In today’s article, Matt Quinn discusses the relation between folic acid supplementation and neural tube defects.

Each year approximately 220,000 babies are born worldwide with spina bifida or anencephaly due to maternal folic acid deficiency during the periconceptual period. [1] These cases account for roughly 70% of the global incidence of spina bifida and anencephaly and have been termed folic acid-preventable spina bifida and anencephaly, respectively. Fortifying food with folic acid could prevent these debilitating illnesses. The current RDA of 400 mg can be found in most over-the-counter multivitamins. This paper will provide a brief overview of the pathogenesis of spina bifida and anencephaly, the evidence supporting the use of folic acid supplementation during the periconceptual period, the disparities between different countries use of folic acid fortified food, and the ethical and safety concerns for why some countries have chosen not to implement mandatory folic acid fortified food programmes.

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MS is the most common cause of acquired neurological disability in young adults and, despite advances, is incurable. Professor Dimitrios Karoussis, Head of the multi-disciplinary Multiple Sclerosis Center at Hadassah University Hospital in Israel, shares the results of his promising research in the field of neuroimmunology and exploits the potential use of adult stem cells for the future treatment of MS and other neurodegenerative disorders.

Professor Karoussis

Why you did you become a neurologist?

I believe that the brain is the center of our existence and a great challenge for research; especially the field of the brain and immune system correlation. That’s why I focused on neuroimmunology.

What is the problem with MS?

In MS, the immune cells attack the myelin causing demyelination, secondary axonal damage and degeneration. Several issues involved in the immunological cascade are still obscure, as is what triggers this autoimmune reaction. Importantly, the affected myelin repair is only partial and the remyelinating mechanisms ineffective. The continuing local CNS inflammation and the insufficient numbers and migration ability of the intrinsic brain stem cells, could be the main reasons for progression, development of chronic accumulating axonal damage, degeneration and neurological disability.

Despite advances, no treatment can repair or halt this disability?

MS seems to continue progressing and there is no way to completely stop or reverse the degeneration of axons/neurons and disability progression, possibly due to the ineffective local immunomodulation inside the white matter and defective repair/re-myelinating mechanisms.

Stem cells may possess these properties?

Stem cells can “home” to demyelinating sites, exert strong immunomodulating effects and may transdifferentiate producing oligodendrocytes and neurons, or at least secrete growth factors supporting local neurogenesis and inducing neuroprotection.

So, how did you become involved in this fascinating research?

I have been working here in Hadassah Hospital since 1990 with MS animal models and novel immunomodulators (we introduced the first oral immunomodulator Linomide for MS and its descendant Laquinimod); our concept, one of the first notions in the literature for autoimmunity, was instead of suppressing the immune system, we could preferably upregulate the regulatory cells and networks.

And then the stem cells…

This was the second concept we suggested for MS and autoimmunity: to suppress autoreactivity by resetting and replacing the immune system with bone marrow haematopoietic stem cells (bone marrow transplantation). After 2000 I focused on the non-haematopoietic population of stem cells in the bone marrow (BM): the mesenchymal stromal cells (MSC).

Why have you focused on this population of adult stem cells?

This type of stem cells, offer practical advantages over conventional embryonic neuronal stem cells:
1. They can be easily obtained from the adult BM and easily cultured and expanded, posing in parallel a very low risk for malignancies development.
2. They can be safely administered as documented in bone marrow transplant recipients. For autologous cells administration, there is no need for immunosuppression.
3. Cumulative experimental evidence suggests that they can facilitate neurogenesis following brain injury.
In extensive experiments with MS animal models, we have shown that their transplantation into the cerebrospinal fluid significantly prevents and improves the paralytic signs and could induce neuroprotection. Several of these cells were shown to express neuron and myelin-producing cells markers, indicating a potential for transdifferentiation and regeneration of damaged neuronal cells.

And these very results formed the rationale for the first clinical trial?

Yes; we moved in 2005-6 to an initial clinical trial (the first of its type) with autologous BM derived MSC transplantation in MS and amyotrophic lateral sclerosis (ALS) patients. We have performed until today transplantations in 35 patients, both intrathecally and intravenously to maximize their possibility to reach affected CNS areas .The sole aim was to explore the feasibility and the safety of this first time applied treatment modality.

Is this first clinical study encouraging?

Although it’s not designed to test the efficacy of stem cells (did not include a control group), we can say that most MS patients have reported stabilization and some a functional improvement, especially in the sphincters controls, arms muscle power, tremor and walking stability. ALS patients initially stabilized but at a later stage continued deteriorating (though at a lesser degree), possibly indicating the need for additional infusions. MRI revealed the migration ability of the transplanted stem cells and the patients’ immunological evaluation has shown strong immunomodulation induced by these cells.

What about the side-effects?

Until today, we haven’t observed any major adverse event except transient fever, headache and some limb pains, and paraesthesias.

Are you scheduled to perform a controlled clinical trial?

After extending this safety study by few more patients, we are preparing to proceed with a controlled clinical trial.

Many patients come to Hadassah from around the world. Do they come to you expecting miracles?

We indeed receive hundreds of patients from all over the world in our MS Center. As in every field in Medicine today, people tend to exaggerate in their expectations. The “unfiltered” internet information available causes the belief that there is already a solution for MS and similar diseases. The truth is that a great first step is done in the field of stem cell therapy for neurology, but we are still in the beginning of a long journey and have to perform each following step patiently and cautiously.

What other possible questions have to be answered?

We have to learn more on the long term safety of stem cell transplantation. Larger patients numbers and longer follow up periods are needed. We have also to better understand their migration abilities and patterns. Most importantly, we have to build a multi-center controlled trial which will provide more efficacy data.

What is your vision for an MS patient in the future?

To tailor individualized immunomodulating treatment, based on each patient’s immune phenotype. We have developed new immunological tests to identify distinct MS immune subtypes and apply the most appropriate immunotherapy. Preventive Medicine is also of great importance in identifying patients at high risk for future progression and apply early immunotherapy (including vaccination methods). Replacement medicine and neuroprotective approaches (including stem cells) are also part of our vision.

Andreas Charidimou is a medical student at the National and Kapodistrian University of Athens, Greece.

charidimou@gmail.com

April 7th marked the start of Parkinson’s disease Awareness Week.  Srimathy Vijayan provides an overview of the disease and information on developments in treatment during the past 50 years. 

The week commencing April 7th marked Parkinson’s disease (PD) Awareness Week. It has been 191 years since the publication of ‘An essay on the Shaking palsy’ by Dr James Parkinson, the London doctor who first established the condition. Since, our knowledge has progressed in all aspects of the condition. Predominantly a disease of the elderly, PD is characterized classically by rest tremor, slowness in initiating movements, and rigidity. The pathogenesis involves a selective and progressive loss of the nigrostriatal dopaminergic neurons located in the brain. At present all medications used to treat PD merely provide symptomatic relief. Consequently, PD is a chronic, progressive neurodegenerative movement disorder.  

The WHO estimates PD to have an incidence rate of 4.5-19 per 100 000 population per year (1). This is a relatively large range most likely attributed to the different clinical methodologies used to evaluate and diagnose PD in various epidemiological studies.  Considering this, it is likely that centres fluctuate between over and under diagnosing cases of PD depending on diagnostic experiences/skill. Another logical reason is that studies are likely to have mixed age distributions within their population cohorts; generally, higher rates are found in more elderly populations. Pezzolia suggested rates ranging from 0.6 for those aged 65–69 years and 3.0 in those aged 80–84 years (2). Nonetheless, it is estimated that 8% of cases occur under the age of 40 years (3). Thus, it has been suggested that age-adjusted rates provide a more realistic picture; such rates give a more restricted range of 9.7 to 13.8 per 100 000 population per year (1). 

Given that PD is a chronic condition, it is unsurprising prevalence data are higher than incidence. Prevalence estimates vary from 18 per 100 000 persons in a population survey in Shanghai, China, to 328 per 100 000 in a door-to-door survey of the Parsi community in Bombay, India (1). Such geographic disparity in prevalence may suggest that environmental and genetic factors both play an important role in the development of PD. Certainly a multifactorial aetiology seems most plausible, and prominent genetic links with PD have now been established (4). Likewise, environmental factors are continuously being evaluated, most recently, pesticides (5). Age-adjusted prevalence of 72–258.8 per 100 000 population have been documented (1). 

A particularly neglected area regarding epidemiological studies of PD are the rates in under-developed countries such as Africa. This might be because PD as a medical condition is undermined in comparison to the other significant health problems in these areas such as HIV, tuberculosis and malaria. In addition, the rates of PD in this part of the world are significantly decreased in comparison to wealthier nations, perhaps due to shorter life expectancy and decreased potential for PD manifestation.  As a result, the level of interest regarding PD research is decreased in these countries.  As such there is paucity of data, thus at present, a drive to research in this area – Dotchin et al. are currently door-to-door prevalence study in Tanzania (6).

Most noteworthy is the implication of an increasing ageing population. As a consequence, a greater proportion of patients are likely to develop PD in the future; one study estimated the number of people with PD over the age 50 will double  worldwide over the next 25 years (7). Therefore, it is important for healthcare providers to acknowledge the imminent increasing burden of PD and plan accordingly.    

The mainstay pharmacological treatment for PD is Levodopa. Since its development in the 1960s to, in effect, replace the diminishing levels of dopamine, the quality of life for patients has improved significantly. Although Levodopa has been and considered the first-line drug treatment of choice, some 50 years later, a number of other pharmaceutical agents have been developed. These, both individually or in conjunction with Levodopa, provide various other treatment regimens, helping to overcome the well known consequences of long term Levodopa treatment (levodopa induced dyskinesias) and to also target the increasingly recognized non-motor symptoms of the condition. Some important classes of these newer drugs are dopamine agonists, COMT inhibitors, MAO-B inhibitors, and glutamate antagonists. Given the extensive list of pharmaceutical agents and the lack of robust clinical evidence present to suggest best treatment strategies for PD, there remains no agreed upon guidelines. Instead, individual physicians have their own preferred regimen, based on personal experiences. This poses two additional problems.  First, treatments are likely to be expensive as physicians may have to experiment with medications in order to find the most beneficial drug for their patient. Secondly, the administration of various medicinal regimens may cause increased and unnecessary side-effects, which in turn will be addressed by prescribing more medication or requiring surgery.  Taken together, this affects the quality of life (QOL) of these patients and poses additional healthcare costs. As such, there remain many uncertainties concerning the most effective (in terms of efficacy and cost) treatment regime for PD and we await the outcome of many on-going clinical trials (8).  

Although Levodopa is relatively cheap, newer pharmaceutical agents are considerably dearer. According to the British National Formulary (BNF) 2008; a pack of Madopar (Levodopa) starts at net price £6.20 for 100 tablet pack. On the other hand, a pack of Cabergoline (a popular dopamine agonist used in conjunction with Levodopa) is net price £53.20 for 20-tablet pack at the minimal dose. Thus, as one may appreciate, drug treatments for PD are expensive. In the UK, the direct cost of treatment to the NHS has been estimated to be approximately £2298 per patient per year (9). In a study conducted in Germany, the authors estimated average parkinsonian drug costs for a 6-month period of 1520 euro +/-1250 euro (18). The costs are likely to reflect the severity of the disease and in particular the presence of motor fluctuations for which a multiple cocktail of drugs are often needed. A group of researchers from USA attempted to evaluate this logic (11), and showed that PD subjects in their first year of diagnosis accounted for $581 cost. But 5 to 10 years later, the same subjects exhibited significantly higher costs at $1146. Thus for physicians treating PD, it is clear they must calculate the initial short term benefits of drugs with that of the long term consequences of such treatments (dyskinesias) and the economic implications of treating these.

As with the expansion of pharmaceutical agents, surgical techniques have been explored and developed. Deep Brain Stimulation (DBS) of the subthalamic nucleus and/or globus pallidus in patients with advanced PD, where all drug treatments have been exhausted, has been shown to alleviate motor symptoms/dyskinesias (12). Despite the relatively recent interest, numerous studies have already looked at long-term outcomes of such patients. In a 4-year follow up, researchers showed a significant therapeutic benefit in 69 patients with severe PD for the whole 4 years (13). In another 5-year follow up of 49 patients, bilateral stimulation of the subthalamic nucleus demonstrated a marked improvement over 5 years in their motor symptoms but worsening of other symptoms (such as akinesia, speech, postural stability, freezing of gait, and cognitive function) which the researchers classified as ‘the natural history of Parkinson’s disease’ (14). However, other studies have also reported variable outcomes following DBS which may be dependant on location and volume of lesions (15). Thus, we are still in the early stages of refining this surgical technique. Currently the National Institute of Clinical Excellence (NICE), states that between 1-10% of all PD patients are likely to benefit from such surgical procedures but the question remains, how do we identify groups of patients that may benefit from this technique? 

The cost of the DBS surgical procedure itself is stated at 18 456 EURO (16). Of course, in addition to this basic surgical expense is the costs acquired as a result of the infrastructure and support team needed to safely carry out and monitor patients. Highly skilled neurosurgeons are essential, and these factors do limit this form of treatment to more affluent societies.   

Despite the obvious costs associated directly with treating the condition, there are other dimensions. PD is a progressively disabling condition, and as the disease progresses the QOL of patients declines.  As a result, patients require additional home care/support. In fact, in a recent study conducted by Findley, it was discovered that the largest component of cost is inpatient and nursing home care (17). Such findings are further supported by other economic analyses; French researchers estimated costs in a cohort of PD patients and concluded hospital stays were the most expensive component of care (39% of costs), followed by ancillary care (30% of costs) (18). 

Treating the accompanying medical problems commonly associated with PD, such as depression and dementia are paramount. These disorders occur in about 50% and 40% of subjects respectively (19, 20). The diagnosis of depression is often complicated by the fact that the anti-parkinsonism drug pramipexole (dopamine receptor agonist) has been shown to cause depression itself (21). Furthermore, the clinical features suggestive of depression often overlap with the motor features of PD, so it may be overlooked. Regardless of these difficulties, cognitive behavioural therapy and anti-depressants are commonly used to treat depression in PD. Although cholinesterase inhibitors have been used successfully in individuals with PD dementia, it is still not clear exactly which patients benefit from this treatment, thus treating dementia is often surrounded by much ambiguity.  

Regarding treatment, a multi disciplinary approach for patients is often implemented.  Such a regimen often requires the participation of PD nurse specialists, physiotherapists, occupational therapists, speech and language therapists, as well as dieticians. Initially most patients do not require these services, however as the disease progresses, and many of the clinical symptoms worsen, a proportion of patients may turn to these options. Remarkably, there are very few clinical trials addressing the utilization / cost of such services by PD patients, possibly because of the ethical hurdles faced when dealing with late stage PD patients as a target population.  

Clearly, overall costs to treat PD vary from country to country. This is likely to reflect individual countries demographic trends, healthcare systems, delivery/availability of services and access to treatment (both pharmaceutical and surgical). This most likely reflects the demographic trends of individual countries, including healthcare setups, delivery/availability of services and access to treatment (both pharmaceutical and surgical). The total annual cost of care including NHS, social services, and private expenditure per patient in the UK has been estimated near £5993 per patient (9). In America total annual direct costs were estimated at 23,101 US Dollars per patient (22). Undoubtedly, in comparison with the demographic trends of the global population, regardless of present day costs, it is apparent that PD will constitute a greater proportion of all healthcare spending in the future.    

Despite these major advances, the fundamental and crucial question about what causes PD is still yet to be answered. A greater understanding of the genetics involved is proving to provide some information. ‘Neuro-protection’ whereby a pharmaceutical agent that has the potential to, in the least part, slow the disease process or better still, halt it, looks promising.  Further down the line, the prospect of ‘Neuro-restoration’ where parts of the brain could be implanted with appropriate nerves/cells to restore function is another key area of research (23). Thus it seems that the disease once thought of as a ‘progressive, chronic neurodegenerative disease with no cure’ will no longer be. Innovative treatment options such as the expanding choices of pharmaceutical agents and potential surgical techniques, is further evidence that PD should be on the agenda of all healthcare providers. 

Srimathy Vijayan

5th year medical student

University of East AngliaNorwich 

s.vijayan@uea.ac.uk 

(1) Neurological Disorders: public health challenges. World Health Organization. 2006.  

(2) G. Pezzolia, M. Canesia, C. Galli. An overview of parkinsonian syndromes: data from the literature and from an Italian data-base. Sleep Medicine 5 (2004) 181–187.   

(3) Bandolier (2003) Incidence of Parkinson’s disease. Bandolier. http://www.jr2.ox.ac.uk/bandolier  

(4) Klein C, Lohmann-Hedrich K. Impact of recent genetic findings in Parkinson’s disease. Curr Opin Neurol. 2007 Aug;20(4):453-64. 

(5) Hancock DB, Martin ER, Mayhew GM, et al. Pesticide exposure and risk of Parkinson’s disease: a family-based case-control study. BMC Neurology 2008, 8:6.    

(6) Dotchin CL, Msuya O, Walker RW. The challenge of Parkinson’s disease management in Africa. Age Ageing. 2007 Mar;36(2):122-7.    

(7) Dorsey, E.R., Constantinescu, R., Thompson, J.P. et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2006: 68(5), 384-386.  

(8) Kalra P.A. Essential Revision Notes for MRCP. Second Edition 2004. PASTEST  

(9) Findley, L., Aujla, M., Bain, P.G. et al. Direct economic impact of Parkinson’s disease: a research survey in the United Kingdom. Movement Disorders 2003:18(10), 1139-1145.  

(10) Spottke AE, Reuter M, Machat O, et al. Cost of illness and its predictors for Parkinson’s disease in Germany. Pharmacoeconomics. 2005;23(8):817-36.  

(11) Leibson CL, Long KH, Maraganore DM, et al. Direct medical costs associated with Parkinson’s disease: a population-based study. Mov Disord. 2006 Nov;21(11):1864-71.  

(12) Volkmann J. Deep brain stimulation for the treatment of Parkinson’s disease. J Clin Neurophysiol. 2004 Jan-Feb;21(1):6-17.  

(13) Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicentre study with 4 years follow-up. Brain. 2005 Oct;128(Pt 10):2240-9.

(14) Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease.N Engl J Med. 2003 Nov 13;349(20):1925-34. 

  

(15) Limousin P, Martinez-Torres I. Deep brain stimulation for Parkinson’s disease. Neurotherapeutics. 2008 Apr;5(2):309-19.  

(16) Valldeoriola F, Morsi O, Tolosa E, et al. Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson’s disease. Mov Disord. 2007 Nov 15;22(15):2183-91.  

(17) Findley LJ. The economic impact of Parkinson’s disease. Parkinsonism Relat Disord. 2007 Sep;13 Suppl:S8-S12.

(18) LePen C, Wait S, Moutard-Martin F, et al. Cost of illness and disease severity in a cohort of French patients with Parkinson’s disease. Pharmacoeconomics. 1999 Jul;16(1):59-69. 

(19) Dooneief G, Mirabello E, Bell K et al. (1992) An estimate of the incidence of depression in idiopathic Parkinson’s disease. Arch Neurol, 49, 305–307.   

(20) Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol. 2003 Apr;2(4):229-37.  

(21) Rektorova I, Rektor I, Bares M et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 2003:10, 399–406.  

(22) Huse DM, Schulman K, Orsini L, et al. Burden of illness in Parkinson’s disease. Mov Disord. 2005 Nov;20(11):1449-54.  

(23) Davie CA. A review of Parkinson’s disease. Br Med Bull. 2008 Apr 8.

Srimathy Vijayan discusses the global burden of migraine

We may have all experienced a headache of some nature during our lives; in fact, just less than 2% of the population have never had a headache. (1) Usually self-limiting and short lived, headaches tend to disappear causing few aftermath symptoms. However, Migraine, a primary headache disorder, is a distinct medical entity with characteristic symptomology, resulting in profound effects on the individual. (more…)

Srimathy Vijayan takes an in-depth look at this important, but often neglected topic

In the January 2008 edition of The Lancet Neurology, reviewed Childhood epilepsies. (1) Such reviews are of great importance as they stress the requirement of ensuring that epilepsy occurring in childhood is considered as a different clinical entity to that occurring in adulthood. The word “epilepsy” is derived from the Greek word “epilambanein” which means “to seize or attack”. The seizures associated with epilepsy are the result of sudden, excessive electrical discharges in groups of brain cells. (more…)

Srimathy Vijayan discusses the global burden of neurological conditions

A consequence of increased life expectancy is the higher incidence of age related neurological disorders, such as dementia and stroke. Many of these disorders have evolved from detailed descriptions seen in medical textbooks to those with many diagnostic and therapeutic options supported by an increasingly robust evidence base. (1) They include neuro-degenerative diseases, neuro-infective diseases, neuro-vascular diseases, neuro-psychiatric diseases, neuro-surgical diseases, and as one may appreciate, are closely linked with various other divisions of medicine. Consequently, it is highly probable that future medical professionals, regardless of specialty pursued will be caring for patients with neurological disorders. (more…)