Dear Editor,

This document is timely and important. It contains a wealth of information about brain disorders and the need for research and testing action where there is evidence for interventions.

There is however, one serious omission: neurodevelopmental disorder. This should have appeared in the section under neurogenesis but it did not.

During the last trimester of pregnancy, the human fetal brain consumes 70% of all the energy directed to the fetus from the mother. This is a critical period for bran development for missing a developmental milestone means it is missed for life, disorder of development means disorder for life. There is no cure for cerebral palsy and disorder which may lead to autism, cognitive defects, learning disabilities, visual, audio and motor distortions are usually life long.

The risk of central nervous system disorder rises from about 1 or 2 per 1,000 live births at normal birthweights but rises to over 200/1,000 at weights below 1.5Kg when the babies will most likely be also born preterm. At the extreme end we have cerebral palsy. The most severe cases will require 24 hour nursing care. However, a high proportion of those who escape severe CNS disorder are likely to grow up with poor learning abilities and behavioural disorders.

Low birthweight is known to affect the lower socio-economic classes more so than others. Moreover there is increasing evidence that environmental factors, both epidemiologically and experimentally will affect gene expression and lead to prenatal programming of gene behaviour which can have lasting effects.

There is a good probability that epilepsy, autism, attention deficit and hyperactivity disorder and schizophrenia may have prenatal and or early post-natal origins..

It seemed to me the whole thrust of the Consensus statement was focussed on measures designed to treat disorder. There is no harm in that but it would be prudent and indeed balanced scientifically if the causes of neurodevelopmental disorders were addressed as well as the means to prevent them.

The Little Foundation has just completed its European Study of cerebral palsy. Four year old children were examined by state of the art MRI.. The results were reported in Monaco and the Royal Society of Medicine, London recently. In effect by identifying the location of the origins of the lesions, the researchers were able to establish that the majority were within 40 weeks after conception.. That combined with the known socio-economic, nutritional and other risk factors identifies areas of scientific enquiry on cause and prevention.

You may know that there was an increase in such disorders amongst the low and very low birthweight infants from the late 1960s to late 1980s. The Little Foundation estimated that the cost in the UK alone is of the order of £4 billion a year which across the EU adds substantially to the overall burden of brain disorders. .

The gravity of the rise in brain disorders cannot be over emphasised. It was predicted that brain disorders would rise following on the previous rise in death from cardio-vascular disease, in view of the common biological requirements as regards environmental and nutritional requirements common to both. The brain just happens to be better protected.

This means that this century there is likely to be a continued increase in brain disorders because of the time lag between the factors operating on CVD and the CNS. That is a very serious matter which I would wish to add to your otherwise superlative document.

Professor Michael A Crawford,
The Mother and Child Foundation.
http://www.mother-and-child.org

Dear Editpor

I read with interest that Wilson et al.[1] have confirmed an association between depressive symptoms and subsequent cognitive decline in a large defined community followed prospectively for an average of 5.3 years. The various possible explanations were discussed by Stewart.[2]

I wish to draw attention to one possible biological model of the risk factor or prodromal interpretation of this association, i.e. impairment of methylation in the brain leading to depression and ultimately cognitive decline on a background of ageing.[3]

In the brain methyl folate is the major source of methyl groups which, in reactions involving S-adenosyl methionine and homocysteine, are donated in innumerable methylation processes involving neurotransmitters, monoamines, membrane phospholipids, proteins, RNA and DNA, the latter influencing gene integrity and expression.[3,4]

I have elsewhere reviewed the evidence in neurological, psychiatric, geriatric and psychogeriatric patients that the commonest neuropsychiatric manifestation of folate deficiency is depression.[3] Impaired folate metabolism may result in a pattern of cognitive dysfunction that resembles ageing.[3] In elderly people folate deficiency contributes to ageing brain processes, increases the risk of Alzheimer’s disease and vascular dementia, and, if critically severe, can lead to a reversible dementia.[3] Recently identified common single nucleotide polymorphisms of several genes coding for folate dependent enzymes increase these risks, especially if associated with impaired nutritional folate status.[4]

A biological sub-group of patients with depression with raised plasma homocysteine associated with impaired methylation and monoamine metabolism has been identified.[5] Raised plasma homocysteine is also a risk factor for Alzheimer’s and non-Alzheimer’s dementia [6] and for vascular disease.[4]

Stewart [2] rightly emphasises the need for more careful evaluation of individual depressive symptoms or their clustering in relation to subsequent cognitive decline. In disorders of methylation the key symptoms are impaired mood and motivation.[3] Future studies of these associations and relationships should include measures of methylation such as red cell folate, plasma homocysteine and screening for polymorphisms of genes for folate dependent enzymes. Brain methylation status and mood are very poorly related to blood counts or serum folate.[3] Controlled prospective studies are also needed of the potential to prevent cognitive decline with prophylactic methyl folate.

References

1. Wilson RS, Mendes de Leon CF, Bennett DA et al. Depressive symptoms and cognitive decline in a community population of older persons. J Neurol Neurosurg Psychiatry 2004; 75: 126-9.

2. Stewart R. Depressive symptoms and cognitive decline – disentangling the effect of affect. J Neurol Neurosurg Psychiatry 2004; 75: 5.

3. Reynolds EH. Folic acid, ageing, depression and dementia. BMJ 2002; 324: 1512-5.

4. Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ 2004; 328: 211-4.

5. Bottiglieri T, Laundy M, Crellin R et al. Homocystine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000; 69: 228-32.

6. Seshaderi S, Beiser A, Selhub J et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346: 476-83.

Dear Editor,

Zephir et al. (1) report on five patients with a syndrome of combined central and peripheral demyelination, characterized by (i) immunological aetiology, proved by CSF findings, nerve biopsy examination, and response to immune treatments; and (ii) recurrent disease course, with central nervous system (CNS) involvement apparently preceding the onset of peripheral nervous system (PNS) damage by several years (2 to 12).

Screenings for systemic autoimmunity and infections were both negative, and only in 2/5 patients a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was hypothesized, possibly related to interferon (IFN) treatment. The Authors conclude for an immune reaction directed against an antigen common to both CNS and PNS.

As the Authors state, and according to our own experience, several hallmarks of acute CNS demyelination distinguish this syndrome from multiple sclerosis (MS), including (i) clinical features, such as bilateral optic neuropathy, transverse myelitis with or without roots enhancement, advanced age of onset; (ii) CSF features, such as absence of oligoclonal bands and marked increase in protein levels; and (iii) MRI features, such as grey matter involvement, mass effect, and multiple enhancing lesions.

On the other hand, peripheral demyelination was not typical for CIDP since the EMG failed to reveal temporal dispersion/conduction blocks, whereas showing marked damage of sensory fibres. We note that the CIDP cases associated with CNS involvement, that are cited by Zephir et al. in support of their hypothesis, differ from those of their own series in two important aspects, that is, the predominance of PNS vs. CNS symptoms, and the simultaneous involvement of both CNS and PNS.

The latter is a crucial point: considering a relapsing immune-mediated disease with common CNS/PNS target antigens, then a relapse episode would indeed be expected to produce simultaneous PNS/CNS damage. Such a combination is known to occur with certain infectious agents, e.g. Mycoplasma pneumoniae, or in post-infectious disorders.

However, this was not the case for the patients reported by Zephir et al, who failed to show signs of infections, with the exception of a possible enteritis in patient 3. In such cases, characterized by “temporal dissemination” of lesions between CNS and PNS, a multifocal, multisystemic autoimmune disorder is a more likely diagnosis. We wonder whether screening for autoimmune disorders was repeated during the relapses, since this search can be entirely negative during the first episode.

Although the Authors exclude the possibility of acute disseminated encephalomyelitis (ADEM) based on the absence of a clinically evident antecedent infection, and in view of the temporal succession of symptoms in their patients, we question this conclusion, since recently reported ADEM variants (2) do include forms with PNS involvement as well as relapsing forms.

For instance, in 60 patients with ADEM prospectively collected through 5 years, we made two observations that are relevant for the present discussion.

First, PNS involvement, that was systematically searched for in all patients, irrespective of their clinical features, did occur in 26/60 patients (43%), with a demyelinating pattern in 17/26 (65%); however, it was symptomatic in only 10/26 patients (38%), due to the predominance of CNS involvement that masked the PNS symptoms. Likewise, in the series reported by Zephir et al. subclinical PNS involvement could well be present right since disease onset, but became clinically manifest later on, once the CNS symptoms began to subside. The only exception may be patient 2, who had a negative EMG examination at the onset of CNS demyelination.

Second, PNS involvement was associated with higher risk of relapse in our patients (2, 3). This can also explain the high relapse rate and long-term disability of the patients reported by Zephir et al. These observations support the notion that, although ADEM is considered a monophasic disease of the CNS, either relapses or PNS damage may occur, and often co-occur, in this condition.

In conclusion, we propose that screening for PNS involvement should be given to all patients with “atypical MS”, irrespective of the presence of peripheral symptoms. The elevated risk of relapse and long-term disability should be considered in deciding a prophylactic treatment, since IFN could be contraindicated or ineffective (4). In the acute phase, agents active on both CNS and PNS demyelination, such as IVIg, may be first choice in these cases.

REFERENCES

1. Zéphir H, Stojkovic T, Latour P, Lacour A, de Seze J, Outteryck O, Maurage CA, Monpeurt C, Chatelet P, Ovelacq E, Vermersch P.
Relapsing demyelinating disease affecting both the central and peripheral nervous systems.
J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1032-9. Epub 2008 Jan 21.

2. Marchioni E, Ravaglia S, Piccolo G, Furione M, Zardini E, Franciotta D, Alfonsi E, Minoli L, Romani A, Todeschini A, Uggetti C, Tavazzi E, Ceroni M.
Postinfectious inflammatory disorders: subgroups based on prospective follow-up.
Neurology. 2005 Oct 11;65(7):1057-65.

3. Ravaglia S, Piccolo G, Ceroni M, Franciotta D, Pichiecchio A, Bastianello S, Tavazzi E, Minoli L, Marchioni E.
Severe steroid-resistant post-infectious encephalomyelitis: general features and effects of IVIg.
J Neurol. 2007 Nov;254(11):1518-23. Epub 2007 Nov 14.

4. Matsuse D, Ochi H, Tashiro K, Nomura T, Murai H, Taniwaki T, Kira J.
Exacerbation of chronic inflammatory demyelinating polyradiculoneuropathy during interferonbeta-1b therapy in a patient with childhood-onset multiple sclerosis.
Intern Med. 2005 Jan;44(1):68-72.

Dear Editor,

We read with interest the paper by Dawes et al (1) regarding the positive influence of a home-based exercise programme on muscle strength and fatigue of patients with muscle diseases. In a similar study (2) we showed few years ago that in patients with amyotrophic lateral sclerosis a moderate daily home exercise programme was able to improve spasticity and fatigue and reduce the rate of functional deterioration.

We agree with the authors that patients with neuromuscular disorders should be encouraged to adhere to regular exercise programmes.

References

1. Dawes H, Korpershoek N, Freebody J et al. A pilot randomised controlled trial of a home-based exercise programme aimed at improving endurance and function in adults with neuromuscular disorders. J. Neurol. Neurosurg. Psychiatry 2006; 77:959-962.

2. Drory VE, Goltsman E, Goldman Reznik J, Mosek A, Korczyn AD. The value of muscle exercise in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 2001; 191:133-137.