In daily neurological practice, peripheral neuropathy remains one of the most common reasons for neurological referral. The worldwide diabetes epidemic will no doubt ensure that more and more patients are seen with the classic syndrome of length-dependent sensory and motor impairment that inevitably sets in train a range of investigations: nerve conduction studies, blood tests including the usual suspects such as B12, folate, creatinine and possibly an oral glucose tolerance test. In some centres, coeliac serology may be added to that panel, although I suspect that your hit rate will be low ¹. Every so often, we are surprised by what we find when we order these tests. I recently had a patient who actually was B12 deficient and who did improve with appropriate treatment. Some of you may have had patients with copper-deficient myeloneuropathy, which again is amenable to therapy ².

 The occurrence of demyelinating changes on NCS is particularly rewarding as it not only alleviates the inevitable boredom of seeing scores of patients with axonal neuropathy, but also provides an interesting intellectual challenge. Some of these patients may have inherited neuropathy and depending on where you live, this may result in little or no further investigation or potentially a mass of ‘neuropathy panels’ looking for one of the zillion genes that we think may underlie charcot-marie-tooth disease. Without a good family history, the greatest beneficiaries of such intense investigation may be the scores of commercial outfits that provide these investigations. Certainly, in my experience the patient does not always benefit beyond testing for the most common genetic abnormalities (PMP 22, MPZ, mitofusin) and further research may be hampered until another family member  comes along with a similar complaint.

 In terms of acquired demyelination, we all think about chronic inflammatory demyelinating polyneuropathy, a condition that I use as a retort against my friends’ frequent verbal assaults that generally centre on the all pervading therapeutic nihilism that apparently still characterises 21^st century neurology. (Neurology can be summed up in two words, they tell me, “Diagnose, adios”: I ask them what the temperature is like on Mars these days). But yes, CIDP is a breath of fresh air: intravenous immunoglobulin, steroids, cyclosporine, methotrexate, mycophenolate, rituximab ³. Wow…. I am not sure if they all work but they certainly sound great in unison.

 Over the years there have been many excellent contributions to JNNP in the area of neuropathy research ^1-5 and the trend continues in the May issue of the journal. Two prominent neuropathy groups from Chiba and Rochester suggest that we keep in mind a rare but potentially underrecognised form of demyelinating neuropathy and just when you were coming to grips with DADS, MADSAM, MMNCB ³ and other forms of neuropathy soup, here is another – POEMS syndrome ^4,5 (polyneuropathy, organomegaly, endocrinpoathy, M-protein and skin changes).  As noted in both these papers and the accompanying Editorial ⁶, the papers provide clinicians with some clues as to how to separate POEMS patients from ‘run-of-the-mill’ CIDP. In particular, they highlight the fact that POEMS patients appear to have more uniform demyelination along the peripheral nerve trunk, while the changes in CIDP patients are relatively polarized either to proximal or distal regions of the peripheral nervous system. In addition, the changes of axonal loss appear to be more prominent in POEMS, with greater muscle atrophy particularly in the lower limbs. The papers also provide potential ways of differentiating these two disorders on the basis of nerve conduction abnormalities. As noted in the Editorial ⁶, there may be a very direct clinical benefit from being able to differentiate these condition as the prognosis of POEMS is largely dependent on early identification and treatment, and as highlighted in these papers, a ‘neuropathy presentation’ of this systemic disorder is a common enough occurrence.

 1. Rosenberg et al. Should coeliac disease be considered in the work up of patients with chronic peripheral neuropathy? J Neurol Neurosurg Psychiatry 2005;76:1415-1419 doi:10.1136/jnnp.2004.048413 http://jnnp.bmj.com/content/76/10/1415.full?sid=27d23c4f-2cc3-459e-bcd8-ff52e2c66545

 2.Goodman BP et al. Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy. J Neurol Neurosurg Psychiatry 2009;80:524-527 doi:10.1136/jnnp.2008.144683 http://jnnp.bmj.com/content/80/5/524.full?sid=a2769e05-41c5-4a16-a551-986d4067440e

 3.Lunn MPT, Willison HJ. Diagnosis and treatment in inflammatory neuropathies. Journal of Neurology, Neurosurgery & Psychiatry. 2009 Mar;80(3):249-58. http://jnnp.bmj.com/content/80/3/249.full?sid=7f5e07bb-96ec-4d0a-9b06-e7cb750886e5

 4. Nasu et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 2012;83:476-479 Published Online First: 15 February 2012 doi:10.1136/jnnp-2011-301706. http://jnnp.bmj.com/content/83/5/476.full

 5. Mauermann et al. Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry 2012;83:480-486 Published Online First: 6 March 2012 doi:10.1136/jnnp-2011-301472. http://jnnp.bmj.com/content/83/5/480.full

 6. Arimura K. Early recognition of POEMS syndrome: what is the role of clinical neurophysiology? J Neurol Neurosurg Psychiatry 2012;83:474 doi:10.1136/jnnp-2012-302477 http://jnnp.bmj.com/content/83/5/474.full.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of motor neurons in the spinal cord, brainstem, and motor cortex, with ea median survival of 3-5 years.  At present, there is no cure for ALS, and the currently available treatments are of limited  efficacy.  Recently, a neuroprotective benefit of lithium carbonate was reported in animal models of ALS and in humans.  Specifically, it was reported that lithium increases survival and retards disease progression, thereby providing a potential ray of hope for the ALS patients.

Since the original studies, a number of large studies have been published refuting any benefits of lithium in ALS.  In this issue of JNNP, a group led by Prof van den Berg, apply the final nail to the notion that lithium may be efficacious in ALS.  Specifically, the authors assessed the efficacy of lithium carbonate in a double blind placebo controlled trial in a large cohort of ALS patients.  the primary outcome measures included survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day.  In addition, secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity.   The study failed to demonstrate any benefits of lithium on primary of secondary outcome measures in ALS.   Given the absence of any effects on survival of functional decline in ALS, this study has helped to resign lithium therapy in ALS to history.

Reference

Verstraete E, Veldink JH, Huisman MHB, et al. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. Journal of Neurology, Neurosurgery & Psychiatry 2012;83:557-64.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disorder of motor neurons in the cortex, brainstem and spinal cord, for which there is no cure.  The pathophysiological mechanisms underlying ALS remain to be fully elucidated, although approximately 10% of cases were previously regarded as familial.  Mutations in the superoxide dismuate-1 gene (SOD-1) were first reported in 1993, accounting for ~20% of all familial ALS cases.  Recently, two independent research groups have made a stunning discovery, whereby large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 gene located on chromosome 9p21 was reported to account for between 23.5-46% of familial and 21.1% of sporadic forms of ALS (DeJesus-Hernandez et al. 2011; Renton et al. 2011).   In addition to the typical ALS phenotype, this genetic mutation was also associated with frontotemporal dementia, suggesting a potential link between these two disorders.  The mechanisms by which this genetic mutation results in the AL/FTD phenotype remains to be fully elucidated, although a loss-of-function and RNA-mediated gain-of-function mechanisms have been proposed.  Further research is required to clarify the precise mechanisms mediating the neurodegenerative processes in ALS.  Resolution of such issues could be of profound therapeutic significance.

In this issue of JNNP, Dr Bryan Traynor, one of the senior authors on the original manuscript in Neuron, provides historical commentary on the discovery of this very important gene.  In addition, Khan and colleagues further expand the phenotype associated with this very important mutation by reporting a behavioural variant from of frontotemporal dementia (FTD).   This underscores the importance of this mutation in development of neurodegeneration and appears to be a game changer for the diagnosis of both ALS and FTD, having significant implications in the counselling of the so called “sporadic ALS” patients and FTD.

References

Traynor, B. J. Road to the chromosome 9p-linked ALS/FTD locus. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83: 356-357.

Khan, B. K., J. S. Yokoyama, L. T. Takada, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83: 358-364.

DeJesus-Hernandez, M., Ian R. Mackenzie, et al. (2011). “Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS.” Neuron 72: 245-256.

Renton, Alan E., E. Majounie, et al. (2011). “A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD.” Neuron 72: 257-268.

According to a recently released study in Current Directions in Psychological Science, the key to self-control is practice. As in, the more you practice self-control, the more inclined you are to engage it when you need it most.

Take Wednesday night for example, when two excellent hours were spent at a concert, leaping around to seminal 1980s band New Order. Amongst the 5,000 or so revellers there were plentiful elbows to the ribs, hair flicked in faces and sprays of beer that were all happily endured in the name of good spirits. In any other circumstance these encroachments on the person would never be tolerated. However, the concert continued unabated without a visit from the riot police.

Nonetheless, my companion, who shall remain nameless but carries the XY chromosome, took a somewhat different approach to the evening. Whenever a flailing limb made contact or a stream of ale breached the meniscus of a fellow rocker’s plastic cup and became airborne in his direction, he would repay the action in kind…and with interest. The recipient of this harangue would stare wide-eyed at the angry man and wonder: why all the negative energy?

One’s tiny mind begins to tick over in these situations and draw tenuous links. And, in deference to New Order and its predecessor Joy Division, the title of the latter’s most intriguing song came to mind: She’s Lost Control. Why is it that one person can control their emotions when another can’t?

Back at the concert, the old grey matter was working overtime and came up with a theory. Where the psychological scientists of the aforementioned study had tortured their subjects by denying them chocolate biscuits or forcing them to hold a nasty King Pigeon pose (some breed of contortive yoga move), my XY friend had merely had “a hard day at work”. A nine-hour conga-line of whining clients and incompetents had slowly sapped his reserves of self-control and here was his chance to let loose.

Miraculously, two hours passed and no actual violence was perpetrated on another individual. However, a quick exit from the venue was followed by what turned out to be a 90-minute queue to leave the carpark. Again, good spirits reigned. Fellow carparkers tooted their horns in the style of New Order and generally made good of a tedious situation.

XY held his own for about 45 minutes…and then lost it. Alighting from the car and confirming that he was merely popping out to get a snack from the nearby convenience store, he returned 10 minutes later out of breath and electric. On enquiring, it turns out that he was probably lucky to have all limbs remaining. Allegedly, on finding a carpark attendant (a very large gentleman from the island of Tonga) behind glass on the lower level, he had engaged in some unsavoury chat and found that the attendant, too, had had a “hard day” and was happy to let XY know about it in a physical fashion. Evidently the flight/fight response had kicked in.

On the drive home, one was reminded of the lyrics of a tune pilfered from Tennessee Ernie Ford by the smooth old crooner, Tom Jones, called Sixteen Tons. “If you see me coming, better step aside. A lot of men didn’t, and a lot of men died.”

Lou Gehrig “Gibraltar in cleats” In the midpoint of the 1938 season, it became clear there was a problem. James Kahn, a reporter who wrote often about Gehrig, noted in one article: “I think there is something wrong with him. Physically wrong, I mean. I don’t know what it is, but I am satisfied that it goes far beyond his ball-playing. I have seen ballplayers ‘go’ overnight, as Gehrig seems to have done. But they were simply washed up as ballplayers. It’s something deeper than that in this case, though.”

"Gibraltar in cleats"

A hot topic in the field of motor neurodegeneration relates to the potential role of exercise.

On the one hand, patients are desperate for information, particularly in regards to potential lifestyle-related benefits of exercise. Conversely, clinicians and scientists continue to argue over a potential role for exercise in terms of disease causation.

Unfortunately, these are complex, largely unresolved areas of debate, and so the potential benefits of exercise in ALS remain an open discussion between physician and patient.

In America, motor neurone disease (or amyotrophic lateral sclerosis) is also known as Lou Gehrig’s disease, named after the famous New York Yankees baseballer (figure). Gehrig was a superb athlete, and as with most MND/ALS patients, there seemed to be no apparent reason for him to contract this universally fatal disease at the young age of 35, to die two years later.

Other seemingly random cases have subsequently been described in high performance athletes. A retrospective study of more that seven thousand footballers from the Italian professional leagues established that standardized morbidity ratios were increased for the development of MND/ALS, particularly younger onset (Chiò et al, 2005). For unexplained reasons, footballers who played for more than five years, particularly in an active midfield position, were at highest risk.

Other studies have suggested a raised risk of ALS in marathon runners, and further epidemiological investigations are currently underway in rugby populations.

Although MND/ALS is typically sporadic, approximately 5-10% of cases are familial, whereby two or more family members are clinically affected.  The exact pathophysiological mechanisms underlying neurodegeneration in familial and sporadic MND/ALS have yet to be defined.  Inheritance of familial MND/ALS is usually autosomal dominant, often linked to mutation of the copper/zinc superoxide-dismutase-1 gene (SOD-1) resulting in the typical adult-onset MND/ALS phenotype.  The key function of the SOD-1 enzyme involves free radical scavenging, with the enzyme catalyzing the conversion of the superoxide anion to molecular oxygen and hydrogen peroxide.

The processes underlying MND/ALS appear multifactorial, involving complex interaction between genetic factors and molecular pathways, with resultant damage of critical target proteins within the motor neurone. In terms of any pathophysiological link between exercise and the development of MND/ALS, oxidative stress, excessive free radical production, and increased glutamate stimulation may all accompany normal motor neurone activation.  However, it is plausible that such processes may potentially become neurotoxic as a result of exercise and excessive activition in susceptible individuals.

Dysfunction of the energy-dependent, axonal Na⁺/ K⁺ electrogenic pump may also be an integral factor contributing to motor neurone loss in MND/ALS.  In addition to regulating the resting membrane potential, the axonal membrane electrogenic pump exerts a significant role in the restoration of gradients after high-frequency impulse activity, as presumably occurs with exercise. Overactivity of axonal Na⁺/ K⁺ pump, in the setting of progressive weakness in ALS, is likely to be a significant contributing factor to the common symptom of fatigue (Vucic et al., 2007).

However, this discussion remains largely hypothetical and relates more to a potential role for exercise in the causation of MND/ALS.

What advice then should a neurologist provide to patients once diagnosed with MND/ALS regarding their lifestyle and specifically, the role of exercise? Unfortunately a Cochrane analysis cited a lack of randomised clinical trial data that may guide appropriate discussion concerning the potential benefits or risks of aerobic type exercise in MND/ALS (Dalbello-Haas et al, 2008).

Similarly, there is limited information concerning resistance training, although recent pilot studies involving inspiratory muscle training suggest potential benefit, with larger multicentre studies currently underway (Cheah et al, 2009).

To further muddy the waters, findings in animal models of ALS have been inconsistent. Criticially, these type of studies must be interpreted with caution, particularly in relation to human disease, given the fact that of the many (> 100) trials undertaken in SOD-1 mouse models of MND/ALS, none of the positive findings from animal studies have translated into meaningful therapy in human MND/ALS.

Any suggestions of a potential role for exercise in either disease causation, or alternatively and somewhat conversely, therapeutic intervention, clearly need further validation.

Discussion may serve to increase the momentum for larger scale, exercise-based clinical trials in MND/ALS patients.

If you have an opinion, let us know!

References:

Cheah BC, Boland RA, Brodaty NE, Zoing MC, Jeffery SE, McKenzie DK & Kiernan MC. (2009). INSPIRATIonAL – Inspiratory muscle training in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10(5-6):384-392.

Chiò A, Benzi G, Dossena M, Mutani R & Mora G. (2005). Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128, 472-6.

Dalbello-Haas V, Florence JM & Krivickas LS. (2008). Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev 16, CD005229.

Vucic S, Krishnan AV, Kiernan MC (2007). Fatigue and activity-dependent changes in axonal excitability in ALS. J Neurol Neurosurg Psychiatry 78, 1202-1208.

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How does a scientific manuscript become highly cited, a trail-blazer for others to develop their theories and practice?

To help us understand this process, the January issue of JNNP launched the Impact Commentary, to provide a modern perspective on some of the most highly cited JNNP studies of all time.

Where possible we have approached the authors of the original study, or in other cases asked key opinion leaders to comment on the original science and subsequent course, to dissect out the reasons behind each publication success.

In addition to providing pearls of wisdom, the Impact Commentary will provide newcomers such as neurology trainees, with an opportunity to put discoveries and developments across the clinical neurosciences into a historical context as a whole. The opportunity to get the ‘long view’ from the original author, the opinion that sets the scene and then goes beyond their particular research study and how this may have influenced important developments in the field, in some cases over many decades, remains all too rare.

An Impact Commentary will be rolled out with each monthly issue of JNNP, and can be found as a topic collection at

The Impact Commentary

http://jnnp.bmj.com/cgi/collection/jnnp_impact_commentaries

A modern perspective on the most highly cited JNNP studies of all time

Can semantics get in the way of progress?

By our roving blogger Dr Susanna Park

Directly over the fence from my new home, there lies a complex with an impressive Victorian façade, proclaimed as the Royal Hospital for Neuro-Disability. It is clear that this facility has been operating here for a long time, probably ever since the Victorian era. What was the history of this hospital next door and how did it come to occupy such a stately building? My interest was further piqued when I found an old map of the area and written in small italic print was ‘Hospital for Incurables’.

The Hospital for Incurables was founded in 1854 by the distinguished philanthropist Dr Andrew Reed and moved to its current location, a former part of the Lord Spencer’s estate with 25 acres of gardens in 1863.  Florence Nightingale advised on the design and the estate was supported by notable personalities of the day such as Charles Dickens, as well as several distinguished royal patrons. At the time, there were very few options for poor patients with so-called ‘incurable’ conditions ¹. Most prominent hospitals of the day were designated as facilities for patients with acutely curable disease and often specifically excluded incurables in their charters ². The difficulties experienced by incurable patients in obtaining care were commonplace in the 19^th century. In the United States, hospitals also routinely excluded patients with incurable diseases from hospital beds³. The term ‘incurable’ was typically reserved for chronic diseases which required long-term care, such as cancer or tuberculosis ³.

The Hospital for Incurables became the only facility specifically designed for such patients in London at the time, although there were “270 hospitals and infirmaries for curable patients” in London in 1860 ⁴. Over time the focus of the hospital has shifted towards neurological conditions, perhaps as public consideration of cancer and tuberculosis as incurable, untreatable diseases has changed.

In his 2009 book Incurable and Intolerable: Chronic Disease and Slow Death in Nineteenth Century France, Jason Szabo suggests that the development of treatments for chronic diseases in the 19^th century was hindered by the widespread belief in their incurability ⁵. Szabo writes that “A critical early step in this crusade involved questioning the scientific validity and social consequences of the term incurable.” Perhaps in line with this type of thinking, the Hospital for Incurables changed its name to the Royal Hospital for Neuro-Disability in 1995. Currently, the focus is on assessment, treatment, care and rehabilitation for patients with neurological disability.

The question remains – Can semantics get in the way of progress? As with cancer and tuberculosis, is it possible that our current attitudes as to the incurability and hopelessness of neurological disorders are hampering the fight to convert these into chronic but treatable conditions? Spinal cord injury, traumatic brain injury, neurodegenerative disease – do these disorders represent the new frontier in the redefining the boundaries of possibility? Perhaps the words of Charles Dickens, in his weekly journal ‘All the year round’ sum it up best:  “What is meant by Incurable? A disease called incurable in one generation, is curable in the next. A disease incurable by one man, is curable by another. A disease called curable, ends in a painful death; a disease called incurable, is borne with little suffering through a long life, and after all is not the cause of death”.⁶

References

1.  Royal Hospital for Neuro-disability http://www.rhn.org.uk/

2. Cook GC.  2004. Caring for “incurables”: the 150^th Anniversary of the Royal Hospital of Neuro-Disability, Putney. Postgraduate Medical Journal; 80: 426-430.

3. Abel EK. 2011. “In the last stages of irremediable disease”: American hospitals and dying patients before World War II. Bulletin of the History of Medicine; 85:29-56.

4. Elliot & Cobbe. 1860. Destitute Incurables in Workhouses: A paper by Miss Elliot and Miss Cobbe,  read at the Social Science Meeting at Glasgow, September 1860: London: James Nisbet and Co.

5. Szabo J. Incurable and Intolerable: Chronic disease and slow death in Nineteenth Century France. New Brunswick New Jersey; Rutgers University Press. 2009.

6. Dickens C. 1861. All the year round: a weekly journal conducted by Charles Dickens. Volume V, March 30 to September 21, 1861 London: Chapman and Hall: 44-45.

Map segment from Old Ordinance Survey Maps, Putney 1866 London sheet 113, Alan Godfrey Maps

For enhanced audio enjoyment click here: Handsome Devil

From our roving JNNP Web Editor Clare Caldwell

This month’s JNNP Featured Patient may well have been a fan of the educational philosopher Maynard Hutchins, whose most memorable quip remains, “whenever I feel the need to exercise, I lie down until it goes away.”

Imagine our patient, if you can: a Byronic figure in his early thirties with a penchant for gothic attire, eyeliner, long capes and the gloaming hours, our young man was surely channelling Vlad the Impaler. A pathological aversion to sunlight and an insatiable appetite for take-away curries, in fact take-away anything, completed the picture of a most unusual lad.

So, when the mysterious figure presented himself, via ambulance, at a large teaching hospital, the interest level was high. Surely the Transylvanian chapter was missing one of their number? But no. It appeared that the patient was a local goth who filled his days with slumber and his nights with the tap, tap, tap of keyboards as an IT consultant.

After the crowd of white coats had cleared and the necessaries had been performed, it turned out that the pale gent had suffered the most humdrum of maladies. Not a goring, an exorcism or a vampiric exsanguination – just a plain old stroke. It appeared that modern-day vamps DID require food, water and oxygen to keep the old red stuff flowing.

The Lord of Darkness was keen to escape the fluorescent glow of the stroke ward, so treatment was quickly administered and he was back on track. But as he lay in those crisp white hospital sheets a vial of his blood winged its way to a pathology laboratory in the United Kingdom. The young man’s decrepit teeth had given the treating professor an idea.

A week later, with the results returned, the night owl readied himself for the answer. Was it a brain tumour, tse-tse fever, Ebola!? No. It was scurvy; the ancient sailors’ curse. Mr Midnight’s decades-long rejection of fruit and vegetable matter had done him a disservice. It seemed that vampires could NOT live on blood (and curry) alone.

Doctor’s advice: Ignore the food pyramid at your peril.

No more takeaways.....!

This week we have a post from Dr Arun Krishnan, Web Editor at JNNP:

Over the last few weeks, I have been helping train and examine candidates for the specialist entry exams for the Royal Australasian College of Physicians. The candidates are fully qualified doctors with 3-4 years of hospital experience, who are planning on entering speciality training in an internal medicine discipline. All have extensive training in general medicine and a few, no doubt, will have spent time in Neurology rotations along the way. None of these doctors are neurologists and only a handful of successful candidates will choose to apply for Neurology training in the future.

Despite this, the enthusiasm for detecting neurological signs has been at an all time high. There has been much consternation about signs: is the weakness truly pyramidal, is there 3mm or 4mm of  proptosis, does the patient with the third nerve palsy have sparing of the 4^th nerve and finally of course, la pièce de résistance - are the plantars truly extensor ¹? I have been unsure how to deal with this sudden reliance on physical signs: should I step in and tell them that it is wonderful to see such unbridled enthusiasm and that Sir William Gowers would have been proud or should I break it to them that none of this really matters in 2011 once you have had an MRI of every neuron and axon, a full genetic ‘panel’ including testing for conditions that have only ever been described in a single North African family and biopsies of muscle, nerve and skin (don’t forget CADASIL² as a potential cause of migraine…in anyone… ever..).

While these thoughts are not without a degree of elaboration, the fact remains that there is little uniformity, even amongst clinicians at the same institution, as to what constitutes an adequate neurological examination. This issue was raised in a general medicine meeting at an institution where I trained some years ago. On that day, a non-neurologist said that his documentation of a normal neurological examination was summarised in two words: ‘CNS- NAD (no abnormal detected)’. Another argued that this was completely misguided and that a more accurate description should be given such as ‘CNS ü’.  Of course, it will be argued that the examination needs to be tailored to the problem, but that is exactly where the debate starts. Just how much do you examine in a patient with migraine or epilepsy, where not infrequently, the ‘general’ neurological examination is normal? Moreover, are we spending too much time focussing on signs in an era where counselling patients, discussing test results and monitoring for medication side effects are becoming increasingly time-consuming?

Clearly there are also cultural factors that weigh heavily on this. As a medical student, I spent time on an elective rotation in Chennai, India. Patients were not at all fussed about being seen in 5 minutes and discharged from clinics, as long as the neurologist examined them. Failure to examine was associated with pleas from patients, who clearly felt that ‘healing hands’ were all they needed. Also, the current focus on extensive investigation seems untenable, especially in the developed world where an ageing population will place huge pressure on resources.  Surely, there is a need to stratify investigations on the basis of clinical signs.

Moreover, in many countries, especially in the developing world, I would suspect that the growing Western philosophy of “investigate first, examine second” is completely impractical. How extensively do clinicians examine in these settings? Are we simply better doctors for examining more, rather than less? Or is this merely a question of timing? In future generations, perhaps we will tell budding doctors something along the following lines:  “show me the MRI and I will tell you which direction those plantar responses are heading.”

1.       Lance JW. The Babinski sign. J Neurol Neurosurg Psychiatry. 2002 Oct;73(4):360-2.

2.       Tournier-Lasserve E, Joutel A, Melki J, et al. (March 1993). “Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12″. Nat. Genet. 3 (3): 256–9.

This week we have a blog from Dr Carinne Piekema covering the potential role of dopamine agonists in the development of pathological gambling. Carinne is a science journalist and neuroscientist who has worked on executive function and memory in neuroscience laboratories in the Netherlands and the UK. She is currently finishing a Masters in Science Media Production at Imperial College London and is particularly interested in communicating science through radio and podcasting.

Dopamine agonists have been used to alleviate the motor symptoms in Parkinson’s disease (PD) for several decades, both alongside levodopa and – as evidenced by the large number of publications, particularly in the JNNP – as a treatment in its own right (e.g. Parkes et al., 1976; Lees & Stern 1981; Montastruc et al., 1989).

Over the past decade, there have been increasing numbers of reports describing problematic side effects of such dopamine agonists (e.g. Seedat et al., 2000). In particular, a growing body of research shows that dopamine agonist medication may cause pathological gambling, compulsive and impulsive shopping, compulsive eating and hypersexuality in approximately 13.6% of PD patients who receive this treatment, thus developing the clinical symptoms of Impulse Control Disorders (ICD).

While such risk-taking and impulsive behaviours have been extensively documented, the reason why they arise in a particular subgroup of patients is still not fully understood. This is perhaps not surprising when considering the complexity of decision-making processes that might give rise to such risk-taking, impulsive behaviours. Before we choose one option over another, we weigh up the costs and benefits of all the options and calculate the likelihood of positive and negative consequences of our potential choice based on our past experience, and dopamine agonists may bias any of these processes.

I was therefore interested to read two papers published in the last few months that have started to shed light on the causes of the increase in risky decisions in these patients (Claassen et al., 2011; Voon et al., 2011). In both studies, PD patients were tested on varieties of risk-based tasks, both on- and off-dopamine agonist medication, in order to probe, in a controlled manner, the aspects of choice behaviour that might be affected by this type of treatment.

Daniel Claassen and his international team reported in Behavioral Neuroscience how PD patients with and without ICD performed on a paradigm called the Balloon Analogue Risk Task.  In this task, participants watch a balloon on a computer screen incrementally filling with air; with every puff of air the value of the balloon is increased by a small amount of money, which they can gain at any time by choosing to pop the balloon. The catch is that, if the balloon pops by accident, all the money in the balloon is lost. Therefore, the participants have to weigh up the cost of an accidental pop against the potential gain from a fuller balloon.

Claasen found that both groups of PD patients, while off-medication, showed a similar pattern of behaviour concerning when to pop the balloon, suggesting that there was no difference in risk-taking behaviour between both groups when they were not taking dopamine agonists. However, when taking dopamine agonist medication, the ICD patients showed an increased tendency compared to those patients without ICD to try to gain more money by letting the balloon inflate further. Moreover, across all PD patients, those who were on the highest doses of dopamine agonist medication were more likely to engage in risky behaviour compared to those who were taking a relatively low dose. Importantly, the researchers found no evidence that ICD patients had problems adjusting their behaviour following negative outcomes, suggesting that these patients are able to respond appropriately to feedback. Thus, it seems that ICD patients’ risk taking is not caused by an inability to learn from mistakes, but instead may result from changes in the way in which each decision is weighed up.

A similar conclusion was reached in a study published in Brain by Valerie Voon and her colleagues in the UK and US. They used a classic gambling task where participants chose between a probabilistic “risky” option and a certain “safe” option. In one condition, the participants were gambling over gains in money (i.e., a choice between a certain small reward or a risky option which could either lead to a high monetary reward or nothing at all) and in the other condition over losses in money (a choice between a certain small loss of money or a risky option which could either lead to a no loss or a large loss of money). In agreement with Claassen and colleagues, the researchers observed that PD patients with ICD who were taking dopamine agonist medication took riskier gambles in the ‘gains’ compared to PD patients without ICD. Nonetheless, these patients with ICD were also still sensitive to the relative level of the risk and chose to gamble less when gambles were more risky and adjusted their behaviour on the trials directly after a loss.

Voon and colleagues also obtained functional neuroimaging data from the patients while they were performing the task in order to look at the underlying neurobiological substrates of these changes in behaviour. They found that PD patients with ICD showed significantly less activity in orbitofrontal and anterior cingulate cortices compared to those without ICD. These regions are known to be involved in the evaluation of risks and value of option and a decreased activity may result in a tendency to behave more riskily.

PD has long been thought of primarily as a disease of the motor system caused by the loss of dopamine-containing cells of the substantia nigra. Such findings have resulted in the idea that the nigrostriatal dopamine system is primarily involved in the selection and control of voluntary movement. However, largely separate from this research, other scientists have been studying another dopamine system – the mesocorticolimbic dopamine system – and have focused mainly on its role in motivational and reward processing. These two strands of dopamine research have largely proceeded in parallel, partly based on an idea that these two dopamine systems were completely distinct (Wise, 2009).

However, these changes in decision-making in subgroups of PD patients documented by Voon, Claassen and other researchers demonstrate that considering PD treatment from the sole perspective of trying to re-equilibrate the loss of nigrostriatal dopamine may have drawbacks.  First, given that PD initially primarily affects the nigrostriatal dopamine system while sparing mesocorticolimbic dopamine, dopamine agonists might in fact impair the functionality of the latter system in certain patients, leading to maladaptive decision-making. It may be that PD patients who develop ICD may have underlying genetic neurobiological vulnerabilities that exacerbate such an impairment, similar to the link between impulsive genetic personality traits and drug taking (Dalley et al., 2011).

Second, several lines of basic research suggest that the different dopamine systems interact both anatomically and functionally. Both systems send projections to parts of the frontal lobe as well as the dorsal striatum (e.g. Fallon, 1988), and the cell bodies in both systems can sometimes be found in the same midbrain structure (Wise, 2009). There is also increasing evidence that interactions between ventral striatum – innervated by mesolimbic dopamine – and dorsolateral striatum – innervated primarily by nigrostriatal dopamine – underlie the development of habitual addictive behaviours, and that these interactions are mediated by dopamine transmission (Belin & Everitt, 2008).

But possibly the most compelling reason for why the strong distinction between “motor” and “motivational” dopamine systems may be regarded as artificial can be found in the fact that movement and motivation can not always be so neatly separated: sometimes we choose to walk to the fridge because we are hungry, to scratch our back to relief an itch, to exercise to stay fit. In a study published a few years ago in the Journal of Neuroscience, Pietro Mazzoni and his colleagues showed that one of the key “motor” symptoms of PD – namely bradykinesia – might arise not as the patients could not make the movements, but because they were less motivated to expend energy on movement (Mazzoni et al., 2007).  This indicates that nigrostriatal dopamine activity plays a role in enabling voluntary movement not just through modulations of motor pathways in the basal ganglia, but also by participating in calculations of the cost/benefit value of a response. In other words, there is an important class of voluntary movements, which are exactly the type that are frequently affected in PD and rely on dopamine, that are motivationally driven.

Studies such as those led by Claassen and Voon are gradually starting to reveal the mechanisms behind pathological gambling and other compulsive behaviours caused by dopamine agonist medication in PD patients with ICD, and in doing so, they aid our understanding of the role of dopamine in risk-taking behaviour. Even as researchers are trying to uncover the exact functioning of such complex systems, it is important for clinicians to use the knowledge that certain interactions between medication and underlying vulnerabilities can lead to highly undesirable side effects.

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Voon V, Gao J, Brezing C, Symmonds M, Ekanayake V, Fernandez H, Dolan RJ, Hallett M. (2011). Dopamine agonists and risk: impulse control disorders in Parkinson’s disease. Brain 134: 1438-1446.

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