an approach to a child with regression of milestones

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An approach to a child with regression of milestones:

An approach to a child with regression of milestones Dr. Anita Lamichhane

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Regression: when child loses previously acquired skills and milestones A progressive deterioration of neurological functions with loss of speech,vision,hearing or locomotion ,often associated with seizure, feeding and intellectual impairment

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Neuroregressive /neurodegenerative disorders are a group of heterogeneous diseases which results from specific genetic, biochemical defect, chronic viral infection, toxic substances Involves both the gray matter and white matter

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Dementia, used for neurodevelopmental regression in children, is associated with loss of memory, ability to think, understand and recognize along with personality changes or distressing behaviour

Gray matter & White matter:

Gray matter & White matter Striations seen in white mater

White matter:

Contains mostly myelinated axons Appears pinkish white to the naked eye ( myelin is composed largely of lipid tissue veined with capillaries ) A 20 year-old male has a 176,000 km of myelinated axons in his brain while that of a female is 149,000 km connect various grey matter areas (the locations of nerve cell bodies) of the brain to each other, and carry nerve impulses between neuron White matter

Gray matter:

Major component of the CNS having a grey –brown color(due to capillary blood vessels & neurinal cell bodies) Consists of neuronal cell bodies ( in contrast to white matter) neuropil ( dendrites and both unmyelinated axons and myelinated axons) glial cells ( astroglia and oligodendrocytes ) & capillaries . Gray matter

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T he grey matter includes regions of the brain involved in muscle control, sensory perception such as seeing and hearing, memory, emotions, and speech .

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Gray matter Disease White matter Disease Processing center Represents networking between these centers Primarily involve neurons± histologic evidence of abnormal metabolic products--> neuronal death and secondary axon degeneration Myelin is disrupted either destruction of normal myelin or biochemically abnormal myelin production

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Differentiating features White matter disorders Gray matter disorders Age of onset Usually late(childhood) Usually early(infancy) Head size May have megaenchepaly 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


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 EEG=electroencephalogram, EMG= electomyography , VEP=visual evoked potential, ABR= auditory brain stem response, ERG= electroretinogram


Gray matter : fits, decrease HMF EEG: early abnormality MRI Brain: cortical atrophy White matter : blindness ,Gait disturbances ,Motor signs-Spasticity ,optic atrophy ,ataxia , pappiledema EEG: late abnormality MRI Brain: Demyelination Nerve conductance + Evoke potentials Classification

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Basal Ganglia :Dystonia,Involantary movements Spinocerebellar degeneration : Ataxia

Classification of neurodegenerative brain disease:

Classification of neurodegenerative brain disease Inherited Acquired Focal manifestations Both White matter Gray matter Metabolic Infections

Acquired causes :

Acquired causes Infections SSPE Progressive Rubella Syndrome Chronic HIV Metabolic Chronic lead poisoning Hypothyroidism Vit B12 & E deficiency Drugs (anticonvulsant)

Inherited causes:

Inherited causes Gray matter involvement:seizure,dementia, visual loss, intellectual impairment. Spike & sharp waves in EEG A. Gray matter involvement with visceromegaly GM1 Gangliosides-Infantile , generalized , juvenile Sandholf disease (GM2) Niemann pick Disease( Sphingolipid storage disease) Sialidosis MPS Gaucher disease( Sphingolipid storage disease)

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B. Gray matter diseases involvement without visceromegaly Tay Sach disease (GM2) Rett Syndrome Neuronal curoid lipofuscinosis Menke’s kinky hair disease

White matter involvement:

Spasticity , optic atrophy, ataxia ,peripheral neuropathy .Seizure , dementia are the late manifestations. Slow waves in EEG A. Leukodystrophies Metachromatic leukodystrophy Krabbe disease Adrenoleukodystrophy Alexander disease , Cannavan disease,P.Merzbacker disease White matter involvement

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B. Acquired causes/ Demyelinating Multiple sclerosis Schilder’s disease Devic disease

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Basal Ganglia Wilson's disease Dystonia muscular Deformans Huntington’s Diseas e Spinocerebellar Friedrich’s Ataxia Ataxia Telangiectasia

Krabbe disease (Globoid Cell Leukodystrophy):

Krabbe disease (Globoid Cell Leukodystrophy) AR Galactocerebroside-B-galactosidase Myelin loss & presence of globoid bodies in white matter Symptom appear by 6 months Irritability Vomiting Bouts of hyperpyrexia Alteration in body tone Convulsions UMN signs with absent jerks

Krabbe disease:

Krabbe disease Investigations Leukocyte & Skin fibroblast enzyme level CSF: Elevated protein NCV: Markedly delayed Prenatal diagnosis: by assays in chorionic villi or amniotic fluid cell culture

Metachromatic leukodystrophy:

Metachromatic leukodystrophy AR Arylsulfatase A deficiency Onset in late infancy Hypotonia Absent deep tendon reflexes Optic atrophy Decorticate posture

Juvenile MLD:

Juvenile MLD Onset at 5-10 yr Deterioration in school performance Alteration in personality Incontinence Incoordination,Dysarthria Spasticity Generalized tonic clonic seizures

Gaucher disease:

Gaucher disease Commonest Galactocerebrocidase deficiency Infantile form (neuropathic) Nuchal rigidity & opisthotonus Juvenile form (non-neuropathic) Diagnosis Bone marrow examination WBCs or fibroblast cultures & enzyme level

Niemann pick disease:

Niemann pick disease Accumulation of sphingomyelin Onset 1 st yr Mental retardation,Hepatosplenomegaly,Cherry red spot Diagnosis Foam cells in bone marrow WBCs or fibroblast cultures & enzyme level

Neuronal ceroid lipofuscinosis:

Neuronal ceroid lipofuscinosis AR Storage of auto fluorescent hydrophobic material in lysosomes of neurons & other tissue 3 subtypes Infantile Late infantile Juvenile

Neuronal ceroid lipofuscinosis:

Neuronal ceroid lipofuscinosis S/S Myoclonic epilepsy Visual symptoms Cerebellar ataxia Dementia Pigmentary abnormalities in retina Max .age 10 yr

Neuronal ceroid lipofuscinosis:

Neuronal ceroid lipofuscinosis Investigation Skin biopsy: Ultra structural abnormalities Cortical biopsy: Distended neurons Staining for ceroid & lipofuscinosis

Leucodystrophy :

Inherited white matter disease Defect in myelin synthesis involve the brain, spinal cord and peripheral nerves . Classic dysmyelinating disorders are Adrenoleukodystrophy, Metachromatic Leucodystrophy, Krabbe's disease and neuroaxonal dystrophy Leucodystrophy

Adrenoleucodystrophy :

L ife-threatening disorder occurring in males affecting the 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 Adrenoleucodystrophy

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Neonatal ALD is not X-lined, is associated with liver and adrenal dysfunction and is a severe disorder Diagnosis is made by estimation of very long-chain fatty acids in plasm a

Metachromatic leukodystrophy :

Deficiency of Aryl sulphatase A or Sphingolipid activator protein (Saponin-B)= accumulation of lipid sulphatide in the myelin sheath, brain and peripheral nerve. Cognitive function is minimally affected initially followed by motor difficulties and dysarthria. Diagnosis is by estimating Aryl sulphatase A in leukocytes or fibroblasts. CSF protein concentration is grossly elevated Metachromatic leukodystrophy

Peroxysomal disorders:

Children with peroxysomal disorders - 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 . Peroxysomal disorders

Mitochondrial disorders :

A defect in the oxidative phosphorylation in the inner mitochondrial membrane involving the respiratory chain which is encoded by two genomes, the mt DNA and nuclear DNA Mitochondrial disorders

Rett syndrome:

Onset in 1 st yr Females affected only Regression of language & motor milestones Repetitive hand wringing movements Loss of purposeful & spontaneous movements Gen. tonic clonic seizures Max. age 2-3 yr Rett syndrome

Creatin deficiency syndromes :

Patients with these disorders develop delay / regression /mental retardation along with severe defects in expression and repetitive speech. Symptoms are due to severe depletion of creatine/phosphocreatine in the brain. Creatin deficiency syndromes


Sialidosis AR Lysosomal Neuraminidase deficiency Accumulation of sialic acid-oligosaccharide complex Type 1: late onset Type 2 Infantile Juvenile


Sialidosis Intractable Myoclonic seizures Cherry red spots Somatic involvement Coarse facial features Corneal clouding Dystonia multiplex


Mucopolysaccharidosis Absence of variety of lysosomal hydrolases Degradation of MPs defective Abnormally large amount excreted in urine


Mucopolysaccharidosis Coarse facial features , Dwarfism , Kyphoscoliosis Hepatosplenomegaly , Cardiovascular abnormalities Neurologic abnormalities Type I Hurler syndrome Type II Hunter syndrome Type III Sanfilippo Type VII

Friedreich ataxia:

Friedreich ataxia AR Early teenage Ataxia Dysarthria Pes cavus Decreased proprioception, vibration Absent reflexes with upgoing plantars Nystagmus Hypertrophic cardiomyopathy

Lesch Nyhan syndrome:

Lesch Nyhan syndrome X-linked recessive Deficiency of hypoxanthine guanine phosphoribosyl transferase Formation of excess of uric acid Normal until late in 1 st yr

Lesch Nyhan syndrome:

Lesch Nyhan syndrome S/S Psychomotor retardation Chorioethetosis Spasticity Severe self mutilation Gouty arthritis Renal calculi

Wilson’s disease:

Wilson’s disease AR Degenerative disease of basal ganglia Inborn error of copper metabolism Academic deterioration Behavioral changes , Dysarthria ,Dysphasia Drooling, Dystonia K F rings

Subacute Sclerosing Panencephalitis:

Progressive slow viral infection of CNS by measles virus Personality changes Aggressive behavior Myoclonic seizures Investigation Anti measles Ab in CSF EEG Subacute Sclerosing Panencephalitis

An approach to a child with regression of milestones:

An approach to a child with regression of milestones

History :

History History of present illness : Onset/Age of onset Fits ,Clumsiness or difficulty in gait Deterioration of HMF Ataxia or imbalance Headache,Blindness,Vomiting, deafness Change in personality and behaviour Deteriorance in school performance Increased startle response or hyperacusis

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Birth history : Term/preterm Postnatal complications Meningitis Head trauma kernicterus

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Developmental history: Detailed development history- decide whether there is delayed development milestones or regression of milestones Family history: H/o of consanguinity Family history of neurological disorder Early or unexplained death Nature of the neurological manifestations should be clarified

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Classically , the loss of previously acquired milestones(regression) marks the onset of most Neurodegenerative brain disease with subsequent progressive neurological deterioration

Clinical examination :

Clinical examination General physical examination Dysmorphism: Zellweger syndrome, Neonatal adrenal leukodystrophy, coarse facial features(MPS) OFC –microcepaly (gray matter disease) Megaenchepaly – certain white mater disorder(Cannavan & Alexander) Jaundice Enlarged tongue

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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

Neurological examination:

Neurological examination Higher mental function, signs of raised ICP Speech, memory Cranial nerves Gait Motor system: Tone-hypo/ hypertonia,Deep tendon reflexes Motor spasticity Sensory loss /neuropathy Abnormal /involuntary movements

Eye examination:

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



Investigations- to identify the underlying diagnosis & examining the associated complications:

Investigations- to identify the underlying diagnosis & examining the associated complications Complete Blood picture-pancytopenia, vacuolated lymphocytes,acanthocytes ABGs-metabolic acidosis(organic acidopathies, urea cycle defects, mitochondrial encephalopathies) S/E (Anion gap), for adrenal insufficiency(adrenoleukodystrophy) Ammonia level,LFTs,RFTs

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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 Uric acid level

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Urine Reducing substances, Organic acids,24 hr (MPS) Imaging Skull & Vertebrae, Long bones CT/MRI Biopsy Skin, Bone marrow, nerve, brain

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Diagnosis Important for genetic counseling Outcome Invariably fatal

Management :

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.

Specific treatment:

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

Counseling the families and educating the public about these potentially preventable disorders is very important.:

Counseling the families and educating the public about these potentially preventable disorders is very important . 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

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Thank you

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