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Archive for April, 2014

c9orf72 and body schema processing: Novel pathophysiological insights!

30 Apr, 14 | by Steve Vucic, Web Editor

Increased hexanucleotide expansion in the c9orf72 gene on chromosome 9p21 has radically altered the understaning of ALS and FTD pathogenesis.  In the case of ALS, it has convincigly elevtaed the disorder to a central level, suggetsing the importance of frontal cortical dysufnction in ALS.  In addition, the understanding of FTD symtomatology, and how it related to undelrying pathology, has also been advanced.


In an upcoming issue of JNNP (, Downey and collegaues report on a novel clinical feature in FTD.  While it is well recognised that psychiatric symtoms are a distinguishing feature of c9orf72 FTD,  the concepot of altered body schema processing has been suggested but not previousy systematically assessed in FTD.  Downey and colleagues established deficits in somatosensory body schema processing, (i.e. tactile discrimination, proprioception, body part illusions and self vs non-self differentiation).  Such deficits could form the pathophysiological basis for the “beahvioural” and “psychiatric” issues  evident in c9orf72 FTD, and link this with anatomical disruption of corticla-subcortical networks.


Read more at:

  • Research paper

Altered body schema processing in frontotemporal dementia with C9ORF72 mutations

Open Access


First ever seizure: How long before I can drive doc?

29 Apr, 14 | by Steve Vucic, Web Editor

The occurrence of a first seizure is perceived as a devastating occurrence by both patient and family.  An issue faced by both patient and physician relates to the length of  driving restriction, so often an emotionally charged discussion that could result in the breakdown of Dr-patient relationship.  Consensus guidelines and treatment practices vary widely, resulting in much confusion for the treating neurologist.  In an upcoming issue of JNNP (FirstOnline) Professor Dunne’s group from Perth, Australia, conducted an elegant and much needed study concerning a safe time to return to driving post first-seizure.  Importantly, 8 months was suggested as the “non-driving” period for unprovoked seizures and 5 months in the case of a provoked first ever seizure.  These results are interesting and somewhat surprising, with important practice and medico-legal implications.  This is a must read article for all neurologists.


Do you agree with these time periods?  What would you suggest?  Comment on twitter and Facebook.


J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-307529
  • Epilepsy
  • Research paper

When is it safe to return to driving following first-ever seizure?

A novel dorsal root ganglionopathy: CANVAS syndrome

29 Apr, 14 | by Steve Vucic, Web Editor

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) syndrome is  a novel cerebellar ataxia clinically characterized by a combination of cerebellar dysfunction, bilateral vestibular dysfunction, and peripheral sensory neuropathy/neuronopathy.  This novel syndrome may be confused with Machado-Joseph disease or Friedreich ataxia, although the genetics remain elusive.

In the April issue of neurology (22nd April), Professor Halmagyi’s group establish the pathology of this unusual disorder, documenting marked loss of Purkinje cells in the cerbellum, predominantly the vermis, along with degeneration of dorsal columns and dorsal root ganglia.


Read more at,


Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS

  1. David J. Szmulewicz, FRACP,
  2. Catriona A. McLean, FRCPA,
  3. Michael L. Rodriguez, FRCPA,
  4. Andrew M. Chancellor, FRACP,
  5. Stuart Mossman, FRACP,
  6. Duncan Lamont, FRCP,
  7. Leslie Roberts, FRACP,
  8. Elsdon Storey, FRACP and
  9. G. Michael Halmagyi, FRACP


Amyotrophic lateral sclerosis: A disorder of the frontal faculties?

28 Apr, 14 | by Steve Vucic, Web Editor

Amyotrophic lateral sclerosis (ALS) was traditionally regarded as a disorder of only the motor neurons and their connections to the brain.  Although Charcot, who described and coined the term ALS, proposed a central origin of ALS, is was Professor Andrew Eisen who set the cats amongst the pigeons by suggesting that ALS was primarily a disorder of the upper motor neurons, with motor neuron degeneration being a secondary event.  The discovery of the c9orf72 gene as a major genetic cause of ALS underscored Professor Eisens’ hypothesis, although other supportive evidence has also been reported.


In an upcoming issue Chio’s group re-affirms that importance of cognitive  dysfunction in a population based study of Italian ALS patients.  Importantly these findings corroborate earlier studies , and have clear pathophysiological and potential therapeutic implications for ALS.




Multifocal motor neuropathy: A blood-nerve barrier disease?

23 Apr, 14 | by Steve Vucic, Web Editor

Multifocal motor neuropathy (MMN) is a rare autoimmune disorder of the peripheral motor nerves leading to muscle weakness, secondary to conduction block, and ultimately axonal degeneration.

Debate emerged over the past decade as to whether MMN is a demyelinating or axonal neuropathy, although the debate seem rather academic as both processes may and do co-exist in a variety of “demyelinating” or better termed “autoimmune” neuropathies.  In the May issue of JNNP, Shimizu and colleagues elegantly demonstrate  the pathogenesis of sera from MMN patients, pointing to a clear “autoimmune” process.  Specifically, sera from MMN patients were shown to disrupt the blood-nerve barrier by up-regulating vascular cell adhesion molecule-1 (VCAM-1) leading to an influx of inflammatory cells.  It would be interesting to determine whether IVIg restored the blood-nerve barrier, a potential therapeutic effect, and whether this correlates with clinical improvement.




Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier

Amyotrophic lateral sclerosis/Lou Gehrigs’ disease: Is it all in the genes?

16 Apr, 14 | by Steve Vucic, Web Editor

Amyotrophic lateral sclerosis/Lou Gehrigs’ disease is a devastating neuromuscular disorder of the motor neurons with a median survival of 3-5 years.   While the pathophysiological mechanisms underlying ALS development remain uncertain, the possibility of being with a predisposition to develop ALS is a popular theory.  Clearly, additional events are needed  to develop ALS, although these factors remain elusive.  In this issue of JNNP, Fratta and colleagues report on yet another genetic mutation (possibility polymorphism) that increases the risk of ALS development.  namely, E117G mutations in the Profilin1 are more frequent in ALS and could predispose to ALS development.  I suspect over the next decade the ALS physician will be able to test for a myriad of genetic mutations (predisposing to ALS), that will undoubtedly enable better counseling.  The question remains, WILL THIS ADVANCE IN GENETIC MUTATIONS lead to better disease understanding and development of more effective therapies.


I hope so?

Read more at :

Lou Gehrig with Babe Ruth-just after diagnosis.

Myasthenia gravis: not so grave anymore

16 Apr, 14 | by Arun Krishnan, Web Editor

A common theme in JNNP blogs has been the major paradigm shift in neurological practice, with a change from diagnosis (without treatment) to another in which making a diagnosis was a prelude to providing effective treatment. There have been few disorders in which this has been more clearly visible than that of myasthenia gravis, an autoimmune disorder in which there are antibodies directed against the neuromuscular junction. Patients typically report significant muscle weakness, which may affect the eyes, limbs, respiration and muscles that control speech and swallowing.  There is a beautiful diagram in Engel’s textbook on myasthenia which outlines the marked reductions in mortality from myasthenia have paralleled the major advances in critical care medicine, particularly in the provision of assisted ventilation (reproduced here in a review in Muscle and Nerve: The diagram also notes that steroids and plasma exchange have been important treatment strategies in combating this illness.

However, one issue that not infrequently rears its head in management of these patients is how to advise and treat a patient with myasthenia who is pregnant. Managing patients with neurological disease who are pregnant is hard and can be quite anxiety-provoking, whether we are talking about epilepsy, multiple sclerosis or myasthenia. As neurologists, we may feel that we need to treat the mother first, but pregnant women are often very understandably concerned about the potential teratogenic effects of the treatments that we use. A lot of my own patients would rather go without treatment than run the risk of congenital anomalies. Of course, this has to be balanced against the risks to the foetus from the mother’s neurological diagnosis itself. Myasthenia at its worst causes respiratory failure, dangerous for the pregnant patient and for her foetus. As neurologists, what should we do?

In this month’s issue of JNNP, Norwood and colleagues have taken on the challenge of providing guidelines for the management of myasthenia and pregnancy . They have done a stellar job in providing guidelines that will assist neurologists around the world. This is an excellent paper, which should be read by all.

We would also be interested in hearing from neurologists around the world about their own experiences in this area. How do you treat these patients and what have you learnt from managing this condition?

The complexities of ALS management: A genetic twist

14 Apr, 14 | by Steve Vucic, Web Editor

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and devastating neurodegenerative disorder of the human motor neurons and the systems that supply it.  Advances in the genetics of ALS have been staggering over the last two decades, although are we much the wiser?  The presence of a specific ALS genetic mutation may predispose a family member to develop ALS, although the age of onset, or indeed whether one will express the phenotype remains uncertain.  factors other than inherited genetic mutations appear to trigger the process since a patient “carrier” live with the genetic mutation for 30, 40, 50 or even more years with a seemingly devastating genetic mutation.


As such, the management of ALS patients has become complicated.  The question remains: “To test or not to test for a genetic mutation”.  A myriad of ethical and other issues have been borne out with the explosion of the number of ALS genetic mutations.

In this issue of JNNP (may 2014), Chio and colleagues write a very important reviewed discussing these issues. This must read review for all ALS physicians (neurologists, geneticist etc)  highlights the poor phenotype/genotype correlation, phenotype pleiotropy and the psychological, social and ethical implications of genetic testing.



J Neurol Neurosurg Psychiatry 2014;85:478-485 doi:10.1136/jnnp-2013-305546
  • Neurogenetics
  • Review

Genetic counselling in ALS: facts, uncertainties and clinical suggestions

Patient's Choice

  1. Adriano Chiò1,
  2. Stefania Battistini2,
  3. Andrea Calvo1,
  4. Claudia Caponnetto3,
  5. Francesca L Conforti4,
  6. Massimo Corbo5,
  7. Fabio Giannini2,
  8. Jessica Mandrioli6,
  9. Gabriele Mora7,
  10. Mario Sabatelli8,
  11. the ITALSGEN Consortium,
  12. Clara Ajmone5,
  13. Enza Mastro1,
  14. Debora Pain7,
  15. Paola Mandich3,
  16. Silvana Penco9,
  17. Gabriella Restagno10,
  18. Marcella Zollino11,
  19. Antonella Surbone12


Neurology and genetics: JNNP leads the way.

14 Apr, 14 | by Arun Krishnan, Web Editor

Recently I was at a weekend lunch when I was quizzed by a recently retired general practitioner about what exactly I did on a day-to-day basis. I went through the usual spiel about research and teaching and the need to quarantine time for these pursuits, given the potentially large clinical load that one could end up taking on. I mentioned that I saw patients in areas of research interest, mainly neuromuscular disease and MS. After listening to this for about a minute, he turned to me and said, “so you are gradually getting to know more and more about less and less”. Bullseye.

On reflection though, that has to be the way of the future and this month’s cracking issue of JNNP only serves to highlight this point: SOD1, C9ORF72, TARDP, FUS, C12ORF65, ADCK3, Profilin1 E117G. What are these? They are not secret CIA codes, just names of genes that may play a role in both rare and relatively common neurological disorders. In this regard, Neurologists, it is time to starting becoming ‘neurogenetically literate’. With respect to this issue of the journal, I am talking about conditions such as amyotrophic lateral sclerosis, inherited neuropathy and cerebellar ataxia. Patients with these conditions may appear to all and sundry as suffering from rare diseases, but ultimately discussions of incidence and prevalence or of little value to these people….suffering is suffering, discomfort is discomfort and to deliver truly excellent subspecialist care for these patients, we are being called upon to rapidly integrate recent research findings, which seem to be accruing at lightning speed, with what we are seeing at the bedside. This speed of Bench to Bedside translation is not for the faint hearted!

The most fascinating aspect of this new genetics is that we are no longer talking about conditions which follow true Mendelian inheritance. These are not disorders that can be conveniently segregated into dominant and recessive inheritance-sometimes yes, but not always. We are now increasingly looking at the role of ‘genetic’ factors in ‘sporadic’ disease. While this may sound like an oxymoron, I use one of the papers in this issue as an example.  Han and colleagues (1) have investigated the role of genetic mutations in the development of small fibre neuropathy, a condition which causes intense pain and burning in limbs. This is a common condition that causes significant morbidity and poor quality of life. Many patients with this condition are either of middle age or elderly and there is hardly ever any point in taking a genetic history or drawing a pedigree. In many patients, we never identify a cause for the small fibre dysfunction and simply label the condition as ‘idiopathic’, which is frustrating for everyone and most of all for the patient. In this paper, the authors have provided strong evidence that a mutation in a gene coding for a sodium channel may be the underlying cause in many of the cases which we (possible erroneously) label as idiopathic. Will these findings change the way that we manage these patients? Not at the moment it won’t, but very possibly in the future as we develop drugs that are capable of targeting certain type of sodium channels. In the meantime, as most neurologists would know, we may soon be able to alleviate some of the mental anguish that a patient feels when a doctor tells them that there is simply no known reason for why they developed a particular neurological disorder and that is progress in itself.

(1)    Han et al., The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. J Neurol Neurosurg Psychiatry2014;85:499-505 doi:10.1136/jnnp-2013-306095

CNS antibodies: How useful are they?

10 Apr, 14 | by Steve Vucic, Web Editor

The detection of autoantibodies in autoimmune CNS disorders has been if immense interest, with implications for undelrying pathophysiology.  A variety of autoantibodies have been detected and associated with various CNS syndromes, although the question remians whether these antibodies are pathogenic, an epiphenomenon, or both.


In this issue of JNNP, Hacohen and colleagues report on antibody biomakers in CNS demyelinating disorders of childhood.  A variety of anibodies and syndromew were reported, with the bottom line being that specific antibodies are associated with specific syndromes.  Consequently, the principles of good medical practice remians to define the phenotype and then look for the “genotype” or in thid case the antibody.  In addition, the relevance of antibodies in the underlying pathophysiology needs further research.


Do you think it is worthwhile looking for these antibodies?  let me know your thoughrs via twitter.



J Neurol Neurosurg Psychiatry 2014;85:456-461 doi:10.1136/jnnp-2013-306411
  • Neuro-inflammation
  • Short report

Autoantibody biomarkers in childhood-acquired demyelinating syndromes: results from a national surveillance cohort

  1. Yael Hacohen1,
  2. Michael Absoud2,3,
  3. Mark Woodhall1,
  4. Carole Cummins3,
  5. Christian G De Goede4,
  6. Cheryl Hemingway5,
  7. Philip E Jardine6,
  8. Rachel Kneen7,8,
  9. Michael G Pike9,
  10. William P Whitehouse10,
  11. Evangeline Wassmer11,
  12. Patrick Waters1,
  13. Angela Vincent1,
  14. Ming Lim1,2,
  15. On behalf of UK & Ireland Childhood CNS Inflammatory Demyelination Working Group


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Latest from JNNP