April 18, 2012 Case Conference

Patient… 16 year old Male presenting with right sided weakness

History of Present Illness 7 days prior to admission Gradual onset of right sided weakness (clumsy, could not write well) Complains of poor sensation over the right face. Brought to an emergency room; Dx: Nerve impingement  Reassurance No relief of symptoms Was transferred to another correctional facility Symptoms got worse Can’t walk straight Loss some feeling over the right leg. Day of admission

History PAST MEDICAL HISTORY Previously healthy; no previous episodes No known allergies to food/medications FAMILY HISTORY No known family history of any cardiac, respiratory, rheumatologic or neurologic conditions PERSONAL-SOCIAL HISTORY Allen McQueen correctional facility for boys since 9 months ago. Receives all medical care/shots. Now in middle school with no issues and learning disabilities. Denies smoking/alcohol. 1 x illicit drug use. Sexual debut at 15 years old, had only 2 lifetime partners with inconsistent use of protection. Previously tested for STI - negative

Physical Examination System Findings Vital signs General Appearance Awake, alert, very cooperative, not in acute distress HEENT NCAT, Pinkish palpebral conjunctiva, anicteric sclerae, moist mucous membranes, nasal septum midline, normal TM’s, no palpable CLAD Cardiovascular NSRRR, Normal S1 and S2, no murmurs, no rubs, no gallops Respiratory CTA b/l, GAEB, no crackles, no wheezes Abdomen Flat abdomen, non-distended, soft, normoactive bowel sounds, Extremities No edema, no cyanosis, cap refill <2 s

Neurologic Examination System Findings Mental Status Cooperative patient and oriented to person, time and place; appropriate affect Cranial Nerves CN 2-12 intact Motor/DTR See diagram  Sensory Decreased cold sensation over the right cheek Cerebellar No ataxia, dysmetria nor nystagmus Gait (+) Antalgic gait on the right Meningeal No meningeal signs 2+ 4/5 2+ 5/5 3+ 4/5 2+ 5/5

Differential Diagnosis Neurologic Ischemic vs Hemorrhagic Stroke Peripheral nerve disease Demyelinating Disease

And so the story goes… Concerned about ischemic stroke Labs were ordered IVF started MRI obtained

Laboratory Tests CBC Chemistries Parameter Results WBC count 5.3 Hemoglobin 15.9 Hematocrit 45.1 Platelets 201 N 56 L 32 Parameter Results Na+ 133 K+ 4.4 Cl- 100 CO2 29 BUN 14 Crea 1.0 Glucose 97 Calcium 9.5

Laboratory Tests CHEMISTRIES OTHER TESTS Parameter Results ALT 28 AST 24 Bilirubin 1.0 Albumin 4.1 Total Protein 6.5 Magnesium 21 Phosphorus 4.9 Parameter Results Vitamin B12 557 RPR Non-reactive Hepa C Ag Hepa C Ab HIV Negative ANA ESR 10

Cerebrospinal Fluid Studies CSF Cell count – normal CSF Proteins – 23 CSF Glucose – 79 CSF Oligoclonal bands - Negative

MRI (1/25/2012)

MRI (1/25/2012)

MRI (1/25/2012)

The Child with A Demyelinating Disease Vincent Patrick Uy, MD PGY-1 The Child with A Demyelinating Disease

Introduction No single diagnostic test is specific to particular diagnosis Must rely on History and PE, clinical features and imaging to arrive at a plausible diagnosis Uncommon in the pediatric age group Think of RARE disorders!

The Working Diagnosis Acute Disseminated Encephalomyelitis Multiple Sclerosis Optic Neuropathy Transverse Myelitis Neuromyelitis Optica

Pathophysiology

Leukodystrophies Adrenoleukodystrophies Cytoskeletal disorders (Alexander’s disease) Myelin Basic Protein disorder Organic acid diseases (Canavan disease) Disorders of energy metabolism (MELAS) Krabbe disease Rare disorders that are typically confused with more common disorders. Symmetric white matter disease is a hallmark of there cases. Imaging will produce a more diffuse picture.

Malignancies CNS lymphomas High-grade glioma Large area of tumefactive demyelination CSF studies show atypical cells

Collagen Vascular Diseases Systemic Lupus Erythomatosus Behcet’s disease Neurosarcoidosis Look for other symptoms Anti-dsDNA, anti-phospholipids, elevated ACE enzymes

Optic Neuritis May be a clinically isolated syndrome or part of another condition Monocular in most adults; bilateral in most children 12-15 years old. Symptoms can progress from several hours to days Risk factor for developing frank Multiple Sclerosis Correlates more if there are lesions developing outside the optic nerve

Optic Neuritis Headache Painful eye movements Partial or complete vision loss Relative afferent pupillary defect Papillitis (75% in the acute phase)

Optic Neuritis

Transverse Myelitis Spinal cord disease without evidence of compression Inflammation of the spinal cord May present as a clinically isolated disorder or part of other conditions. Most cases are idiopathic Subset of patients develop TM after vaccination

Transverse Myelitis Weakness, paresthesias, urinary and bladder problems Hyperacute presentation MRI shows contrast enhancing lesions on the cord Swelling of the segments at T2 imaging.

Transverse Myelitis Idi0pathic Transverse Myelitis Spontaneous but partial recovery in 1-3 months 40% will have a persistent disability

Neuromyelitis Optica Devic’s Disease Combination of: Optic neuritis Transverse Myelitis Seropositivity to NMO IgG antibodies >3 contiguous spinal levels involved Presentation can be primarily progressive with a fulminant course on presentation Any child with a severe and rapidly progressive clinical course should be investigated for NMO

Acute Disseminated Encephalomyelitis Acute or subacute onset of multifocal neurologic deficits with encephalopathy Often follows a viral infection or vaccination Very uncommon illness Autoimmune disorder of the CNS, triggered by environmental factors, in genetically susceptible individuals Any vaccine can cause ADEM, but as in most identified cases, the MMR vaccine has been implicated most of the time.

Acute Disseminated Encephalomyelitis CLASSIFICATION DESCRIPTION Classic Monophasic; happens only once Relapsing Recurs more than 3 months after recovery - or - More than 1 month from stopping steroids Recurrent Subtype of relapsing ADEM presenting with similar symptoms and MRI lesions Multiphasic Subtype of relapsing ADEM presenting with different symptoms and different MRI lesions The condition is very self-limited in recurrences that generally have no neurologic sequelae after an episode. Patients with ADEM, no matter what form, should have complete recovery to baseline.

Acute Disseminated Encephalomyelitis Clinical Presentation Febrile illness occurs in about 50-75% of children a month before neurologic symptoms appear. Headache and meningeal signs Encephalopathy (changes in mental status) Acute hemiparesis, cerebellar ataxia, optic neuritis and spinal cord dysfunction are also common ADEM typically lasts for about 2-4 weeks

Acute Disseminated Encephalomyelitis The lesions are typically bilateral. As the name implies, the lesions are disseminated in nature and will involve multiple sites, often with no particular pattern. Symptoms noted from large lesions are often related to mass effect.

Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis Treatment Fever, meningisimus, headaches, change in mental state, etc. Treat for suspected meningitis/encephalitis Imaging may be obtained High dose IV Glucocorticoids treatment for 3-5 days + steroid taper for 4-6 weeks Methylprednisolone (10-30 mg/kg/d) Dexamethasone (1 mg/kg/d) Appropriate IV antibiotics and acyclovir are usually considered – change in mental status in the setting of fever; maybe it’s a viral encephalitis? There is no evidence to support that prolonging steroid taper after IV steroids will result in faster recovery IVIG may also be used as rescue therapy in patients who do not respond to steroids Plasma exchange is recommended in patients with very extensive transverse myelitis with failure to respond to conventional treatments

Pediatric Multiple Sclerosis Chronic disease characterized by repeated episodes of demyelination separated by space and time Pediatric multiple sclerosis  age of onset before 16 years old 2.5/100,000 children

Pediatric Multiple Sclerosis Genetic Susceptibility Higher risk in monozygotic twins Certain HLA subtypes are associated with increased risk Environmental factors Epstein-Barr Virus infection Vitamin D deficiency Any viral or bacterial infection can increase the risk to develop MS. Among the most studied is EBV because of the molecular mimicry phenomenon. Research has also been geared toward poor sun exposure resulting in deficiency of vitamin D. Viamin D is an immunoregulatory effect by enhancing T-cell activity, up-regulation of anti-inflammatory cytokines and downregulation of pro-inflammatory cytokines. This factor is suggested by the higher incidence of MS in children in Northern hemispheres and among communities where sun exposure is limited.

Pediatric Multiple Sclerosis EBV nuclear antigen has similar structure to Myelin Basic Protein. The body will produce antibodies to EBV and these antibodies may gain access to the CNS.

Pediatric Multiple Sclerosis SUBTYPES OF MULTIPLE SCLEROSIS Description RELAPSING REMITTING MS Repeated episodes of MS with partial or complete recovery between episodes 97-99% of children PRIMARY PROGRESSIVE MS Continuous and worsening disease activity over time. Very rare in both adults and children CLINICAL ISOLATED SYNDROME Does not fit the diagnostic criteria of MS. Acute demyelination x 1 episode

Pediatric Multiple Sclerosis Diagnostic Criteria for Diagnosis of MS Dissemination in Space Dissemination in Time Another criteria called the POSER criteria may be useful in areas where MRI is unavailable. Because of the widespread use of MRI, the McDonald criteria has gained popularity.

Pediatric Multiple Sclerosis Dissemination in Space T2 lesions on MRI in at least two of the four MS-typical regions of the brain: Periventricular Juxtacortical Infratentorial Spinal Cord Development of a further clinical attack implicating a different CNS site The findings of a positive CSF oligoclonal bands was part of the criteria in the 2001 version. However, elevated CSF IgG depends on timing of CSF collection, age of the patient and the laboratory methods for assaying the protein. Thus, it was removed in the 2010 version of disseminatinon in space.

Pediatric Multiple Sclerosis Dissemination in Time Simultaneous presence of asymptomatic gadolinium-enhancing and non enhancing lesions at anytime or a new T2 lesion on a follow-up MRI (irrespective of timing) Development of a second clinical attack

Pediatric Multiple Sclerosis Clinically Isolated Syndrome INCREASED RISK for MS Age 10 years or older Optic nerve lesions MRI pattern very typical for MS DECREASED RISK for MS Spinal cord lesions Acute Mental status change (ADEM)

Pediatric Multiple Sclerosis Treatment strategy (Acute setting) IV pulse methylprednisolone 20-30 mg/kg/d x 5 days Steroid taper 1 mg/kg/day for 4-6 weeks if without complete resolution May re-treat with IV pulse methylprednisolone if symptoms recur during steroid taper

Pediatric Multiple Sclerosis Treatment strategy (Chronic Therapy) Glatiramer acetate Interferons For patients with recurrent attacks of MS, immunomodulatory agents may be considered. Treatment is based on family preference. However, randomized trials with these agents are lacking, and most studies were conducted in adults. This only shows the rarity of the condition. Alternate conditions should be considered in patients with progressive MS.

Pediatric Multiple Sclerosis Monitoring patients after and ACUTE ATTACK Completion of steroid taper Neurologic exam at 1/3/6 months thereafter For treatment failures, consider switching to immunomodulatory agents after stabilization. Treatment failure with immunomodulatory agents are beynd the scope of this lecture. Clinically stable Symptomatic Send for MRI Annual Physical Examination

Patient Update… Received 5 day high dose methylprednisolone therapy via IV Completed steroid taper with prednisone PO On follow-up 4/3/2012  Complete resolution of symptoms with return to baseline Dismissed as a case of Acute Demyelination – Clinically Isolated Syndrome

Let’s demyelinate YOUR neurons! A 9 year old girl with anxiety disorder was diagnosed with acute demyelination because of sudden onset of left sided weakness and ataxia. Typical MS lesions which included the cerebellum and spinal cord were discovered after MRI. She comes to the clinic for the first time after completing 6 weeks of steroid taper. On further questioning, mom has missed several doses of her prednisone at home. So far, she never experienced symptoms again. Mom is concerned that the catastrophe might happen again. Which of the following conditions increases her risk to develop frank multiple sclerosis? Non compliance to steroid taper Her young age Typical lesions were seen on MRI Concomitant anxiety disorder She doesn’t have risk factors that increase her risk to develop MS.

Now let’s give YOU ADEM! A 17 year old boy was brought to the ER for change in mental status. Ultimately, he was diagnosed with ADEM. He recovered after 5 days in the ICU and is now back to baseline. Which of the following environmental triggers could have increased his risk for developing the condition. Receiving an unrecalled vaccine from the PMD a month ago during annual visit Getting daily morning sun exposure for 15-20 minutes Blurring of vision without eye pain Experiencing an exudative sore throat which was negative on rapid strep test Spider bite 2 weeks ago

Thank You!