Mycophenolate mofetil - use in pediatric neurology

 

A 9 year old boy presented with progressive difficulty in walking for 2 months and weakness of upper limbs for 20 days. He had received 5 days of high dose methyl prednisolone 1 month into the illness which brought a temporary improvement for 10 days followed by progressive worsening. CSF was acellular with mildly elevated proteins. MRI spine showed enhancing lumbar nerve roots and the nerve conduction velocity demonstrated severe sensory motor demyelinating neuropathy. 

We made a diagnosis of CIDP and he showed a gratifying response to a repeat dose of IV methyl prednisolone. We discharged him on oral steroids on which he continued to do well but started showing cushingoid features. We decided to add a steroid sparing agent and after mulling over the various options finally zeroed in on mycofenolate mofetil. 

This was a good opportunity to review this important drug in autoimmune disorders. It is often overlooked    and overshadowed by more glamorous drugs like rituximab and cyclosporine. 

If was first discovered serendipitously by an Italian physician Gosio who was investigating the link between mouldy corn and pellagra. He isolated a crystalline substances which he found could inhibit the anthrax bacteria. Nobody bothered much about this interesting finding till several decades later, after many false starts it use as an immunosuppressant was established by people at Roche.

It inhibits the de novo production of purines. This reduces T and B cell proliferation and explains the immunosuppression. 

Besides, it also has directly inhibits dendritic antigen presenting cells. This probably explains why it is a much more potent immunomodulator than other drugs like azathioprine. 

Plus it is less nephrotoxic than cyclosporin because it also inhibits endothelin which mediates ischemic renal injury.

Its used orally in a dose of 20mg/kg twice a day or 600mg/me/dose BD.

Its use in transplant medicine ( renal, cardiac, intestinal) is well established. Rheumatologists are now comfortable using it in SLE ( especially renal disease) and myasthenia. Pediatric nephrologists use it for steroid dependant or frequently relapsing nephrotic syndrome.

Its use in paediatric neurology was reviewed by Dale et al in 2017. They found it was effective and safe in primary CNS vasculitis and NMOSD. Evidence was scantly but encouraging for MOG associated CNS disease. There was inadequate data for autoimmune encephalitis and multiple sclerosis. https://doi.org/10.1111/dmcn.14020

It was probably ineffective in Opsomyoclonus Ataxia syndrome.

It may take upto 6 months before its action kicks in and so needs some other support like oral steroids during this period. 3 monthly counts need to be monitored. Avoid using PPI's which interfere with its action. Abdominal cramps were the commonest side effect.

Intracranial calcification in children - clues to etiology

 

This was a 5 month old baby boy who presented with developmental delay and seizures. He was born term with no perinatal asphyxia but weighed just 1.5 Kg at birth. His MRI brain at 5 months had right frontal pachygyria, cerebellar hypoplasia, white matter asymmetric hyperintentsities on FLAIR/T2 and CT Brian showed periventricular  and basal ganglia calcification.

Our first possibility of course was congenital CMV infection. But he was already 5 months old, his urine PCR for CMV was negative. And the big question was - Can the pattern of calcification alone predict etiology?

I sat down to understand this further. There were some useful tips I learnt. 

You need to ask some questions:

1. Is it calcification? Make sure you are not looking at haemorrhage, iron or manganese which can look similar.

Generally CT will pick up calcification much better than MRI brain. However SWI images are probably as good as CT. SWI wins over CT because it can differentiate bleeds form calcium. This happens in the phase images of SWI not the routine magnitude images. In corrected phase images calcium appears bright and blood appears dark. https://doi.org/10.1007/s13244-011-0086-3

2. Is it metastatic calcification as seen in hypo/hyperparathyroidism or dystrophic calcification ( seen in a range of brain injuries)?

Metastatic calcification due to disorders in parathyroid metabolism will have a symmetric basal ganglia, thalamic calcification with sometimes deep gyral calcification.

3. What is the pattern of calcification?

Is it dot like, linear, conglomerate masses, rock like, blush or gyrinform band like? For eg congenital CMV patients will often have nodular mass like calcification in the periventricular region but dot like pattern in the basal ganglia. Most intra-axial tumours have nodular, clumped mass like lesions. A cyst with an eccentric dot of calcification is likely to be neurocysticerscosis and a central dot of calcification is seen in tuberculomas. The gyriform calcification of Sturge Webers is unmistakable. https://dx.doi.org/10.3941%2Fjrcr.v13i8.3633

4. Where is the calcification?

Characteristic locations sometimes help to nail the etiology. Calcification in the pineal gland and choroid plexus is often physiological. Cerebellar calcification is a clue to SLE, neurosarcoidosis and neurofibromatosis. True periventricular calcification is common in congenital CMV. Krabbes disease has a peculiar internal capsule and corona radiata calcification. Subependymal calcified nodules are typical of tuberous sclerosis.

5. Are there associated brain malformations? 

Presence of cysts along with calcification is seen in congenital CMV, RNASET2 disease, COATS plus disease and COL4A mutations ( porencephaly). https://doi.org/10.1111/dmcn.12359

While cortical malformations like polymcrogyria are common with congenital CMV, it is unknown with its closest mimic Aicardi Gautiere Syndrome. True periventricular calcification is also uncommon in AGS.

My patient was finally found to have chorioretinitis typical of CMV and so we deferred further genetic testing!

Polymicrogyria- how do I investigate further?

This 2 year old child came in with global developmental delay and microcephaly. Antenatal and perinatal period had been unremarkable. There was no dysmorphism, nor organomegaly or other malformation.

The MRI brain was reported to have right sided pachygyria over the parietal-occipital cortex, polymicrogyria in the perisylvian region also more on the right. There were also some white matter abnormalities in the underlying subcortical regions.

Questions which I needed to answer were- is this acquired or genetic? How do I investigate further?

New recommendations for the diagnostic work-up of malformations of cortical development (MCD) were recently published in Nature Reviews Neurology in September 2020 https://doi.org/10.1038/s41582-020-0395-6

Some useful tips this article gave are as follows:

Focal versus generalised abnormalities do not reliably separate the acquired versus genetic disorders!

Polymicrogyria and pachygyria are sometimes confused. A simple tip is that pachygyria will usually have a thick cortex while the polymicrogyric cortex is thinner.

Always look at the parasaggital image to scrutinise for polymicrogyria. The abnormal posterior extension of the sylvan fissure and sulcal branching can be a real give away.

 

 Another term to remember is 'dysgyria'. This means an abnormal gyral pattern which doesn't fit into the classical malformations of cortical development. Often a clue for the tubulinopathies.

Polymicrogyria or microcephaly must always prompt an assessment for possible intrauterine infections like CMV, TORCH and Zika. The presence of white matter changes and calcification is a clue to congenital CMV.

Intra-uterine vascular disruptive events and twinning ( probably due to hypo perfusion in the twin to twin transfusion syndrome) are also important causes of polymicrogyria.

Chromosomal microarray is the first genetic test to be used for all MCD followed if necessary by exome sequencing. 36% of patients with periventricular nodular heterotropia will have an abnormal CMA and the number is 9% for those with polymicrogyria alone.

A genetic cause of polymicrogyria is most likely to be found in children with macrocephaly- especially the PI3K-AKT-MTOR related disorders.

Metabolic disorders like Zellwegers syndrome of the d-bifunctional protein deficiency can also be associated with polymicrogyria. These children are sicker and the dysmorphism, hepatomegaly and leukoencephalopaty of Zellwegger's is also a clue.

Childhood stuttering- neglected and misunderstood

 

A 3 year old boy came in with the complaints of recent onset of stuttering of just 1 week. Both parents were extremely anxious.  They had a video of him trying to speak- the repetition, the prolongations, the blockages...were something they had never observed in him so far.

         Stuttering has now got a brand new label- childhood onset fluency disorder. About 5% of children stutter but longitudinal studies show that upto 65-80% remit by 16 years of age.

It has afflicted both kings and commoners. How King George VI conquered his stuttering to address his country is beautifully depicted in the movie "The Kings Speech". But a complete understanding of the pathophysiological underpinnings of this angst-ridden disorder eludes us still.

Functional MRI and PET scan studies in people who stutter have shown that the complex, perfectly coordinated loops (between the motor speech areas, auditory speech cortex, basal ganglia, thalamus and cerebellum) which underlie fluent speech are dysfunctional.

 One key area is considered to be the auditory feedback received during speech which decides our motor speech rates and rhythms. This is the basis of many therapeutic interventions which have been tried such as choral reading, masking, metronome use and delayed auditory feedback systems.

Choral reading is reading out aloud with 2 or more people. It has been shown to instantaneously reduce stuttering by more than 80%. 

A dreaded phenomenon in stuttering is silent blocks, where they are unable to utter a single sound. Masking auditory feedback ( MAF) devices have been sometimes found to be useful. This device produces a masking auditory feedback in ones ear when desired and enables the patient to restart speaking.  The device can be switched on during silent blocks.

Electronic metronomes which can be worn behind the ear and provide a beat to which the patient must read aloud daily, (for 10-15 minutes) have also been used.

The Lidcombe therapy which was developed in Sydney has been particularly useful in preschoolers who stutter. They train the parents to provide appropriate feedback with effusive praise for fluent speech.

In view of the several overlapping clinical features of stuttering and Tourettes, dopamine blocking drugs have been tried and found useful. Medications which have shown some efficacy include haloperidol, risperidone, olanzapine and pimozide. Tricyclic antidepressants and SSRI's have not been shown to be useful. VMAT2 ( vesicular monoamine transporter2) inhibitors are under investigation in view of their use in Tourette's. https://dx.doi.org/10.3389%2Ffnins.2020.00158

TMS and DBS are some other options which are also being explored for refractory cases.