Cerebral palsy mimics and differential diagnosis

Dr Ram Kumar and Professor Anil Israni, consultant paediatric neurologists at CYP Neuro Academy, meet to discuss the important topic of differential diagnosis in children presenting with features of cerebral palsy - "cerebral palsy mimics"

Transcript

 
RK: Hello, welcome. I'm Dr. Ram Kumar, consultant paediatric neurologist and founding partner of CYP Neuro, which is an initiative to provide high quality clinical and educational services in paediatric neurology. Today I'll be speaking to Professor Anil Israni again, who's also a consultant paediatric neurologist and friend and fellow founding partner of CYP Neuro. Now, we're both experienced paediatric neurologists able to bring our combined wisdom and experience over many years to others, such as yourselves listening, who would like to improve your knowledge and practice and learn from where we could have done things better. Now in this episode, or episodes, we'll discuss conditions that can mimic cerebral palsy. Now, this is an important topic that's an everyday clinical practice situation because cerebral palsy is a common cause of abnormal neurology in children, specifically abnormal motor conditions, and we're very likely to come across individuals with cerebral palsy. So we'll discuss approaches to the investigation of children where there's a query of cerebral palsy or suspected cerebral palsy and when to consider an alternative cause for the child's presentation other than cerebral palsy. Now because this is quite a long discussion we'll do this in two parts to give enough justice to the detail required. In the first section, we'll talk about definitions of cerebral palsy and what is a mimic of cerebral palsy and what are the red flags that should raise concern that you're dealing with someone who does not have simple cerebral palsy and discuss some illustrative case examples as well. So, welcome Professor Israni. Can you start by explaining why it's important to identify mimics of cerebral palsy?
 
 

AI: Thank you, Dr. Kumar. This is indeed an important topic, distinguishing the common cerebral palsy from the less common cerebral palsy mimics because it can significantly impact the patient outcomes. And this is more important in four key areas. Firstly, to identify treatable causes early. To provide appropriate genetic counselling, whether it's a genetic cause, thirdly, enabling participation and signposting to relevant emerging precision treatment trials, and fourthly, and importantly, addressing medical legal implications.
 
 

Many conditions can present similarly to cerebral palsy, even though some of these conditions are individually rare. Increasingly, in the modern gene molecular therapy era, the specific management and prognosis of these individually rare conditions is often very different for each individual, despite the child appearing to have cerebral palsy at first sight.
 
 

RK: Thank you, Professor Israni. Now, we'll go through examples of where all of these issues that you mentioned arise. Before we delve deeper, could you clarify what exactly we mean by the term cerebral palsy and what defines a mimic of cerebral palsy?
 
 

AI: As we know cerebral palsy is not a specific diagnosis in itself, but it rather is an umbrella term. And it is defined as a group of permanent disorders affecting strength, movement, tone, and posture, so predominantly motor features, that occur due to non progressive disturbances in the developing fetal or infant brain.
 
 

So the key elements in the definition are that it's permanent, it's non progressive, which means non degenerative, and it occurs because of an insult during early brain development. A cerebral palsy mimic, on the other hand, is a condition that may superficially present like cerebral palsy phenotype. But it doesn't meet the specific criteria in the definition.
 
 

So, it might be progressive, it might occur later, later as in after the developing period of the brain, or have a different underlying mechanism.
 
 

RK: Thank you very much. So, I'll point out here that there have been some recent revisions or proposed revisions for the definition of cerebral palsy, just because of some inconsistencies about what a progressive condition is or what the developing brain is in terms of age groups. But we'll come back to that later.
 
 

I think an important point to point out here that is that cerebral palsy is not really a single condition with a single cause akin to say Dravet syndrome, so rather cerebral palsy is more like a group of conditions with various motor signs some overlap some different potential causes like Prematurity related white matter injury or intrauterine CMV infection HIE or inflicted head trauma in general. So if you contrast that with Dravet Syndrome, which is a more tightly defined condition with a single gene, leading to generally similar presentation, cerebral palsy is more like a group of conditions with different underlying causes, but a similar prognosis and similar care needs.
 
 

AI: Yes, absolutely. The term cerebral palsy is still helpful because it excludes certain conditions, for example, degenerative brain disorders, where there is ongoing loss of neurons. The term cerebral palsy also is helpful to give some degree of prognostication and expected management, especially with regards to multidisciplinary rehabilitation inputs.
 
 

RK: Okay, now, one of the important features here is that we do not know if the child has a progressive or potentially progressive condition when we first meet the child in the clinic. So it may just be inferred from the history of slow motor development since birth and the finding of increased muscle tone or excessive movements, perhaps with some other comorbid global delay.
 
 

AI: Yeah, that is indeed true for real life clinical practice, and we expect children with cerebral palsy to present with late motor developmental milestones and other motor difficulties, including pain, increased muscle tone and delayed general development. Often the problem with identifying if the child or even an adult has cerebral palsy or a mimic is that we do not have that history to define the clinical trajectory.
 
 

For example, in a looked after child, or a child born abroad where we don't have the relevant medical records of antenatal and postnatal period, or an adult with minimal historic investigations. The non-progressive nature of the condition may only be inferred or be assumed, and at times falsely unless the child or the adult is followed up over a period of time.
 
RK: That's absolutely true, and I think here it's useful to have some statistics and some understanding of the condition, the child's condition that you're faced with. So, now we usually assume that a child with slow motor development and abnormal signs like spasticity or dystonia has cerebral palsy because that's the most common situation.
 
 

So the broad worldwide statistics suggest somewhere between 150 to 600 per 100,000 children overall have cerebral palsy with prevalence depending very much on the socioeconomic context. So being much lower in high income countries and being much higher in low income countries. Now if you take that number of 150 to 600 per 100,000 and you compare that to rare progressive conditions, which individually we're talking about 1 to 5 per 100,000 for some of these rare conditions, or even much less. And even if you add up all of the very many rare conditions, it still amounts to a smaller chance that you're facing a child who looks like they have CP, but rather has a CP mimic. There are some different differences in the prognosis and disease specific treatments, however, and that's why it is important to identify the child with the CP mimic compared to the child with CP. So Professor Israni, how can we go about distinguishing cerebral palsy from its mimics? I mean, let's take a scenario. So we'll take the scenario where we're seeing a young child in the clinic with slow motor development and abnormal muscle tone or movements. What are some of the key red flags in the history and examination that would make us suspect that what appears to be a child with cerebral palsy, which is a static, non degenerative condition, might actually have something else?
 
 

AI: So the red flags can be divided into several categories. In terms of clinical history, we should be concerned when there are no clear risk factors available, especially common risk factors like prematurity, low birth weight, neonatal hypoglycaemia or perinatal hypoxic ischemic problems or a postnatal severe neurological illness like meningitis or encephalitis.
 
 

A positive family history of supposed CP or other early onset neurological conditions should also raise suspicions as cerebral palsy is not typically an inherited condition. We might get some additional clues on clinical examination that might point to a diagnosis different to cerebral palsy. For example, presence of congenital cataracts or other ocular abnormalities like progressive vision loss or unusual skin lesions, for example, chilblains or reddening of the fingertips that we see in interferonopathies like Aicardi-Goutieres syndrome or craniofacial dysmorphic features.
 
AI: Certain body habitus or behaviours that suggest another condition. For example, in Rett syndrome, we see unusual breathing patterns, a presence of spinal dysraphism cutaneous markers of spinal dysraphism may point to a spinal cord disorder that can mimic a spastic diplegic form of cerebral palsy. Apart from that, diminished reflexes with hypotonia especially may point to a peripheral neuromuscular condition that can masquerade as central hypotonia or cerebral palsy.
 
 

Then there are other red flags like fluctuation in motor symptoms, especially diurnal variation or relation to meals and fasting, as well as paroxysmal movement disorders like dyskinesia and ataxia. An unusual distribution of tone and strength problems for cerebral palsy, such as a pure ataxic form or a pure hypotonic form, which are very, very rare in cerebral palsy.
 
 

And any regression of previously achieved milestones or periods of regression with incomplete recovery are also red flags that should make us reconsider a diagnosis of cerebral palsy.
 
 

RK: Okay, thank you very much, Professor Israni. I mean, that's a very comprehensive set of invaluable pointers to an alternative diagnosis to cerebral palsy, and I'm sure that will be very helpful for our listeners. It's important to remember that although we have these red flag historical features and examination findings, they may not all be there at that very first meeting.
 
 

And I think this is a point that we come back to repeatedly. So, for example, the family history of other children with palsy like condition may only become positive in an autosomal recessive condition when a younger sibling is born some years later and develops a similar condition. I'm sure we've both come across that type of situation where we've had to re-evaluate the initial diagnosis in the older sibling. So, Professor Israni, you mentioned regression of milestones or developmentally acquired skills. Can you elaborate further on how we distinguish between true regression and what might appear to be regression in a child with a static brain disorder such as cerebral palsy?
 
 

AI: Yes, that is a very important distinction. Cerebral palsy, as we know by definition, is a non progressive disorder and any apparent regression should have a clear explanation. Loss of previously achieved skills is not necessarily a true regression always. It might be due to development of new onset of a movement disorder over time, for example, worsening dystonia or deterioration of spasticity leading to contractures or secondary bone and joint deformities, for example, a hip dislocation.
 
 

Occurrence of secondary pain or new onset of epilepsy or mental health problems like a mood disorder. These can appear de novo in a child with cerebral palsy but could also be features of a cerebral palsy mimic as a progressive condition also.
 
 

RK: Okay, thank you very much. I mean, those are important pointers that should make you think, okay, this actually is a child with cerebral palsy and shouldn't lead us down a path of red herrings looking for a rare condition. Now, much of my practice is dealing with cerebral palsy, and we do often see children with a type of what I'd call a pseudo regression of motor function, and that's a very well recognized phenomenon in typical cerebral palsy.
 
RK: We tend to see that in adolescents as they're growing bigger and heavier, so they appear to be regressing in their strength and mobility because their muscles were always weak, but now with their increased size and weight, they're no longer able to hold themselves up against gravity so well. Now, in the cerebral palsy field, there are well established centiles of motor function scores, which often show a decrease in walking ability in late adolescence and adulthood. I think the other issue we mentioned was about the movement disorder component about spasticity and dystonia. Now there's much less literature on the evolution of spasticity and dystonia in cerebral palsy. My impression is that it often evolves at a brain microstructure or cellular network level over time and age. Essentially a form of negative neuroplasticity. So macroscopically on neuroimaging, there's no degeneration of the brain. So the MRI scan looks exactly the same even as the dystonia is increasing, but we see it in the need for escalating tone medications as the child becomes older.
 
 

And I don't think it's just because their weight has increased. So now in this situation, we don't consider this a manifestation of a progressive degenerative condition with loss of brain cells. And usually other aspects of function, aside from the motor function and mobility, remain unchanged.
 
 

AI: Yes, although cerebral palsy is a predominantly motor disorder, it usually occurs in presence of other comorbidities, including cognitive, behavioural, epilepsy, vision and hearing related problems, sleep related disorders as well. So true developmental regression, particularly early loss of skills across domains, not just motor domain, would be more supportive of a neurodegenerative or a progressive neurometabolic disorder, other than the motor pseudo regression that we describe in cerebral palsy.
 
 

However, there are rare conditions that lead to progressive motor deterioration only after an initial period of slow development without any involvement of other developmental domains, so without any global deterioration, so to say. For example, certain genetic hereditary spastic paraplegias. The trajectory in the simple hereditary spastic paraplegias like SPG4 and SPG3A can appear indistinguishable to the typical spastic diplegic form of cerebral palsy.
 
 

And we know that spastic diplegia is one of the most common forms of cerebral palsy, which we'll all come across as paediatric neurologists and paediatricians. And SPG4 and SPG3A gene related hereditary spastic paraplegia are common forms. So it is likely that these rarer conditions will be encountered by a clinician dealing with children with cerebral palsy at some time point in clinical practice.
 
 

RK: Okay, well, you know, that's good you've started mentioning about some specific conditions and how they can very much mimic certain types of cerebral palsy. So that's a good start in discussing some specific examples. Hereditary spastic paraplegias are definitely an important group of genetic conditions to consider in the differential diagnosis of the child with a spastic diplegia like presentation.
 
 

AI: Yes, I can share a particularly illustrative case I saw recently. So this was a five year old girl who had been diagnosed with spastic diplegia since early childhood. What caught my attention was that she had been walking normally at around 19 months or so, but then developed progressive difficulty over the preceding year.
 
 

When I examined her, I also noticed her mother was using a walking frame, though she mentioned being investigated for multiple sclerosis. This prompted genetic testing which revealed SPG11 mutation confirming hereditary spastic paraplegia in both mother and the child. The diagnosis completely changed their management approach and enabled proper genetic counselling for the family too.
 
 

RK: Okay, well that is a very salient story, particularly as SPG11 has significant prognostic implications, even within the group of hereditary spastic paraplegia. This is because SPG11 has degenerative outcomes. Now, there are over 80 hereditary spastic paraplegia genes identified so far, and a number of them can have degenerative features, while others behave more like static disorders, sometimes even within the same family. Initially, at least, they can appear similar to a child with typical spastic diplegia. Now, in this case, what I found interesting is that you said both the mother and the child had SPG11 related disease, because SPG11 is one of the autosomal recessive or classically an autosomal recessive hereditary spastic paraplegia.
 
 

So in the UK, at least we expect to see an affected individual with this type of SPG11 without a relevant family history, whereas SPG4 and SPG3A are autosomal dominant forms of hereditary spastic paraplegia and can present de novo or with an unaffected carrier parent. So usually these SPG3 are simple HSPs in terms of only causing motor deterioration.
 
 

AI: So in this case, I think both the mother and child were affected and SPG11 indeed is an autosomal recessive disorder. We do not know the status of the father, but very likely he was a carrier and because of milder and delayed onset of hereditary spastic paraplegia in the mother, the diagnosis got delayed.
 
 

I think the other important issue here is the red herring story of an acquired inflammatory condition being investigated in her mother - the multiple sclerosis.
 
 

RK: And that's another important issue. So that's a good illustrative example where the mother's adult diagnosis was taken forward by the genetic investigations in the child. And we're seeing this increasingly, and I'm sure we've both come across that situation. I think the other key feature in this case that you presented was the atypical trajectory for the child with cerebral palsy.
 
 

AI: Yes, I can share a particularly illustrative case I saw recently. So this was a five year old girl who had been diagnosed with spastic diplegia since early childhood. What caught my attention was that she had been walking normally at around 19 months or so, but then developed progressive difficulty over the preceding year.
 
 

When I examined her, I also noticed her mother was using a walking frame, though she mentioned being investigated for multiple sclerosis. This prompted genetic testing which revealed SPG11 mutation confirming hereditary spastic paraplegia in both mother and the child. The diagnosis completely changed their management approach and enabled proper genetic counselling for the family too.
 
 

RK: Okay, well that is a very salient story, particularly as SPG11 has significant prognostic implications, even within the group of hereditary spastic paraplegia. This is because SPG11 has degenerative outcomes. Now, there are over 80 hereditary spastic paraplegia genes identified so far, and a number of them can have degenerative features, while others behave more like static disorders, sometimes even within the same family. Initially, at least, they can appear similar to a child with typical spastic diplegia. Now, in this case, what I found interesting is that you said both the mother and the child had SPG11 related disease, because SPG11 is one of the autosomal recessive or classically an autosomal recessive hereditary spastic paraplegia.
 
 

So in the UK, at least we expect to see an affected individual with this type of SPG11 without a relevant family history, whereas SPG4 and SPG3A are autosomal dominant forms of hereditary spastic paraplegia and can present de novo or with an unaffected carrier parent. So usually these SPG3 are simple HSPs in terms of only causing motor deterioration.
 
 

AI: So in this case, I think both the mother and child were affected and SPG11 indeed is an autosomal recessive disorder. We do not know the status of the father, but very likely he was a carrier and because of milder and delayed onset of hereditary spastic paraplegia in the mother, the diagnosis got delayed.
 
 

I think the other important issue here is the red herring story of an acquired inflammatory condition being investigated in her mother - the multiple sclerosis.
 
 

RK: And that's another important issue. So that's a good illustrative example where the mother's adult diagnosis was taken forward by the genetic investigations in the child. And we're seeing this increasingly, and I'm sure we've both come across that situation. I think the other key feature in this case that you presented was the atypical trajectory for the child with cerebral palsy.
 
 

AI: But a macrocephaly is very unusual in a typical cerebral palsy. It made me think of an intracranial mass lesion, hydrocephalus, or rare group of genetic disorders that are recognized to cause macrocephaly with abnormal motor function.
 
 

RK: Yes, I mean, that's an important and wide differential even just from macrocephaly and the presentation. So what was the ultimate diagnosis in this case?
 
 

AI: In this case, I undertook neuroimaging with MRI of the brain. This excluded hydrocephalus but identified the classic white matter leukodystrophy appearance of Canavan disease in keeping with the macrocephaly and the global delay. The diagnosis was confirmed with detection of elevated N-acetyl aspartate in the urine organic acids and also by genetic confirmation of ASPA gene mutation.
 
 

RK: Okay. Thank you. That is another interesting rare case. So Canavan's disease is a rare autosomal recessive degenerative condition, which we broadly put under the heading of the leukodystrophies or inherited white matter disease. In this case, there are important recurrence risks since one in four future pregnancies may be affected.
 
 

AI: Yes, unfortunately, in this specific leukodystrophy, there are no currently approved disease modifying treatments, although gene therapy trials are ongoing. So watch this space. There are an increasing number of leukodystrophies for which disease modifying treatments are now available, such as for metachromatic leukodystrophy, another early onset condition with delayed motor milestones.
 
 

This underscores the importance of detecting these individually rare conditions since you can offer some hope by participation in trials.
 
 

RK: Okay, and these examples are very helpful because you've identified why it's important to identify the child with a rare disease instead of just saying the child has cerebral palsy because of potentially high recurrence implications and there may be specific disease modifying treatments or just relevant research trials up and coming that offer some hope in this territory. So, we've had substantial discussion and introduction to this challenging topic. So to do talks justice, we'll have a break in the session and then have in the next episode cover some additional topics around more deeper delve into the neuroimaging around CP mimics and the differential diagnosis and investigation methods that we can think about to arrive at the diagnosis.
 
 

AI: Calcification is an important clue as well, which may be detected on susceptibility weighted imaging as well as on a CT scan of the head. And that can narrow down the differentials to Aicardi-Goutieres syndrome or COL4A1 gene disorder. COL4A1 can also demonstrate susceptibility weighted imaging signal indicating intraventricular haemorrhage unexpected at the child's gestation of delivery or other wider problems that can look like periventricular leukomalacia or porencephaly that we see more often in cerebral palsy.
 
 

RK: Okay, well, thank you very much, Professor Israni. That's a very extensive list of rare conditions that can mimic cerebral palsy and the neuroimaging clues that can direct our further investigation approaches. Now, it's not possible to give an exhaustive list of each and every rare condition here, but you've drawn out the more specific neuroimaging categories there.
 
 

So, just to recap, there's the classic normal or near normal MRI which should really raise our concern that this child does not have cerebral palsy. There's the white matter hypomyelination leukodystrophy disorders pattern. There's the basal ganglia or deep grey matter disorder pattern, the brainstem lesion pattern, the cerebellar lesion pattern, and the intracranial calcification and bleeding pattern. And you've remarked how these findings can point to certain categories of rare conditions that can mimic cerebral palsy.
 
 

AI: Yes, neuroimaging is critical, but it's important to interpret the neuroimaging findings in clinical context of history and examination. Sometimes what's reported as kernicterus or hypoxic ischemic injury on MRI of the brain, usually from changes in the basal ganglia in a child with evolving dystonic motor disorders, suggesting cerebral palsy might actually be something quite different.
 
 

For instance, I had a case of a 10 year old boy who was labelled to be having dystonic cerebral palsy, supposedly due to kernicterus. However, when we noted his new onset night vision problems and reviewed his MRI of the brain, we found the characteristic eye of the tiger sign leading to a diagnosis of PKAN, which is pantothenate kinase-associated neurodegeneration.
 
 

This completely changed our approach to his management.
 
 

RK: Thank you very much. That's another salient case that you've mentioned regarding a child with a basal ganglia pattern. For further reading, I can recommend the article by Mohammed and colleagues, which was published in Brain Communications in October 2020 issue, which is titled, "Magnetic Resonance Imaging Pattern Recognition in Children with Bilateral Basal Ganglia Disorders."
 
 

RK: And we'll include this reference on the CYP Neuro podcast website for further reading, it is a very good article with a detailed table with differential diagnosis and the different sub patterns of basal ganglia involvement. Now although this study was mainly discussing the differential diagnosis of basal ganglia abnormalities, there is an excellent description of how to distinguish the basal ganglia lesions you find in these rare conditions from those the type of basal ganglia injury that you can see in typical causes of cerebral palsy, which can lead to a similar appearance particularly with HIE, where you get putamen, ventrolateral thalami, and perirolandic cortex T2 hyperintensity, and bilirubin induced injury or kernicterus, where you get globus pallidus hyperintensity. And these will often result with very similar phenotype of dyskinetic cerebral palsy or cerebral palsy like appearance. The article by Mohammed and colleagues also gives a wider description of conditions that cause combined basal ganglia and cerebellar atrophy and white matter abnormalities as well. So it's a good read and I recommend it. So now Professor Israni, coming back to clinical correlation and different types of cerebral palsy or cerebral palsy mimics, could you break down the mimics based on the type of cerebral palsy phenotype, in terms of spasticity, dystonic cerebral palsy, hypotonic cerebral palsy and ataxic cerebral palsy?
 
 

AI: Yeah, so for spastic presentations, the key mimics include HSP, so the hereditary spastic paraplegia, leukodystrophies, including the hypomyelinating and the dysmyelinating type of leukodystrophies, spinal cord disorders, including neural tube defects and other spinal cord dysraphisms. And metabolic disorders like arginase deficiency, which is a rare condition.
 
 

There is a specific enzyme therapy which has shown positive outcomes in a recent randomized clinical trial. In children presenting with dystonia, we need to consider neurotransmitter disorders, for example, DOPA responsive dystonia, Lesch-Nyhan syndrome, Wilson disease, ADCY5 and other genetic related dyskinesias, and many neurodevelopmental genetic disorders which have a predominant motor disorder component, for example, Rett syndrome and Angelman syndrome.
 
 

AI: For ataxic presentations we need to consider mimics that would have ataxia as the predominant problem. This can include structural cerebellar problems like Joubert syndrome where there may be important systemic organic problems that are not seen in cerebral palsy, for example, renal issues.
 
 

Friedreich's ataxia, which can have significant cardiac involvement and ataxia telangiectasia. For hypotonic presentation, there is again a wide range of conditions to consider, since it is such a nonspecific feature. And it could be central hypotonia, because of a number of reasons including genetic, for example, Prader-Willi syndrome.
 
 

Or it could be a primary neuromuscular disorder, for example, spinal muscular atrophy. The pattern recognition is crucial because each group has distinct diagnostic and therapeutic implications.
 
 

RK: Okay. And that's an extensive list again and breaking it down into the subtypes and sub phenotypes of cerebral palsy. It's also worth bringing back some of our discussion back to the situation where the MRI brain is normal within these groups because as we talked about before, that finding of a normal MRI brain in somebody with a significant motor disorder should really make us stop and consider investigating for a rare condition. So here the MRI is often normal in the hereditary spastic paraplegias that can mimic spasticity or the spinal cord disorders, obviously, because you're missing the spinal cord because you've just imaged the brain, but also neurotransmitter disorders, Lesch-Nyhan syndrome, and with Friedreich's ataxia as well. Now, the other thing to mention is it's easy when you've got all the information to hand, but often the MRI brain initially appears normal, but can only show progressive abnormalities on repeated later MRI brain scans, as for example, progressive cerebellar atrophy in ataxia telangiectasia or the lysosomal disorders where the first MRI scan done at a young age can appear normal, but a later MRI scan may show these abnormalities.
 
 

AI: Yes this is a very important point to acknowledge, and it is often necessary to repeat the MRI brain scan periodically to identify conditions and mimics. For example, iron deposition in the basal ganglia in neuronal brain iron accumulation or distinguish progressive cerebellar atrophy from a static cerebellar hypoplasia or intrauterine static damage.
 
 

So if there is a high clinical index of suspicion for a cerebral palsy mimic, it is important to consider repeat neuroimaging, to identify emerging neuroimaging findings.
 
 

RK: Absolutely. So I think this is once again indicates why you cannot sometimes give a diagnosis at the very first meeting, sometimes a period of follow up and repeating earlier investigations is often needed to make a diagnosis. You may have to revise the previous diagnosis of cerebral palsy that someone else made in the past.
 
 

I mean, that's a very common situation for both of us, I'm sure. So many of the classical physical features that purportedly distinguish a genetic cause from cerebral palsy are not often present when the child is at a young age, and often only evolve over time and age. So, I'll give you an example. I can remember one girl who later ended up with a diagnosis of Rett syndrome due to a mutation in the MECP2 gene. And when I first met her, it was in the first year of life and she had very remarkable hypotonia and muscle weakness and she had a low muscle mass as well. So I was very much going down the line of investigating for a primary neuromuscular disorder. But one thing that I remember was very unusual was that despite her low muscle mass, significant hypotonia weakness, she actually had brisk reflexes and it stuck in my mind. And I wondered, why has she got brisk reflexes. Now we ended up doing SMA investigations. We did muscle MRI scan, CK, obviously all of these were normal. And then a number of years later, I was discussing her with one of the clinical geneticists and I saw his letter and he said, "Rett syndrome? Absolute nonsense. You know, this girl does not have Rett syndrome. She's just got pure hypotonia. She's got brisk reflexes." And then I actually called her up to see her in the clinic and she came in and as she came through the door I went, well, she's obviously got Rett syndrome because now she had developed the classical phenotype about three or four years later with hand wringing movements and the hyperventilation. So that shows how within that first year in this child who had a particularly severe form of Rett syndrome may not show the classical features that we all think of as part of Rett syndrome.
 
 

AI: Absolutely.
 
 

RK: So I mean, and I remember another child, once again, in the first year of life, had a pure dyskinetic presentation. She had Angelman Syndrome, which became very much clearer after, you know, one had seen her at age seven or eight. So, the MRI scan was normal in both of those.
 
 

AI: Yeah, so it is important to not only recognize the importance of repeat neuroimaging, but also to carefully examine an evolving clinical phenotype where there are anomalous examination findings in the initial examination. For example in your case there was a presence of brisk reflexes that did not go with the clinical phenotype of a primary neuromuscular disorder.
 
 

So reassessment and periodic re-evaluation for emerging clinical phenotype is also extremely important.
 
 

RK: So now I've seen a number of young children who later turned out to have Lesch-Nyhan syndrome as well, and once again, they can present with a pure dyskinetic cerebral palsy and normal MRI brain. The classical self injury behaviour that we all know of as part of Lesch-Nyhan may only appear later in the disease course as well, well after the initial presentation with what appears to be a child with a typical dyskinetic or athetoid form of CP.
 
 

Albeit often there's no risk factor present to have caused the condition.
 
 

AI: That is indeed interesting. There is currently no disease specific treatment for Lesch-Nyhan syndrome, but identifying this condition can allow for early intervention of the self injury behaviour, which is a very challenging feature of this condition, which otherwise would seem bizarre in a typical cerebral palsy.
 
 

The child often feels more safe with arm restraints and removal of the teeth, which would be seen as bizarre and cause for social services referrals without the knowledge of the child's condition. And of course, uric acid scavenging agents can also be helpful in Lesch-Nyhan syndrome.
 
 

RK: Okay. So now let's consider treatable conditions. Can you elaborate on some of the treatable cerebral palsy mimics that we really shouldn't miss?
 
 

AI: Absolutely. This is probably the most critical aspect and it is becoming increasingly relevant as more and more precision treatments for novel disease and rare disorders are becoming increasingly available. Several treatable conditions can mimic cerebral palsy and it is important to prioritize these conditions when we are investigating for a possible mimic. DOPA responsive dystonia, particularly Segawa disease or GTP cyclohydrolase deficiency, is very sensitive to L-DOPA. It is not considered neurodegenerative, but individuals become progressively disabled, especially without treatment. And there is a remarkable reversibility of disability with L-DOPA.
 
 

Other genetic DOPA responsive dystonia should also not be missed because of the simple nature of treatment.
 
 

RK: Absolutely. So I think the DOPA responsive dystonias are one of the more important set of conditions not to miss. And I've certainly seen more than one child with this condition misdiagnosed as having spastic diplegia, who seem to have this motor regression problem over a period of time. They also presented with some paroxysmal phenomena as well, particularly pain and spasms. And that child improved excellently with a relatively small dose of L-DOPA. So the condition often evolves over time and age with deterioration of motor ability, can mimic that CP mobility decline, but usually it's somewhat earlier than the pseudo regression that we see in individuals with cerebral palsy. Now the clue here was that the scan was normal in the child that I just mentioned, who was misdiagnosed as having spastic diplegia. So what other treatable conditions can you suggest?
 
 

AI: GLUT1 deficiency is a chameleon when it comes to clinical phenotype and it can present in a multitude of ways, including motor presentations. And epilepsy as well as ataxia, spasticity dyskinetic kind of a movement disorder, or Parkinsonian type of a movement disorder. And we know that it responds to ketogenic diet and also other disease specific treatments.
 
 

RK: Okay, I mean, I've certainly seen individuals with GLUT1 deficiency who have a predominant ataxic disorder and ultimately develop a very physical pattern of disability similar to spastic diplegia including significant knee contractures. I mean, I can remember one teenager with GLUT1 deficiency developed a DOPA responsive Parkinsonian presentation over time.
 
 

In fact, his epilepsy, which is what we tend to think of as a primary phenotype of GLUT1 deficiency, actually settled down as a problem by the age of presentation.
 
 

AI: That's interesting. There are numerous other individually rare genetic metabolic conditions who have movement disorder and often progressively increase in tone or ataxic abnormalities. Biotinidase deficiency and biotin thiamine responsive disorders respond to biotin supplementation. There are folic acid responsive disorders.
 
 

AI: They can present with spasticity due to reduced cerebrospinal fluid folate and brain folate availability. Vitamin B12 deficiency, including in the mother of a breastfed infant with evolving spasticity. That's also a tremor-like vitamin B12 deficiency condition called infantile tremor syndrome quite common in Southeast Asia because of predominantly vegan diet in mothers and infants end up having infantile tremor syndrome due to B12 deficiency.
 
 

So broadly these are vitamin responsive or vitamin deficiency states which respond to vitamin replacement. Other disorders are responsive to dietary adjustments, such as a number of organic acidaemias and aminoacidurias that would respond typically to low protein diet. Ketogenic diet is of course a form of dietary adjustment, as in pyruvate dehydrogenase deficiency and GLUT1 that we discussed earlier.
 
 

RK: So, you know, you've made a number of important points about dietary treatment or dietary supplementation responsive conditions. Now, as you mentioned earlier, even when there are no approved treatments, there are numerous clinical trials that offer hope and potential cure in these devastating conditions.
 
 

AI: Yes, there are an increasing number of gene and enzyme replacement therapies specific to a rare gene and sometimes even a rare variant in a rare gene, such as in arginase deficiency, which can mimic a spastic diplegic cerebral palsy. Often, the underlying disease can be treated more effectively and sometimes even cured with early identification and treatment, whereas later treatment leads to suboptimal outcomes, we often have a therapeutic window that we don't want to miss.
 
 

RK: Yes, and I think, you know, one of the other things I think we should mention is that structural anatomical conditions that can appear to be cerebral palsy, but are progressive in that they ultimately require neurosurgery, adverse outcomes. So, I'm thinking here of early onset brain tumours.
 
 

RK: Which we shouldn't forget about. So I can certainly remember children who were thought to have hypotonic cerebral palsy or even a child who had hemiplegic cerebral palsy because they presented at the appropriate age in the first year or two of life. But they turned out to have developmental slow growing tumours which required excision. Now after they had the surgery they did end up by definition having cerebral palsy because it had essentially caused a lesion in the brain causing motor disability at the developing brain stage. But in effect, they had a treatable disorder that would have ended up killing them or causing more permanent damage if the diagnosis had been delayed.
 
 

So I think it should be remembered that tumours in young children are often developmental in nature and can develop at an early stage, even in utero. And seen other brain structural problems, which are non-malignant, not tumours, such as interhemispheric cyst, which is a developmental lesion, but can grow during infancy and cause acute and chronic spasticity and motor weakness.
 
 

So appear very much like spastic hemiplegia, but then have a secondary acute deterioration. And these are rare situations, but I think it is worth pointing out that there are neurosurgically treatable mimics of cerebral palsy as well.
 
 

AI: Absolutely, this again underscores the importance of neuroimaging, particularly in children who do not have the typical historical risk factors.
 
 

RK: Okay, so now we've discussed large number of rare progressive conditions that we should keep in mind when faced with a child who could have cerebral palsy and some of the neuroimaging appearances and phenotypes that could direct our attention towards one or other of these. But we've also identified some of the challenges in making an early diagnosis, such as the lack of well recognized textbook signs at the early stage of the condition. So, trying to bring things together, what approach do you recommend for investigating a child where you suspect their cerebral palsy might be something else?
 
 

AI: From a clinical perspective, we discussed earlier in this episode, the clues in clinical history and examination which would be red flags for the diagnosis of cerebral palsy, and when to consider alternate differentials. I'll discuss the place of investigations in a minute. However, as even MRI and genetic tests can be reported normal early on, I think follow up is crucial because time can be very revealing both for neuroimaging as well as clinical phenotype. I generally see these children every three to six months initially carefully documenting any change in their condition. I pay particular attention to developmental trajectory, any new symptoms and response to interventions.
 
 

I also tend to explore any extra neurological features, for example, renal, cardiac, and others. For instance, I saw a six month old with irritability and dystonia, who was initially thought to have cerebral palsy. A regular follow up revealed progressive symptoms with appearance of MRI abnormalities leading to the diagnosis of Krabbe disease. So there were symmetric white matter signal changes along with the typical tigroid appearance, which prompted enzyme testing for galactocerebrosidase deficiency, and subsequently was also confirmed genetically.
 
 

RK: Okay, so that's another good example. So now that leads to an important practical question. How do we balance the need for thorough investigation of possible mimics of cerebral palsy against not over investigating every child who does actually have cerebral palsy? We said, you know, it's far more common for the child to have cerebral palsy in the end, even after a number of these investigations.
 
 

AI: Absolutely. We need to be pragmatic about this. It's about recognizing patterns and red flags. We don't need to extensively investigate every child with cerebral palsy like presentation, particularly those who have a very clear history of perinatal injury and who have consistent clinical examination findings.
 
 

The Pearson criteria, and the updated criteria from Aravamuthan et al for cerebral palsy expand on the discussions and are helpful here. Cerebral palsy related motor symptom onset before two years, non progressive course by five years of age and exclusion of predominant non motor disorders are important criteria.
 
 

RK: Yes, I mean, you've mentioned a couple of very helpful articles there. So there's an article by Pearson and colleagues in the May 2019 issue of Movement Disorders and another very recent useful article by Aravamuthan and colleagues in the December 2024 issue of Neurology. So the Pearson article lists very much similar to the discussion we've had here with the relevant investigations and screening tests, mainly from a genetic metabolic nature, but now updated with next generation sequencing genetic tests in our modern era. So, we can provide a list of recent investigations from our perspective on the CYP Neuro website under additional resources. Now, rather than getting mired in the intricacies of each individual specific investigation Professor Israni, could you summarize your key practice points for our listeners who are evaluating children with possible cerebral palsy or a mimic?
 
 

AI: Certainly. To start with, first be mindful of the red flags we have discussed and recognize that clinical history and examination findings evolve over time, often over years. Secondly, MRI brain changes can also evolve. So imaging should be repeated if the child shows unusual clinical progression.
 
 

AI: Thirdly, when brain MRI features don't match the clinical history, we need to reconsider and re-evaluate the diagnosis. Always think of a treatable entity. Consider a trial of levodopa in cases of dystonia where causation isn't clear. And finally, and perhaps most importantly, prioritize looking for treatable causes with high recurrence risk.
 
 

We don't want to miss conditions that could respond to specific interventions and which could recur in the family causing additional problems.
 
 

RK: Okay, those are very practical points in a nutshell. As we conclude, is there anything else that you'd like to add about improving diagnosis and care for these children?
 
 

AI: Yes, I would emphasize that diagnosing cerebral palsy versus its mimics isn't just an academic exercise. It has real implications for families. A specific diagnosis can open doors for treatment options, can provide clarity about prognosis and help with family planning. I always remind colleagues that while the diagnosis of cerebral palsy makes children eligible for support services, we shouldn't let this stop us from looking deeper when things don't quite fit the pattern.
 
 

RK: Okay. Thank you, Professor Israni, for sharing your expertise in this important topic. And I think this discussion highlights how critical it is to maintain diagnostic vigilance while managing children with motor disorders. Now, I'm someone who undertakes both diagnostic focused clinics and rehabilitation focused clinics, and it's important to review both aspects when dealing with children with motor disorders with an apparently established diagnosis of CP who presents to you predominantly in the rehabilitation and treatment focused clinics because the change in that presentation may not be the pseudo motor regression of cerebral palsy, but rather a true regression of a cerebral palsy mimic. So now for our listeners, we'll be sharing more educational content on paediatric neurology topics through the CYP Neuro platform. So please visit our website for a transcript of this episode and additional resources, including a list of references. So this has been myself, Dr. Ramkumar with Professor Anil Israni discussing the clinical approach to mimics of cerebral palsy. And thank you for listening.
 
 

AI: Thank you, Dr. Kumar for this very insightful discussion and thank you to all our listeners.