developmental delay

5 month old girl child brought  with complaint of not achieving milestones.

Sixth child of non consanguineous marriage  between 35 year old mother and 39 year old father.

First baby conceived after treatment of infertility.Father,he had oligospermia. There were three abortions in the first trimester, first third and fourth. Second baby delivered normally,did nt thrive and died at  64 days of age  (poor sucking and activity,respiratory distress,procedure s/o peritoneal dialysis done,birth weight-2.3 kg, and weight at 64 days wt-1.3 kg).
There is only one  normal living girl child,now 3 years old.

No family history of early child death, in other members or developmental delay or significant neurological illness on both parent sides.

Present child-

During pregnancy  mother had gestational diabetes and,was on insulin.Diabetes was well controlled.Delivered at full term LSCS 2.7 kg.female baby cried immediately after birth.Breast fed normally and was normal for the first week.Mother and baby discharged on seventh day.

After first  week mother noticed poor activity and poor  feeding compared to previous child. There was stridor . Since then baby did nt gain weight and did nt attain normal milestones. 

Here weight is 3.7 kg at 5 months just one kilogram weight gain in five months.

no h/o abnormal smell of urine/sweat.

Present admission is with low grade fever and running nose.During this admission there were four  episodes of generalized tonic posturing lasting less than 5 mins and lethargy.child presented with dehydration and respiratory distress.

Discussion at this stage 

Major issues

1. Not attaining milestones
2. No weight gain

we ll take one by one,try to see if there is a link between them.

We ll take the failure of achievement of milestones. How to evaluate a case of developmental delay,

First question is .......

Is there a delay at all? because this may be just a parental anxiety.They may be comparing the kid with other family kids or neighbor hood kids.
Here comes the importance of our assessment.
Do a development assessment in detail in all the fields. This ll be helping not only to answer the above question, but to answer few more questions in the next steps in the systematic analysis. If the question number one is answered yes only we need to proceed further.

Step 2.

Is it a global delay or in isolated field?
.Isolated field delay may help one to pin point or narrow down the problem,eg isolated language delay we ll assess the hearing, isolated gross motor delay commonest reason is malnutrition,chronic systemic illness and out of the neurological problems motor unit disorder eg muscle peripheral nerve muscle etc.
If delay in social and language autistic spectrum disorder.
Global delay argue that the problem is not a peripheral one ie not a motor unit disorder or spinal cord disorder.At this stage itself top priority should be given to easily treatable central causes like hypothyroidism without wasting time.

Step 3.

Most important yet a bit difficult to answer.
Is this a delay or regression? 

This step needs a bit more of explanation.

Developmental delay means the milestones are achieved late ,but once achieved it ll remain. No loss of attained milestones.We call it as a static disorder.

Developmental regression means, attained milestones are lost. We call it as progressive disorder.

What you mean by static disorder? 

Brain starts developing from third week of fetal life and completion is by two years of post natal life.
A injury occurring one time or a problem with the seed, will lead to a pattern where initially there may be a delay because some part of brain get injured or bit deviant from the usual when we consider the genetic potential of an abnormal seed.

An injury happening antenatal natal or developing stage may lead to total burned out type of severe damage where no potential for healing or regeneration possible.
Or the other extreme very little areas damaged which can easily circumvented by new roots and connections.
Basis of the static disorder is the compensatory efforts on the part of brain by different mechanisms. The level of compensation depends on the extent of injury and damage, Only one point to highlight here is , the damage or injury is one time only 

In the case of progressive disorders or regressive pattern of development 

• the injury happens in a different way IE repeated injuries over time. Some enzyme ,receptor or transport protein in the brain is missing, leading on to accumulation of a bad chemical or deficiency of a needed product lead to damage of different part of brain .The pattern of injury depends on the area where the product is most relevant or needed.
• The deficiency /toxicity keep on increasing as time passes . Manifestations will be least at the beginning and gradually worsens and may succumb later. 
• The course and progression varies.
• There can be episodic worsening due to different triggers.

Now comes the practical application of the above knowledge

Even though easily we described the concept of progressive disorder and static disorder there is high chance of missing /mistaking one for the other.

Eg.few of the progressive disorders can mislead you and we may take it as static disorder.Classical example is arginase deficiency which may present just like diplegic CP.
Most important situation this should be considered is when we encounter a situation where every point look like CP but the reflexes are on lower side. This is very unlikely to be CP and we need to revise your diagnosis.

Few situations where static disorder may be mistaken for progressive disorder eg a seizure occurring at one and half year without fever , and recurring, Few of the events in a static disorder may express at late age.

One very important situation is when no milestones is achieved.

This can happen in a static disorder where the injury is maximum and no chance of new connections compensating for the injury and no milestones achieved. The same situation some times happen when the regressive injury due to the neuro metabolic problem is so severe that the injury to brain starts so early.

This is very difficult to solve in a very young, but if the kid lives beyond certain age we can rule out the possibility of severe metabolic/neuro regression from the above situation because most of them are eliminated as the problem is so severe that it started very early, They are unlikely to survive long.

Step 4

From the above steps we have an idea about the type of problem.Next step is to find the reason for the pathology.In the static type of disorder it may be genetic malformations, first trimester injuries or perinatal or early post natal injuries.The time and pattern of injury decides the type of sequel e so this may help us to support our clinical examination and possibilities.

Here family history and pedigree chart ll be helpful to a little , only in case of genetic problems eg neuro cutaneous syndromes

In case of progressive disorders, we need go in depth about family history pedigree chart. History, examination of family members, past reports ,family photos all helpful.

Now comes possibilities in our index case

Three first trimester abortions argue for genetic problems.
Maternal diseases or pregnancy related problems mostly lead to second trimester fetal loss.

Bit of dismorphism in the examination of baby also supports this concept.

But other details?......

• Four times ultra sonogram done showed normal baby growth,
• normal amniotic fluid.biophysical profile normal.
• At delivery bay weight was adequate.
• No asphyxia and bay was normal in the first week.
• The delay had its onset from second week onward.

This pattern is very unlikely in case of malformation, and perinatal event responsible. So this argues against one of the commonest reason for developmental delay CP.

Now we ll try to link the growth faltering part

There are three patterns of situations when we consider this

• .Normal growth (except may be the head size) but the development delay in one or more fields
• Normal development in all fields with not gaining weight length
• .Both development and growth are affected.

First situation classical is the cerebral palsy where the injury to brain only happening somewhere near term wont in anyway affect the body growth provided there is no problem in the intake.

Second situation many systemic diseases

Our case - is third situation in the above

Here there is affection of brain, at the same time body growth.What all situations this can happen?

• Metabolic problem especially small molecule disorders
• Intra uterine infections/first trimester insults leading to hypoplastic IUGR
• Genetic disorders and syndromes

General examination 

dysmorphism+ in the form of low set ears,hypertelorism,small cafe au lait spots in left leg,high arched palate.

HC-39 cm,almost normal for age.

At the end of history we had more points towards metabolic problem than a genetic condition. But here few dismorphic features,we need to consider again the left out possibility.

discussion

What does malformation mean?.
Does that mean always genetic or first trimester insult during organogenesis?
Can there be abnormal appearance due to an injury occurring later in pregnancy or perinatal period? 

Possible.

How ?

Consider the mechanism how a metabolic product affect the fetus and newborn.
Why a newborn is normal at birth and till few days to weeks before the onset of problems?
During pregnancy most of the metabolic problems are tackled by the normal liver of mother. This happens in most of the situations where the molecules cross the placenta. This is the classical situation of small molecule diseases eg amino acid disorders most of the carbohydrate problems.

But if these molecules can not cross placenta manifestations the foetus may be affected  in utero. Eg peroxisomal disorders

Another situation is abnormal appearance of babies with decreased muscle pull, leading to deformation of bone.

But in our case both the above possibilities less likely , Baby was normal in the first week rule out the first possibility 

System examinations 

P/A -liver 2 cm under RCM,

No spleen.CNS-

CNS examination 

vision-not fixing ,no cateract,fundus normal.

and following hearing-startle +

NO  other cranial nerve involvement,

Both upper and lower limb hypertonia,spasticity  with exaggerated reflexes,

discussion

As there is no features of intra uterine infection,
No features of significant genetic malformation features which can explain the whole problem
So metabolic problem was high in the list.

As there is significant problem with the weight gain,drowsiness and new onset seizures small molecule disorder was considered.

No abnormal smell or color of urine or diaper,skin.

No jaundice ,bleeding manifestations.

No skin thickening, corneal clouding,abnormalities of hair.

No hepatosplenomegaly are important in the analysis of the above situation

Investigation

urine sugar  ketone.results awaited 

serum .ammonia-80micromol/L(18-74),

Blood sugar normal

MRI-done 

diffuse white matter edema in b/l cerebral and cerebellar hemisphere,int.capsule and brain stem and diffusion restriction in myelinated white matter.

Final diagnosis?

metabolic work up results awaited

What we consider at this stage is

White matter disease,as mostly posterior aspect possibility of neonatal adrenoleukodystrophy considered

Not sure at this stage.

In the above situation we expect the evidence of peripheral nerve involvement, But here ankle jerk is normal

No pigmentaion

Let us wait for final results. Presented just for discussion 
(prepared by KKP,Dr.Nimitha,Dr.Neethu,Dr.Remya)