, Li-Fraumeni syndrome, tubular sclerosis complex. So NF2 is known for multifocal meningiomas, which make up less than 3% of all brain tumors. That is largely the end of the presentation. Here are my references. Thank you for watching.

neurodegenerative conditions

pediatrics

multiple sclerosis

acute disseminated encephalomyelitis

encephalitis

demyelination