Neuroscience Lectures Child Neurology

1. Neuroscience LecturesChild Neurology November 12, 2009 Gail I. Schuman, DO Department of Neurology

2. Objectives Know normal development Learn about Neural Tube Defects and associated conditions Learn about some common conditions that can lead to abnormal development: before birth at birth due to genetic/metabolic abnormalities

3. Initial Development The part that is important for neural development is the ectoderm All neural tissue arises from the ectoderm Process is very complex

4. Neural Tube Formation Gastrulation Formation of 3 primary germ layers needed for induction (ecto-, endo- mesoderm) Primary Neurulation Formation of Brain and Spinal Cord Secondary Neurulation Formation of Lower Sacral Segments of the Spinal Cord

5. Gastrulation Formation of primary germ layers needed for the inductive processes to follow Formation of neural tube at 3rd and 4th weeks of gestation

6. Gastrulation Induction of neural plate by notochord Folding into neural tube Joining of edges Neural tube is ectoderm Neural crest cells form dorsal root ganglia Neural tube forms nervous system

7. Primary Neurulation First fusion of neural fold occurs at the level of the medulla (upper cervical region) at about 22 days � so the tube fusion doesn�t occur all along the tube all at once Closure proceeds both rostrally and caudally Anterior end closes at about 24 days Caudal end closes at about 26 days Lower end closure is at the lumbosacral level, more caudal cord segments are formed during secondary neurulation

8. Primary Neurulation Process is dependent on a variety of cellular and molecular and signaling mechanisms Most important cellular mechanisms involve the function of the cytoskeletal network of microtubules and microfilaments - movement Microtubules are involved in development of neural plate Microfilaments lead to formation of neural folds and then the neural tube Molecular mechanisms involve cell-cell recognition and adhesive interactions

9. PROLIFERATIVE ZONE Ventricular or Proliferative zone starts as a single layer of ectodermal cells that lines the inner margin of the neural tube. Proliferative zone begins to divide at Embryonic Day (ED) 28. Both neurons and glial cells are produced in the proliferative zone.

10. Proliferative Zone This development of zones occurs along the length of the neural tube Different parts of the neural tube will form different parts of the nervous system Upper level � brain Lower level � spinal cord

11. PROLIFERATIVE ZONE- symmetric division - Symmetric division = each cell gives rise to two identical daughter cells. Each round of mitosis doubles the number of cells in the proliferative zone. ED 28 � ED 42 (a 2 week time period!!) Cells produced during this period are called �progenitor cells�. Progenitor cells are multipotent cells that give rise to both neuronal and glial lineages.

12. PROLIFERATIVE ZONE- asymmetric division - Asymmetric division = each cell gives rise to one identical daughter cell and one more differentiated (committed) cell. Begins after ED 42 Committed cells migrate away from the proliferative zone.

13. PROLIFERATION Most neurons are produced in the first half of the pregnancy � between Embryonic Day (ED) 42 and 125 Within a region most neurons are produced before most glial cells Without cell signaling causing inhibitory signals, all the cells would become neurons

14. A SINGLE CELL UNDERGOING DIVISION Interactions between adjacent cells direct what type of neuronal cell will be formed Asymmetric division of cells occurs Cells divide to become two identical cells (glia) or two different cells (one glia, one neuron)

15. BIRTHDAY OF A NEURON Cell birthday is a day on which an individual cell stops dividing and migrates out of the proliferative zone. On its birthday the cell is considered to be a Primitive Neuron.

16. MIGRATION The Primitive Neuron moves out of the proliferative zone, but only for a small distance. It is pushed out by newly born neurons. So, the earliest formed neurons are furthest from the proliferative zone.

17. JOURNEY THROUGH RADIAL GLIA Radial glia form a scaffold that extends from the proliferative zone to the outer edges of the brain. When primitive neuron is pushed by newly born neurons, it attaches to the radial glia and propels itself along. It �recognizes� its final destination and detaches from radial glia.

19. What happens when things go wrong?

20. Primary Neurulation Disorders Craniorachischisis - total failure of neurulation Anencephaly - failure of anterior tube closure Myeloschisis - failure of posterior tube closure Encephalocele - restricted disorder of neurulation involving anterior tube closure Myelomeningocele - Restricted failure of posterior tube closure

21. Neural Tube Defects Epidemiology Incidence 3-6/10000 in US � decreasing due to folate supplementation as preventative measure F>M Whites > Blacks, Asians Higher incidence in poorer socioeconomic class Genetics Familial tendency, non-Mendelian, multiple genes involved. Risk of one child with spina bifida is 0.05%. If one sibling is affected, risk increases to 5%, if two sibs affected, risk rises to 12-15%

22. Anencephaly Complete failure of anterior closure Worst case is level of Foramen Magnum up (holoanencephaly) If not to foramen magnum then called meroanencephaly Usually involves forebrain & part of brainstem

23. Anencephaly Exposed neural tissue is a hemorrhagic, fibrotic, degenerated mass of neurons and glia No defined structure Frontal bones, parietal bones and squamous part of occipital bones are usually absent Gives patient a frog-like appearance when viewed from the front Timing onset is no later than 24 days gestation Associated with polyhydramnios in mother

24. Anencephaly 75% are stillborn, remainder die as neonates, 60% die by 24 hrs, 85% dead at 48 hrs, 98% at 7 days, nearly all by 14 days More common in whites than blacks, in Irish more than any other ethnic group Most often female (F:M = 37:1) More common in very young mother or very old mother 0.2 per 1000 in US

25. Encephalocele Restricted/Partial failure of anterior tube closure Pathogenesis unknown Occipital region 70-80% of cases Occasionally frontal with protrusion into nasal cavity Protruding brain tissue is usually from occipital lobe with normal gyri and subcortical white matter (i.e., brain tissue is normal) 50% of cases have associated hydrocephalus

26. Encephalocele Onset no later than 26 days GA Later onset causes cases involving overlying meninges or skull Associated with subependymal nodular heterotopia 1/5000 live births worldwide 60-70% require shunts for hydrocephalus

27. Partial Failure of Anterior Closure

28. Myelomeningocele Restricted failure of posterior tube closure 80% of lesions occur in lumbar region, the last area to close Many associated with dorsal displacement of neural tissue creating a sac on the back Onset no later than 26 days Most survive, highest incidence in Ireland and Great Britain Herniation of meningeal tissue and nervous tissue through defect in skull or spine

29. Myelomeningocele Neurological function disturbances depends on level of the lesion Important to examine motor, sensory and sphincter function Lesions below S1 - walk unaided Lesions above L2 - wheelchair dependent, and develop significant scoliosis L3 � ambulatory with aids L4/L5 - ambulatory

30. Myelomeningocele

31. Myelomeningocele - Hydrocephalus Hydrocephalus can be present in 80% by 2-3 weeks - examine fontanel and cranial sutures Pulls cord downward and blocks CSF flow, compression of ventricular and ductal system Monitor head circumference: HC > 90%ile then 95% chance HC < 90%ile then 65% chance The lower the lesion, the more chance of hydrocephalus � more traction on cord Dx: serial CT or US

32. Myelomeningocele - Arnold-Chiari Malformation When myelomeningocele is below thoracic level Inferior displacement of medulla and fourth ventricle, elongation and thinning of upper medulla, lower pons with persistence of embryonic flexure, inferior displacement of lower cerebellum through foramen, bony defects Associated with syrinx in cervical spinal cord

33. Myelomeningocele - Encephalocele Treatment Careful consideration of delivery of infant by cesarean section Human fetal surgery - lower rate of needing VP shunt later Early closure of back lesion if feasible Prevention of infection VP Shunt for Hydrocephalus - earlier surgery improves cognitive function of infant Decompressive upper cervical laminectomy for Arnold-Chiari malformation

34. Etiology Multifactorial inheritance Single mutant genes - e.g., Meckel Syndrome (Chrom 17, MKS1, large dysplastic kidneys, occipital encephalocele, polydactyly) Chromosomal abnormalities - e.g., trisomies Rare syndromes with unknown transmission Specific teratogens (valproate, thalidomide) Phenotypes of unknown cause - cloacal extrophy, myelocystocele Increased occurrence in sibs with one affected sib

35. Prevention - Prenatal Diagnosis Increased levels of alpha - fetoprotein in maternal serum Optimum test time at 16 - 18 weeks of gestation Also can use ultrasound for prenatal diagnosis Prevention by vitamin and folate supplementation - lack of folate causes increase in homocysteine which has been shown to cause neural tube defects in avian embryos

36. Occult Dysraphic States Disorders of Secondary Neurulation in development of lower sacral and coccygeal segments Incorporation of mesodermal and/or epithelial elements or incomplete fusion of elements They will have a covering of intact skin and are lower on the back (skin cover is already formed) Timing is 4th to 6th week of gestation

37. Spina Bifida - Comparison

38. Spina Bifida

39. Spina Bifida

40. Intrauterine Infections

41. TORCH(S) Infections Organism Route Time Symptoms Symp Asymp Toxoplasmosis Transplacental T1, T2 + ++++ Syphilis Transplacental T2, T3 + ++++ HIV Transplacental T2-T3, birth + ++++ Parturitional Rubella Transplacental T1 ++ +++ CMV Transplacental T1, T2 + ++++ Herpes simplex Ascending Birth ++++ + Parturitional

42. Common outcomes of TORCH infections Microcephaly MR (IQ<50) � Abnormal Brain Development Cerebral Palsy Seizures Sensorineural hearing loss Ocular pathology (cataracts, chorioretinitis) Always ask about febrile illness during pregnancy, flu-like illness, even any minor illness

43. TORCH infections - unique features - CMV: Periventricular calcifications Cerebellar hypoplasia � 33% Migrational disorders Polymicrogyria � 33% Lissencephaly � 7% Schizencephaly Toxoplasma: Granulomatosis Diffuse cerebral calcifications Hydrocephalus

44. Congenital CMV infection - periventricular calcifications + cerebellar hypoplasia

45. Toxoplasmosis Can present with lymphadenopathy and mild flu-like symptoms in mother Hard to determine if this CT is CMV or Toxo � both types of calcifications are present

46. TORCH infections - unique features - Rubella: Vasculopathy with focal ischemic necrosis Delayed myelination Chorioretinitis (Toxo also can have) Meningoencephalitis Hearing loss Herpes: Multifocal parenchymal necrosis hemorrhagic Multicystic encephalomalacia

47. Chorioretinitis

48. Herpes simplex: multicystic encephalomalacia 2/1000 mothers HSV+ Most babies are born asymptomatic Irritable, poor feeding, bulging fontanels, temp instability, fever Only some will have vesicular rash

49. What happens when things go wrong?

50. Neonatal Neurology Intraventricular hemorrhage Hypoxic-Ischemic encephalopathy Periventricular Leukomalacia

51. INTRAVENTRICULAR HEMORRHAGE Bleeding of Germinal Matrix around frontal horns of ventricles Can bleed within the germinal matrix (subependymal hemorrhage � Grade I) Can bleed into the ventricles as well (intraventricular hemorrhage � Grades II & III) Can also bleed into parenchyma and ventricles (Grade IV) Primarily occurs in premature babies

52. Germinal Matrix and ZonesFetal MRI at 23 weeks GA Arrowhead � germinal matrix Single arrow � ventricular or proliferative zone Dbl arrow � subventricular or intermediate zone Dbl arrowhead � subplate Triple arrow � developing cortex or marginal zone

53. Germinal matrix size Size Gestational age 2.5mm 23-24 weeks 1.4mm 32 weeks 0.0mm 36 weeks We now know that there is persistent stem cell development in both the brain and the spinal cord

54. Ventricular System Blood can move through the ventricular system As blood clots it will block the free flow of CSF � usually within the ventricle where bleeding took place Gravity will make blood accumulate in back of head also (babies are lying down)

55. Neuropathological consequences Germinal matrix destruction � loss of stem cells for neuronal/glial development Depending on timing of IVH � usually glial cells are more affected (remember neurons are made first and early) Periventricular white matter changes hemorrhagic infarction (PVHI) leukomalacia (PVL) Posthemorrhagic hydrocephalus

56. Intraventricular Hemorrhage Left � Grade II � no change in size of ventricle, confined to ventricle Right � Grade IV � ventricle nearly obliterated, bleed into brain parenchyma

57. Hydrocephalus after IVH Occurs 1-3 weeks after IVH Rapidity of evolution directly correlates with severity of hemorrhage Clinically - rapid head growth - signs of increased ICP CT head � anterior horns dilate before and more severely than posterior horns May require ventriculo-peritoneal shunting

58. Hydrocephalus Originally a right sided IVH resulting in right sided hydrocephalus Left sided symptoms in child Spastic hemiparesis Focal seizures

59. Break Time!!

60. HYPOXIC-ISCHEMICENCEPHALOPATHY Loss of oxygen (hypoxia) to the brain for prolonged amount of time Long enough to cause a stroke (ischemia) Diffuse process as opposed to a stroke in an elderly person which is a focal process

61. Causes of Drop in Oxygenation Maternal shock hypoxia placental thrombophlebitis (blocks flow) abdominal trauma hypo/hypertension Fetal infection (arteritis, hypotension) hydrops fetalis � compression of heart fetal embolism (placenta, other sources) fetofetal transfusion Placental premature placental separation excessive placental infarction

62. Clinical features Stupor or Lethargy Hypotonia (Floppy) > hypertonia Weakness Abnormal sucking, swallowing and gag, poor feeding Seizures

63. Hypoxic Ischemic Event Loss of oxygen causes neuronal tissue damage Cystic lesions where neurons are lost � diffuse � all over High signal in thalami indicative of loss of oxygen

64. Periventricular Leukomalacia Damage to the white matter around ventricles Location and extent of damage will define the disability of the patient

65. Cerebral Palsy

66. What happens when things go wrong?

67. Genetic Disorders

68. Metabolic disorders Mainly Autosomal Recessive Defects in Amino Acid, lipid or protein metabolism - mostly do not affect brain size Storage diseases - may cause macrocephaly

69. Urea Cycle Disorders Deficiency in pathways responsible for urea synthesis Multiple possible defects (5 enzymes in pathway) Most have increased ammonia levels which cause symptoms All are autosomal recessive except Ornithine Transcarbamylase (OTC) which is X-linked

70. CPS1 � Carbamyl Phosphate Synthetase Arginase deficiency does not cause symptoms in the newborn 1/30,000 birthsCPS1 � Carbamyl Phosphate Synthetase Arginase deficiency does not cause symptoms in the newborn 1/30,000 births

71. Ornithine Transcarbamylase (OTC) Deficiency Urea Cycle deficiencies have an incidence of 1/30,000 Age of onset of OTC Deficiency: newborn (males); childhood (females) X-linked recessive - M > F

72. OTC Deficiency Homozygote Males Usually normal at birth with onset of symptoms 24-72 hours after feeding (protein load) 1. Neurological Manifestations lethargy -> coma infantile hypotonia neonatal seizures 2. Gastrointestinal Manifestations persistent vomiting (+/- dehydration) poor feeding hepatomegaly 3. Others hyperventilation (due to a respiratory alkalosis) hypothermia

73. OTC Deficiency  Heterozygote Females In 10% of heterozygote females, onset of symptoms in childhood characterized by recurrent episodes of: 1. Neurological Manifestations lethargy -> coma acute ataxia hyperactivity migraine-like headaches 2. Gastrointestinal Manifestations persistent vomiting (+/- dehydration) hepatomegaly triggered by sudden protein loads or intercurrent infection

74. OTC - Diagnosis 1. Serum hyperammonemia >500 mM homozygotes >100 mM heterozygotes normal anion gap; respiratory alkalosis amino acids low citrulline and arginine elevated glutamine and alanine 2. Urine high orotic acid 3. Diagnosis deficiency of OTC activity in liver, duodenal, and rectal tissue samples (but not leukocytes or cultured skin fibroblasts)

75. OTC - Management Diet - Protein Restriction High Calorie/Protein Restricted Diet to minimize tissue catabolism and thus the breakdown of endogenous protein, limit nitrogen, supplement arginine Convert Nitrogen to an Excretable Compound 1. Sodium Benzoate - conjugates with glycine and excreted as hippuric acid 2. Sodium Phenylacetate - conjugates with glutamine and excreted as phenylacetyl-glutamine 3. Dialysis

76. OTC - Prognosis 100% mortality if untreated a direct correlation between the duration of hyperammonemic coma and morbidity (mental retardation, developmental delays, cortical atrophy) good prognosis if disorder is treated prospectively from birth

77. NEUROCUTANEOUS DISEASES Remember that the nervous system was derived from ectoderm The skin is also derived from ectoderm Skin lesions can be indicative of a problem within the nervous system as well Neurofibromatosis 1&2, Tuberous Sclerosis

78. NEUROFIBROMATOSIS 1 (NF1) Incidence: ~1:3,300 � pretty common Inheritance: Autosomal Dominant New Mutations: 50% Penetrance: 100% (variable expressivity) Gene Defect: Neurofibromin (NF1) on 17q11.2 Pathophysiology: NF1 protein related to ras GTPase downregulates cellular growth & proliferation. LOF leads to loss of this tumor suppressor activity

79. WHO WAS VON RECKLINGHAUSEN? German physician 1800�s 1862- Introduced the term hemochromatosis 1882- Recognized the origin of neurofibromas from peripheral nerves NF1 is also called Von Recklinghausen disease

80. NEUROFIBROMATOSIS 1 (NF1) NIH criteria for NF1 Caf�-au-lait spots, 6 or more > 5mm in prepubertal child > 1.5 cm in postpubertal child Two or more neurofibromas or 1 plexiform neuroma Axillary or inguinal freckling Optic Glioma Lisch Nodules (Iris Hamartomas) Dysplasia or thinning of long bone cortex 1st degree relative with NF1

81. NEUROFIBROMATOSIS 1 (NF1) Learning Disabilities ADD (not ADHD) Performance IQ < Verbal IQ (Mean IQ: 90-95) Lifetime cancer risk: ~5% Optic glioma Pheochromocytoma Malignant peripheral nerve sheath tumors Juvenile chronic myelomonocytic leukemia Rhabdomyosarcoma Astrocytomas, schwannomas, neuroblastomas

82. NEUROFIBROMATOSIS 1 (NF1)

83. NEUROFIBROMATOSIS 1 (NF1) Prognosis: Life Expectancy: Reduced by ~15 years Major Mortality: Malignant peripheral nerve sheath tumors (1-4% of pt�s) Major Morbidity: Plexiform Neurofibromas (Disfigurement, loss of function) Optic Pathway Gliomas (Disfigurement, loss of vision, affect chiasm)

84. NEUROFIBROMATOSIS 2 (NF2) Incidence: 1:40,000 � much less common Inheritance: Autosomal Dominant New Mutations: 50% Gene Defect: NF2 gene on 22q Pathophysiology: Protein product, Merlin/Schwannomin, is a tumor suppressor Onset: 18-24 yo (range 2-70 yo) Negative MRI at 30 yo essentially excludes NF2 Multiple CNS tumors- rarely malignant

85. NEUROFIBROMATOSIS (NF2) - Diagnostic Criteria NIH Diagnostic Criteria B/L vestibular schwannomas (acoustic neuromas) � 95% 1st degree relative with NF2 plus unilateral acoustic neuroma before age 30 yrs Any 2 of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular opacity No distinct skin lesions, but can have caf�-au-lait spots but not diagnostic featureNo distinct skin lesions, but can have caf�-au-lait spots but not diagnostic feature

86. NEUROFIBROMATOSIS 2 (NF2) Left � bilateral acoustic neuromas Right - meningioma

87. NEUROFIBROMATOSIS (NF2) Genetic Testing DNA based testing - Sequencing 65% sensitivity Linkage (2 or more affected individuals) Treatment (ENT, NeuroSurg, Neurology) Supportive/Symptomatic No disease altering therapy Acoustic Neuromas: small (<1.5cm): Surgical excision large (>1.5 cm): Debulking

88. TUBEROUS SCLEROSIS Incidence: 1:6,000 Inheritance: Autosomal Dominant New Mutations: 66% Gene Defect: TSC 1 (hamartan) on 9q34 TSC2 (tuberin) on 16p13.3 TSC3, TSC4 Pathophysiology: All tumor suppressor genes. LOF leads to loss of tumor suppressor activity Penetrance: 100% (variable expressivity)

89. TUBEROUS SCLEROSIS Classic triad: Adenoma Sebaceum (Angiofibroma; 50-80%) Epilepsy (~75%) Mental Retardation/Dev. Disability (~50%) Diagnostic Criteria (1999 NIH Consensus) Definite TSC: Two major features or one major feature plus two minor features Probable TSC: One major feature plus one minor feature Possible TSC: One major feature or two or more minor features

90. Tuberous SclerosisSkin Manifestations Ash-Leaf Macules � hypopigmented lesions in 87% of pts, congenital Confetti Macules � 1-3mm, hypopigmented, on pretibial area Shagreen Patches (subepidermal fibrous patches) � 1-10cm, flat, flesh-colored plaque, mainly in LS region, with orange-peel appearance Facial Angiofibromas (adenoma sebaceum) diagnostic of TS, appear between age 4 � 10 yrs Koenen tumors on nail plates (ungual fibroma), appear at puberty

91. Tuberous SclerosisDiagnostic Criteria Major Adenoma sebaceum, ungual fibroma, hypomelanotic patches, Shagreen patch, Cortical Tuber, Subependymal Nodule, Subependymal Giant-Cell Astrocytoma, Retinal Hamartomas, Cardiac Rhabdomyoma, Renal Angiomyolipoma, Facial plaques Minor Dental pitting, rectal polyps, bone cysts, white matter migration tracts, gingival fibromas, confetti skin lesions, renal cysts

92. TUBEROUS SCLEROSIS Clinical signs of Tuberous Sclerosis

93. TUBEROUS SCLEROSIS Cardiac Rhabdomyoma 50-80% of patients with cardiac rhabdomyoma have TS � can be present at birth Frequently multiple May cause LV obstruction, arrhythmia, CHF Regress with age Epilepsy Frequently have Infantile Spasms in childhood 20% of patients with Infantile Spasms have TS Treatment of choice is ACTH or Vigabatrin Variety of types in adults

94. Tuberous Sclerosis Cortical Tubers � nodules of glial proliferation occurring in cortex, ganglia or ventricle walls Other CNS tumors subependymal hamartomas, paraventricular calcifications (�Candle Gutterings�) giant cell astrocytomas

95. Tuberous Sclerosis Left � Cortical Tubers � MRI Right � Paraventricular Calcifications - CT

96. TUBEROUS SCLEROSIS Prognosis Major mortality is due to uncontrolled Epilepsy & MR Renal Disease Tumors Otherwise may have normal lifespan

97. Leukodystrophies Diffuse Cerebral Degenerative Diseases affecting the white matter Grouped by the characteristics of the myelin breakdown that occurs Demyelinating � loss of myelin Dysmyelinating � cannot form appropriate myelin Myelinolytic � irregular breakdown of myelin (spongy myelinopathy)

98. Dysmyelinating Diseases Classical � Adrenoleukodystrophy Globoid cell leukodystrophy (Krabbe) Metachromatic leukodystrophy Hypomyelinative � Pelizaeus-Merzbacher disease Alexander disease Spongiform - Canavan disease Miscellaneous � Vanishing white matter disease Cockayne�s syndrome

99. Common Featuresof Leukodystrophies Reduced brain weight Optic nerve atrophy Ventriculomegaly � due to loss of brain tissue Atrophy of corpus callosum � basically the CC is all white matter Sparing of Subcortical U fibers � except Canavan and PMD B/L symmetrical, diffuse to confluent loss of cerebral and cerebellar wm - except PMD PMD � Pilezeus-MerzbacherPMD � Pilezeus-Merzbacher

100. Common Microscopic Features Reduced myelin staining Loss of oligodendrocytes � which produce myelin sheathing in CNS Macrophages with myelin debris Reactive astrocytosis (early) � try to fix Fibrillary astrogliosis (late) � fibrous scar Significant axonal loss eventually

101. Adrenoleukodystrophy Disorder of the peroxisomes Transmitted as a X-linked trait Accumulation of very long chain fatty acids (VLCFA) Due to impaired function of peroxisomal membrane transporter protein Results in the accumulation of saturated, VLCFA in the rough Endoplasmic Reticulum of tissues throughout the body Leads to progressive dysfunction of CNS white matter and the adrenal cortex.

102. ALD - Epidemiology Incidence: 1/10,000 Childhood and Adult onset forms Familial - X-linked recessive Chrom Xq28 (terminal segment) gene: peroxisomal membrane protein that is part of ATP Binding Cassette transporter superfamily (Gene is ABCD1 coding protein ALDP) Affects synthesis of VLCFA-CoA and transport across membrane into peroxisome >500 mutations reported

103. ALD � CNS Pathology CNS White Matter acute and symmetric demyelinating lesions perivascular infiltration of lymphocytes at least 1/3 of patients with ALD are free of neurological manifestations and thus CNS involvement may depend upon some factor other than VLCFA accumulation No correlation between genotype and phenotype considered one of the degenerative diseases of white matter of the cerebral cortex

104. ALD - Neurologic Manifestations 1. Presenting Symptoms - Childhood Normal until about 4 � 8 years old, progressive neurological dysfunction � gait disturbances Impaired auditory discrimination - difficulties hearing speech in a noisy room or over the telephone parietal lobe dysfunction - construction & dressing apraxia, stereognosis, graphesthesia, impaired spatial orientation visual disturbances - field cuts, strabismus, visual acuity focal or generalized seizures (33%)

105. ALD - Neurologic Manifestations 2. Later Symptoms tends to progress rapidly with increased spasticity and paralysis, visual and hearing loss, and bulbar musculature dysfunction (loss of ability to speak +/- swallow), cognitive loss -> vegetative state mean interval between onset of neurologic symptoms and the vegetative state is 1.9 +/- 2 years may continue in vegetative state for >10 years

106. ALD - Endocrine Manifestations Primary adrenal insufficiency FTT, nausea & vomiting, postural hypotension, weakness, weight loss, salt craving mild hyper-pigmentation (over joints, scar tissue, lips, nipples, buccal mucosa) usually presents after the neurologic manifestations

107. ALD � Diagnosis 1. VLCFA very high levels of VLCFA in the plasma (C26, C24 saturated fats) positive in 100% of affected males positive in 85% of carrier females Mutation Analysis 2. Adrenal Insufficiency hyponatremia, hyperkalemia, mild metabolic acidosis low serum cortisol level with elevated ACTH levels impaired cortisol response to ACTH stimulation in 85% 3. MRI imaging Cerebral White Matter Lesions (80%) even in the early stages, striking changes may be found

108. ALD � MRI Imaging Left - FLAIR image showing myelin loss, appears flame-like Right � T2 after contrast shows leading edge of demyelination

109. Adrenoleukodystrophy White matter tracts � Diffusion Tensor MRI Left � Normal Right - Adrenoleukodystrophy

110. ALD - Management Adrenal hormone replacement mandatory, life-saving, no effect on CNS symptoms Bone marrow transplant mild progressive cerebral involvement Diet - to decrease both the exogenous source of VLCFA and the endogenous production of VLCFA (Lorenzo's Oil) Gene therapy trial

111. References Clinical Pediatric Neurology � Fenichel Fundamental Neuroscience for Basic and Clinical Applications � Haines Neurology of the Newborn - Volpe Principles of Neural Science � Kandel Child Neurology - Menkes My patients Good Luck on the exam � We have only scratched the surface!