Approach to Milestone Regression
- 1. APPROACH TO MILESTONE REGRESSION DR. PIYUSH OJHA DM RESIDENT DEPARTMENT OF NEUROLOGY GOVT MEDICAL COLLEGE, KOTA
- 2. DEVELOPMENTAL REGRESSION • Delayed achievement of developmental milestones is one of the most common problems evaluated by child neurologists. • Two important questions : – Is developmental delay restricted to specific areas, or is it global? – Is development delayed or regressing? • Loss of developmental milestones previously attained usually indicates a progressive disease of the nervous system.
- 3. • The Denver Developmental Screening Test - an efficient and reliable method for assessing development. • Rapidly assesses 4 different components of development: • Personal- Social • Fine motor adaptive • Language and • Gross motor.
- 5. • A progressive deterioration of neurological functions - loss of speech, vision, hearing or locomotion ,often associated with seizure, feeding and intellectual impairment. • Neuroregressive / Neurodegenerative Disorders - a group of heterogeneous diseases which results from specific genetic, biochemical defect, chronic viral infection and toxic substances. • May involves both the gray matter and white matter
- 7. “PSEUDO-REGRESSION” • Increasing spasticity • New-onset movement disorder • New-onset seizures • Worsening of previous seizures/ NCSE • Severe malnutrition • Systemic illness • Progressive hydrocephalus • Parental misperception of attained milestones • Side effects of drugs • Emotional deprivation • Emotional problems: depression
- 8. APPROACH TO A CHILD WITH MILESTONE REGRESSION
- 9. IMPORTANT CONSIDERATION • Regression AND NOT Delay ???? • Age above 2 Years OR Less than 2 Years ??? • Is only the Central nervous system involved, or are other organs involved? – Other organ involvement suggests lysosomal, peroxisomal, and mitochondrial disorders.
- 10. IMPORTANT CONSIDERATIONS • Are the clinical features referable only to the central nervous system or to both the central and peripheral nervous systems? – Nerve or muscle involvement suggests mainly lysosomal and mitochondrial disorders. • Does the disease affect primarily the gray matter or the white matter? – Early features of • Gray matter disease - personality change, seizures, and dementia/cognitive decline. • White matter disease - Focal neurological deficits, spasticity, and blindness. – Whether the process begins in the gray matter or white matter, eventually clinical features of dysfunction develop in both.
- 11. Fenichel’s Clinical Pediatric Neurology 7th edition
- 12. Fenichel’s Clinical Pediatric Neurology 7th edition
- 13. Fenichel’s Clinical Pediatric Neurology 7th edition
- 14. Differentiating features White matter disorders Gray matter disorders Age of onset Usually late (childhood) Usually early (infancy) Head size May have megalenchepaly Usually microcepaly Seizures Late , rare Early, severe Cognitive functions Initially normal Progressive dementia Peripheral neuropathy Early demyelination Late, axonal loss Spasticity Early, severe Later, progressive Reflexes Absent(neuropathy) or exaggerated(long tracts) Normal or exaggerated
- 15. Differentiating features White matter disorders Gray matter disorders Cerebellar signs Early, prominent late Fundal examination May show optic atrophy Retinal degeneration EEG Diffuse delta slowing Epileptic form discharges EMG Slowed nerve conduction velocity Usually normal Evoked potentials (VEP, ABR) Prolonged or absent Usually normal ERG Normal Abnormal
- 17. ACQUIRED CAUSES Infections SSPE Progressive Rubella Syndrome Toxoplasma (8% cases) Chronic HIV infection Metabolic Chronic lead poisoning Hypothyroidism Vit B-12 & E deficiency
- 18. INHERITED CAUSES • Gray matter involvement: A. Gray matter involvement with visceromegaly – GM1 Gangliosides-Infantile , generalized , juvenile – Sandholf disease – Niemann pick Disease – MPS – Gaucher disease – Sialidosis
- 19. B. Gray matter diseases involvement without visceromegaly – Tay Sach disease – Rett Syndrome – Neuronal ceroid lipofuscinosis – Menke’s kinky hair disease
- 20. WHITE MATTER INVOLVEMENT Leukodystrophies – Metachromatic leukodystrophy – Krabbe disease – Adrenoleukodystrophy – Alexander disease
- 21. OBJECTIVE OF EVALUATION • Confirmation of Developmental regression • Categorization of domains involved • Identification of possible underlying etiology • Referral to appropriate rehabilitation services • Management of associated co-morbidities • Multidisciplinary approach • Counselling Shevell, 1998
- 22. • Birth history: – Term/preterm – Postnatal complications • Meningitis • Head trauma • kernicterus
- 23. • Developmental history: – Detailed development history- decide whether there is delayed development milestones or regression of milestones • Family history: – Family history of neurological disorder – Early or unexplained death – Nature of the neurological manifestations should be clarified • H/o of consanguinity - ethnic heritage – Origin from same village – Same last names
- 24. • Gestational history – Prior pregnancies/ abortions/ Early postnatal deaths – Adverse perinatal events – hypoxia/hypoglycemia – Delivery details – Apgar, birth weight – Duration of hospital stay/ difficulties in Nutrition – Possible neonatal encephalopathy : seizures, feeding difficulty, obtundation
- 25. • Developmental history – First domain of concern – Timing of milestones – Loss/regression – Current skill level in domains – Degree of independence in daily activities – Scholastic performance; special needs • Coexisting medical problems • Past medical history; treatment • Social history • Access to rehabilitation
- 26. CLINICAL EXAMINATION • General physical examination – Dysmorphism: Mitochondrial disorders, Neonatal adrenal leukodystrophy ,coarse facial features (MPS) – Occipito-Frontal Circumference – • Microcepaly (gray matter disease) • Megalenchepaly – certain white mater disorder(Cannavan & Alexander) – Jaundice – Enlarged tongue
- 27. • Skin & hair ( Hartnup Diseases-pellagra like skin rash, Menkes disease-kinky hair) • Examination of the spine- for associated complications (scoliosis) • Contractures of joints • Systemic examination: – Hepatosplenomegaly – Chest deformity – Cardiomyopathy
- 28. NEUROLOGICAL EXAMINATION • Higher mental function, signs of raised ICP • Speech, memory • Cranial nerves • Motor system: – Tone – Deep tendon reflexes • Sensory loss /neuropathy • Abnormal /involuntary movements • Gait
- 29. EYE EXAMINATION • Optic atrophy (white matter- due to demyelination) • Retinal degeneration (gray matter)- as the retinal receptors are neuronal cells): Cherry red spot, retinitis pigmentosa • Cataracts • Telengiectasias • K.F ring
- 30. INVESTIGATIONS • To identify the underlying diagnosis & associated complications • CBC- pancytopenia, vacuolated lymphocytes, acanthocytes • ABG - metabolic acidosis(organic acidopathies, urea cycle defects, mitochondrial encephalopathies) • Electrolytes (Anion gap), for adrenal insufficiency (adrenoleukodystrophy) • Ammonia level, LFTs, RFTs
- 31. • Special tests: – Lactate & pyruvate levels, Lysosomal enzyme level – WBCs, Fibroblast enzyme level – Wilson’s disease-serum ceruloplasmin level, serum copper – Amino acids – Urinary organic acids
- 32. • Urine – Reducing substances, Organic acids,24 hr (MPS) • Imaging – Skull & Vertebrae, Long bones – CT/MRI • Biopsy – Skin, Bone marrow, nerve, brain • Diagnosis – Important for genetic counseling • Outcome - Prognosis poor
- 33. BELIEVE IN HISTORY AND EXAMINATION !!! (GLOBAL DEVELOPMENTAL DELAY AND REGRESSION)
- 34. MANAGEMENT • Directed towards the treatment of the underlying disorder, other associated features and complications • Supportive : The treatable complications : • feeding difficulties, Gastoresophageal reflux • spasticity, drooling • skeletal deformities, and recurrent chest infections • epilepsy, sleep disorder, behavioral symptoms • A multidisciplinary approach (Pediatrics, neurology, genetics, orthopedics, physiotherapy, and occupational therapy).
- 35. SPECIFIC TREATMENT Neurodegenerative disorders Specific treatment modality Krabbe leukodystrophy Bone marrow transplantation Metachromatic leukodystrophy Bone marrow transplantation Adrenoleukodystrophy Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrow transplantation Mucopolysaccharidosis Bone marrow transplantation, recombinant human α-L-iduronidase Menkes kinky hair syndrome Copper sulfate
- 36. Neurodegenerative disorders Specific treatment modality Mitochondrial encephalopathies Nicotinamide, riboflavin, dichloroacetate, L-carnitine, CoQ10 Wilson disease D- penicillamine, trietine, zinc acetate, liver transplantation Refsum disease Reduction of phytanic acid intake Lesch-Nyhan disease Allopurinol Fabry’s Disease Recombinant human α galactosidase A
- 37. Guanidinoacetate Methyltransferase Deficiency • Rare but treatable disorder • Amidinotransferase converts glycine to guanidinoacetate and guanidinoacetate methyltransferase converts guanidinoacetate to creatine. • Autosomal recessive inheritance (19p13.3) • Affected children appear normal at birth and may develop normally during infancy. • By the end of the first year, development fails to progress and hypotonia is noted. • Regression of development follows and is associated with dyskinesias, dystonia, and myoclonic jerks.
- 38. • MRI -marked demyelination • MR Spectroscopy - creatine depletion and guanidinoacetate phosphate accumulation. • Management - Early oral administration of creatine monohydrate significantly prevents and reverses all symptoms, and late treatment provides some reduction of abnormal movements.
- 39. • Main defect - almost complete deficiency of the enzyme cystathionine- b -synthase (Picker and Levy, 2006). • Two variants – – B 6 - responsive & – B 6 –nonresponsive • AR inheritance HOMOCYSTINURIA
- 40. HOMOCYSTINURIA • Affected individuals appear normal at birth. • Neurological features - mild to moderate MR, ectopia lentis, and cerebral thromboembolism. • Developmental delay ( 50% cases) and intelligence declines progressively with age in untreated children. • Most eventually function in the mildly retarded range. • Intelligence generally higher in B 6 –responsive cases. • Thromboembolism - first clue to the diagnosis in 15% cases. • The presence of either thromboembolism or lens dislocation strongly suggests homocystinuria.
- 41. HOMOCYSTINURIA • Diagnosis - increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine b-synthase enzyme activity. • Molecular genetic diagnosis available. • Management. Challenge all patients with Pyridoxine (vitamin B 6 ) before starting treatment. • IF responsive – Pyridoxine (200 mg/day) • IF Not responsive - still receive doses of 100 to 200 mg/day. • All patients - protein-restricted diet. • Treatment with betaine, 5 to 10 g/day in two divided doses, provides an alternate remethylation pathway to convert excess homocysteine to methionine.
- 42. Autosomal Recessive Galactosylceramide b -galactosidase deficiency Myelin loss & presence of globoid bodies in white matter EARLY ONSET VARIANT : Symptom appear by 6 months ◦ Irritability Vomiting ◦ Bouts of hyperpyrexia Progressive hypertonicity Startle Myoclonus, Seizures UMN signs with areflexia Within 2 to 4 months, the infant is in a permanent position of opisthotonos, and all previously achieved milestones are lost. Blindness occurs, and before 1 year, 90% of these infants are either dead or in a chronic vegetative state.
- 43. LATE ONSET VARIANT : Neurological deterioration usually begins at 2-6 yrs. May start as early as the second year or as late as adolescence. Major features - Mental regression, cortical blindness, and generalized or unilateral spasticity. Initial feature may be progressive spasticity rather than dementia. Unlike the infantile form, peripheral neuropathy is not a feature of the juvenile form. Progressive worsening -> a vegetative state.
- 44. Investigations ◦ MRI – diffuse demyelination ◦ Leukocyte & Skin fibroblast enzyme level ◦ CSF Protein : Early variety – elevated Late Onset Variety - Normal ◦ Motor NCV: Markedly prolonged latencies Management - Hematopoietic stem cell transplantation slows the course of disease in children with infantile-onset Krabbe disease diagnosed before symptom onset. Neurological manifestations may reverse.
- 45. TAY SACHS DISEASE • N-acetyl- b -hexosaminidase deficiency • Intralysosomal storage of the glycosphingolipid GM 2 ganglioside. • Complete deficiency - Tay-Sachs disease • CNS – the only affected organ. • Partial deficiencies cause the juvenile and adult forms of GM 2 gangliosidosis.
- 46. TAY SACHS DISEASE • Typical initial symptom - between 3-6 months - an abnormal startle reaction (Moro reflex) to noise or light. • Motor regression begins between 4 and 6 months of age. • The infant comes to medical attention because of either delayed achievement of motor milestones or loss of milestones previously attained. • Cherry-red spot on macula present in almost every patient (NOT Pathognomic) • By 1 year - infant is severely retarded, unresponsive, and spastic. • 2nd year - the head enlarges and seizures develop. • Most children die by 5 years of age.
- 47. JUVENILE VARIANT :- • Often begins with ataxia and incoordination between 2 and 10 years of age. • Speech, life skills, and cognition decline. • Spasticity and seizures present by end of 1st decade • Loss of vision occurs much later than infantile form. • Cherry-red spot not a consistent finding. • Optic atrophy and retinitis pigmentosa occur late. • A vegetative state with decerebrate rigidity by 10-15 years. • Followed by death, usually due to infection. • Sometimes may follow a aggressive course, culminating in death in 2 to 4 years.
- 48. TAY SACHS DISEASE • Diagnosis - Suspect the diagnosis in any Jewish child with psychomotor retardation and a cherry-red spot on the macula. • Demonstration of absent to nearly absent b -hexosaminidase A enzymatic activity in the serum or white blood cells or Fibroblast. • Mutation analysis identifies the carrier state. • Management - Treatment is supportive.
- 49. Commonest AR inheritance (Chr 1q21) Deficiency of Glucocerebrosidase 5 types ◦ Type 1 – Perinatal lethal form – spares Brain ◦ Type 2 – onset < 2 years, rapidly progressive course by 2-4 years ◦ Type 3 – onset > 2 years, slowly progressive course with longer survival ◦ Type 4 ◦ Type 5 – cardiovascular form
- 50. Gaucher disease type 2 – symptom onset usually < 6 months • Initial features – motor regression and cranial nerve dysfunction. • Children are first hypotonic and then spastic. • Head retraction - an early and characteristic sign - probably due to meningeal irritation. • Difficulties in sucking and swallowing, trismus, and oculomotor palsies are typical. • Mental deterioration is rapid , seizures uncommon. • Splenomegaly >> hepatomegaly, jaundice not expected. • Hypersplenism - anemia, thrombocytopenia, and leukopenia. • Death usually occurs during the first year and always by the second.
- 51. Gaucher disease type 3 – • Age of onset – early childhood to adulthood • Hepatosplenomegaly usually precedes neurological deterioration. • MC neurological manifestations - seizures and mental regression (mild memory loss to severe dementia) • Myoclonus and myoclonic seizures present in many patients. • Combination of spasticity, ataxia, and cranial nerve dysfunction may be present. • Vertical oculomotor apraxia, as described in Niemann-Pick disease, may occur in late-onset Gaucher disease as well.
- 52. • Diagnosis – – Assay of acid b –glucosylceramidase enzyme activity in peripheral blood leukocytes or hepatocytes – Gaucher cells in bone marrow - pathognomic • Management - Symptomatic treatment includes partial or total splenectomy, blood transfusion, analgesics and supplemental treatment such as oral bisphosphonates for severe osteopenia. • Type 3 disease - may benefit from bone marrow transplantation to correct the metabolic defect. • Enzyme replacement therapy, using Imiglucerase (CEREZYME), is effective in reversing the hematological and liver/spleen involvement BUT NOT NEUROLOGICAL SYMPTOMS.
- 53. Bone marrow smear showing Gaucher cell. The cytoplasm has a fibrillary and striated appearance with nuclei small and eccentric in location MGG ×100
- 54. Absence of variety of lysosomal hydrolases involved in the catabolism of dermatan sulfate, heparan sulfate, or keratin sulfate. Defective degradation of Mucopolysacharides 7 types recognised – Type 1,2,3 and 7 affect nervous system Multisystem involvement Coarse facial features , Dwarfism , Kyphoscoliosis Macrocephaly, with or without communicating hydrocephalus Hepatosplenomegaly , Cardiovascular abnormalities Hearing loss , contractures
- 55. Type 1 & 3 – onset in infancy Type 2 & 7 – onset after > 2 yrs of normal development Type 2 – Hunter syndrome (X linked inheritance)- deficient Iduronate Sulfatase Diagnosis : - ◦ Mucopolysacchariduria with equal excretion of dermatan sulfate and heparan sulfate ◦ enzyme deficiency in cultured fibroblasts or serum. Enzyme replacement therapy with Aldurazyme, licensed for treatment of the non–CNS manifestations of MPS I, improves liver size, growth, joint mobility, breathing, and sleep apnea.
- 56. Onset is usually after age 2 with slow progression. AR inheritance Early development is normal. Mean age of onset = 3 years Cerebellar ataxia or dystonia is initial feature Apraxia of vertical gaze and cognitive difficulties follow (6yrs) Vertical gaze apraxia always suggests Niemann-Pick disease type C. Relentless progressive neurological degeneration. Dementia, seizures, and spasticity cause severe disability during the 2nd decade. Impaired cholesterol esterification and positive filipin staining in cultured fibroblasts confirm the diagnosis.
- 57. Inherited white matter disease Defect in myelin synthesis Involves brain, spinal cord and peripheral nerves. Classic dysmyelinating disorders are Adrenoleukodystrophy, Metachromatic Leucodystrophy, Krabbe's disease
- 58. Autosomal Recessive Arylsulfatase A deficiency deficiency Infantile (50-60% cases) and Juvenile variety(20-30%) Age at onset within a family usually similar. All individuals eventually lose motor and intellectual functions. The disease course - 3 to 10 or more years in the late- infantile-onset form and as long as 20 years or more in the juvenile- and adult-onset forms. Death – due to pneumonia or other infection. Treatment is mainly supportive .
- 59. Onset in late infancy • Hypotonia initially • Peripheral neuropathy • Dysarthria • Optic atrophy • Mental regression • Decorticate posture finally Expected life span ~ 3.5 years after onset of symptoms but can be as long > 10 years Onset at 5-10 yr • Deterioration in school performance • Alteration in personality • Incontinence • Seizures • Incoordination, Dysarthria • Gait disturbances • Spasticity • No peripheral neuropathy • Slow progression • Spastic quadriplegia eventually •Death usually during 2nd decade.
- 60. Life-threatening disorder deficiency of a peroxisomal acyl coenzyme A synthetase. occurring in males, affects white matter & adrenal gland. Very long chain fatty acids accumulate in the cells & tissues causing myelin sheath damage as well as dysfunction of the adrenal gland. X-linked form is the commonest Diagnosis is made by estimation of very long-chain fatty acids in plasma
- 61. AR Storage of auto fluorescent hydrophobic material in lysosomes of neurons & other tissue 3 subtypes – Infantile / Late infantile / Juvenile Symptoms/ Signs ◦ Myoclonic jerks , seizures (5-9 years) ◦ Visual symptoms ◦ Cerebellar ataxia ◦ Cognitive decline (5-9 years) ◦ Pigmentary abnormalities in retina (4-5 years)
- 62. Mean age of survival = 10 yrs Investigation Skin biopsy: ◦ Ultra structural abnormalities- characteristic Finger-print bodies Cortical biopsy: ◦ Distended neurons – characteristic Finger-print bodies ◦ Staining for ceroid & lipofuscinosis Treatment – symptomatic
- 63. Zellweger syndrome : dysmorphic features &severe psychomotor retardation, sensory neuronal deafness, peripheral neuropathy & hepatocellular degeneration. Diagnosed by demonstrating the elevated very long chain fatty acids, pipecolic acid and bile and derivatives.
- 64. Females affected only Mutations in the gene encoding methyl-CpG-binding protein-2, located on chromosome Xq28 Normal during 1st year Initial features - deceleration of head growth leading to microcephaly, lack of interest in the environment & hypotonia. Followed by rapid developmental regression characterized by loss of language skills, gait ataxia, seizures, and autistic behavior. Characteristic feature - loss of purposeful hand movements before the age of 3. Stereotyped activity develops that looks like hand wringing or washing.
- 65. Repetitive blows to the face – another stereotyped hand movement. Following the initial rapid progression - continued slower progression of neurological deterioration. Spastic paraparesis and quadriparesis - frequent endpoints. Dementia is usually severe. Stimulation produces an exaggerated stereotyped reaction consisting of jerking movements of the trunk and limbs with episodes of disorganized breathing and apnea followed by hyperpnea.
- 66. Seizures - most children before age 3 years. After the period of rapid deterioration, the disease becomes relatively stable, but dystonia may develop later. Patients usually survive into early adulthood An increased incidence of sudden, unexplained death. Diagnosis - Clinical features & molecular genetic testing. Management - Supportive.
- 67. Wilson’s disease AR Degenerative disease of basal ganglia Inborn error of copper metabolism Academic deterioration Behavioral changes , Dysarthria ,Dysphasia Drooling , Dystonia K F ring
- 68. Acquired Immunodeficiency Syndrome Encephalopathy • Human retroviral disease (Lentivirus subfamily) • Transplacental or perinatal transmission of HIV from mothers • Breast-feeding • The mother may be asymptomatic when the child becomes infected. • Evidence of infection is apparent during the first year in 30% of children born to AIDS-infected mothers. • Outcome is worse when the onset of symptoms is early, and the rate of progression in the child relates directly to the severity of disease in the mother. • 20% children present with severe symptoms or die in infancy.
- 69. Acquired Immunodeficiency Syndrome Encephalopathy • The spectrum of neurological and non-neurological manifestations in HIV-infected children is somewhat different from that of adults. • Hepatosplenomegaly and bone marrow failure, lymphocytic interstitial pneumonia, chronic diarrhea and failure to thrive, acquired microcephaly, cerebral vasculopathy, and basal ganglia calcification occur more frequently in children. • Opportunistic infections (e.g., cerebral toxoplasmosis, progressive multifocal leukoencephalopathy) are rare in infants.
- 70. Acquired Immunodeficiency Syndrome Encephalopathy • AIDS encephalopathy - subacute or indolent • Not necessarily associated with failure to thrive or opportunistic infections. • Onset of encephalopathy may occur from 2 months to 5 years after exposure to the virus. • 90 % affected infants show symptoms by 18 months of age. • Progressive loss of developmental milestones, microcephaly, dementia, and spasticity characterize the encephalopathy. • Other features (< 50% cases) - ataxia, pseudobulbar palsy, involuntary movement disorders, myoclonus, and seizures. • Death usually occurs a few months after the onset of AIDS encephalopathy.
- 71. Acquired Immunodeficiency Syndrome Encephalopathy • DNA PCR - preferred method for the diagnosis in infants and children > 18 months of age. • Combined treatment with zidovudine (azidothymidine), didanosine, and nevirapine is well tolerated and may have sustained efficacy against HIV-1.
- 72. Form of chronic measles encephalitis In a nonimmunized population, the average age at onset is 8 years. As a rule, children have experienced natural infection with the rubeola virus at an early age, half of them before age 2 years. First symptoms - Personality change and declining school performance. Personality change - aggressive behavior or withdrawal.
- 73. • Retinal examination during early stage shows pigmentary changes in the macula. • Generalized seizures, usually myoclonic, develop next. • EEG - characteristic pattern of periodic bursts of spike-wave complexes (approximately every 5–7 sec) occurring synchronously with the myoclonic jerk. • After the onset of seizures, the child shows rapid neurological deterioration characterized by spasticity, dementia, and involuntary movements. • Within 1 to 6 years from the onset of symptoms, the child is in a chronic vegetative state.
- 74. • Diagnosis – demonstration of an increased antibody titre, usually associated with increased g –globulin concentrations, in the CSF. • Intraventricular interferon-alfa combined with oral isoprinosine, 100 mg/kg/day. • Repeat courses up to six times at 2- to 6-month intervals.
- 75. THANK YOU
- 76. REFERENCES • Bradley’s Neurology in clinical practice 6th edition • Adams & Victor’s Principles of Neurology 10th edition • Fenichel’s Clinical Pediatric Neurology 7th edition
- 77. COST OF VARIOUS TESTS AT DNA LABS INDIA