22 Aug, 14 | by Steve Vucic, Web Editor
Thinning of the motor cortex has been suggested as a biomarker of cortical dysfunction in ALS, although the specificity of the finding remains to be determined. In an upcoming issue of JNNP Walhout and colleagues report on the fact that cortical thinning was a specific feature in ALS, related to pathology of upper motor neurons. Consequently, the possibility of cortical thickness measures serving as potential biomarkers of ALS remains very real.
Must read more at: http://jnnp.bmj.com/content/early/2014/08/13/jnnp-2013-306839.abstract
J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-306839
Cortical thickness in ALS: towards a marker for upper motor neuron involvement
22 Aug, 14 | by Steve Vucic, Web Editor
Cervical radiculopathy is a common issue for neurologists. While motor dysfunction has been traditionally assessing using needle EMG techniques, thereby confirming the diagnosis, frequently only sensory symptoms may be evident. In such cases, the diagnostic time may be protracted.
In an upcoming issue of JNNP (ON-LINE FIRST) Lin and colleagues tackle this issue in a novel manner assessing sensory axonal excitability distal to the site of dysfunction. Interestingly, distal axonal hyperpolarisation was noted even in the presence of normal sensory nerve conduction studies, as traditionally expected. This provides a novel pathophysiological insight into this disorder.
Must read more at: http://jnnp.bmj.com/content/early/2014/08/20/jnnp-2014-308088.abstract
J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2014-308088
Sensory axonal dysfunction in cervical radiculopathy
22 Aug, 14 | by Arun Krishnan, Web Editor
Recently, I was talking to a young man in my clinic whom I had recently diagnosed with MS. We went over the potential options for treatment and he said that he would think it over and get back to me. A few weeks later I received an email from him stating that he wanted to start dimethyl fumarate (Tecfidera), a new disease modifying-drug for MS. What was his rationale? Here it goes:
“I feel that its effects on the NF2 oxidative pathway mean that I am more likely to experience a clinical benefit, without the adverse effects of immunosuppression”.
Wow. This from an intelligent person who has absolutely no background in medicine. It is truly amazing what you can learn on the internet. While in this case, the young man did not take it upon himself to make the diagnosis of MS, there are people whom I have seen who are absolutely convinced that they have a particular neurological condition based on reports that they have read on the web. In some cases, patients initiate a process of investigation and then arrive at a neurologist’s office armed with objective data that need interpretation. This of course turns the basic process of diagnostics on its head- it becomes a case of find an abnormality first and then ask the doctor to make sense of what it means clinically.
Those of who you work closely with clinical geneticists would have seen a similar situation arising due to the advent of commercial gene panels, which can screen for pretty much anything you want them to screen for. The panels are expensive and once the results are produced it is up to the clinician to make sense of what it all means. This is a major problem in some situations as these panels can make the diagnostic process much harder, particularly where there is more than one abnormality uncovered. At the end of the day, the clinician will need to make a diagnosis and that means resorting to the traditional clinical method of taking a history and doing a physical examination.
In this issue of JNNP, Foley and colleagues provide an interesting report http://jnnp.bmj.com/content/85/9/1012.abstract on a diagnostic journey that commenced with two patients who had independently decided to obtain whole-genome sequencing. As you will read, the results initially side-tracked diagnostic efforts before the treating team were able to utilise a more traditional pathway of investigation, which ultimately led to the diagnosis.
16 Aug, 14 | by Steve Vucic, Web Editor
The risk of fetal malformations is a considerable therapeutic consideration in pregnant patients that suffer epilepsy. the need to control seizures effectively is counterbalanced by toxicity of medications. While lamotrigine was considered as a safer option than other anti-epiletics, doubt was cast upon this assertion. In this issue of JNNP, an important study conducted by Campbell and colleagues elegantly demonstrate that lamotrigine is safer that than valporate and tegretol. Indeed, valporate seemed to bear the highest risk of malformations. Of relevance, higher dose lamotrigine (>400 mg) did not seem to impart a significant increase of risk. Anyone managing epilepsy patients with the potential of falling pregnant must read this very important article.
J Neurol Neurosurg Psychiatry 2014;85:1029-1034 doi:10.1136/jnnp-2013-306318
Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers
- E Campbell1,
- F Kennedy2,
- A Russell3,
- W H Smithson4,
- L Parsons5,
- P J Morrison6,
- B Liggan7,
- B Irwin1,
- N Delanty8,
- S J Hunt1,
- J Craig1,
- J Morrow1
13 Aug, 14 | by Steve Vucic, Web Editor
Facial onset sensory and motor neuronopathy (FOSMN syndrome) is a rare neurodegnerative disorder of unknown etiology. Clinically it may resemble ALS, albeit only in the motor component. The marked sensory abnormalities, which dominate the phenotype in the early stages of the disease process, and the prolonged survival, clearly argue against an ALS phenotype. In this issue of JNNP, heterozygous D90A SOD-1 mutations were reported in a single FOSMN patient. The question remains as to whether this is a pathogenic mutation and whether there are other factors governing the expression of the genotype. A point hat is underscored, however, is that genotypes are predisposing and not causative, with other factors clearly important in expressing the phenotype.
Read more at http://jnnp.bmj.com/content/85/9/1009.abstract
J Neurol Neurosurg Psychiatry 2014;85:1009-1011 doi:10.1136/jnnp-2013-307416
Heterozygous D90A-SOD1 mutation in a patient with facial onset sensory motor neuronopathy (FOSMN) syndrome: a bridge to amyotrophic lateral sclerosis
13 Aug, 14 | by Arun Krishnan, Web Editor
Many moons ago it would have been unthinkable that MS treatment would take about 2-3 hours a month. It would have been impossible to imagine that you could simply turn up to your local hospital, have an infusion while you read a book and then tell the ward staff that you would see them again in 4 weeks. This pipe dream became reality with the advent of Tysabri (natalizumab), a monoclonal antibody that has proven to be highly effective in reducing inflammatory activity in MS. Some of my MS patients who are on Tysabri say that they forget for most of the month that they actually have MS. That really says it all. From a scientific perspective, there has been a recent paper in JNNP that provides data on the safety and tolerability of this drug in a large cohort of patients http://jnnp.bmj.com/content/early/2014/02/14/jnnp-2013-306936.abstract?sid=8e3fc276-adf8-49ab-a852-1deb37906d4b . That study also confirms just how incredibly effective Tysabri can be in treating MS.
However, it hasn’t all been sweet sailing for this drug. There was a period when Tysabri’s prospects looked less than rosy, following the discovery that treatment with this drug could lead to activation of a potentially lethal virus, the John Cunningham or JC Virus. Following the discovery of the first few cases in 2006, many hundreds of patients have developed progressive multifocal leucoencephalopathy (PML), a brain infection caused by JC virus. While early cases of PML due to Tysabri were fatal, more recent attempts at doctor and patient education are helping to improve outcomes in patients who develop this complication. We now also have the means to screen patients for prior JC virus infection using an antibody test. A large proportion of the population have had prior exposure to the virus, usually manifesting as a flu-like illness. Once a person has been exposed, the virus remains dormant in the kidneys and can reactivate, especially when the immune system is suppressed.
For patients who are on Tysabri, a positive JC virus test does not mean that PML will develop, but it places patients in a high risk group. In these situations, many will need to stop Tysabri after ~2 years of treatment, the time period after which PML risk rises. The problem is that Tysabri is very effective at controlling MS disease activity and cessation of this medication may lead to worsening of MS symptoms, even if an alternative drug is introduced.
In this issue of the journal, Gueguen and colleagues from Paris provide us with interesting data on exactly how patients fare after Tysabri has been ceased http://jnnp.bmj.com/content/85/9/1038.abstract . While decisions regarding cessation need to be made on a case-by-case basis, the study helps inform clinical decisions making in what is a particularly difficult and frequent problem in MS clinics around the world.
8 Aug, 14 | by Arun Krishnan, Web Editor
Of all the types of functional difficulties that a patient with multiple sclerosis (MS) can experience, cognitive change remains the area that is hardest to delineate. MS patients may experience changes in memory, attention, reasoning and executive function that can be subtle and therefore hard to detect clinically, but significant enough to compromise their daily function. Many are forced to change occupation and cut down workloads and personal responsibilities due to these changes. It may be tempting to put a lot of these cognitive changes down to fatigue and medication side effects, but it has long been suggested that there are discrete changes in cognition in MS that occur without any contribution from other factors. The difficulty has also been finding a way to measure this. In some patients, cognitive difficulties fluctuate and yet without knowing how to evaluate these changes we are not able to view them in the same way that we would view a sudden change in visual function or in walking speed. Therefore, cognitive deterioration has never sat well in the minds of clinicians as a legitimate form of MS relapse and yet there is no scientific basis to exclude it from consideration.
In the current issue of JNNP, Pardini and colleagues from Genoa http://jnnp.bmj.com/content/85/9/1035.abstract provide some very interesting data that may be viewed as a platform to further studies investigating the possibility of cognitive changes as a bona fide form of MS relapse. In their study, the authors undertook serial studies in 99 patients with relapsing-remitting MS. The authors used a validated cognitive test, the symbol digits modality test as a measure of cognitive change. They found that there were isolated cognitive relapses in 17 patients, i.e. a significant proportion of the group.
The study is interesting and important as it provides clear insights into the cognitive changes that may occur in otherwise ‘stable’ MS patient. The authors also show that these changes occurred without any other alteration in mood or fatigue, suggesting that isolated cognitive relapses are a real phenomenon and a potential contributor to cognitive decline in MS.
7 Aug, 14 | by Steve Vucic, Web Editor
Sensory tricks, also called geste antagoniste, is a typical feature of primary and secondary dystonias. The sensory tricks may take many forms and if not recognized, may lead to misdiagnosis and mislabeling as “psychogenic”. Importantly, the sensory tricks are associated with neurophysiological changes, including normalization of TMS parameters such as intracortical facilitation as well as normalization or improvement in blink reflexes. In the September issue of JNNP, Hallett and colleagues publish an authoritative and an elegant review encompassing clinical, neurophysiological and mechanistic issues pertaining to sensor tricks in dystonia.
This must read review can be found at: http://jnnp.bmj.com/content/85/9/987.full
J Neurol Neurosurg Psychiatry 2014;85:987-993 doi:10.1136/jnnp-2013-306971
Tricks in dystonia: ordering the complexity
6 Aug, 14 | by Steve Vucic, Web Editor
Glutamate is a major excitatory neurotransmitter in the human brain vital for multiple functions, including memory and cognition. Importantly, excessive glutamate activity may be harmful
to the CNS, leading to neurodegeneration. In this issue of JNNP, Muhlert and colleagues report a link between glutamate levels and memory, a unique link in MS. Given that forgetfulness is a common symptom in MS, the possibility of using glutamate agonist, or enhancer of the glutamatergic system, has real potential.
Read more at : http://jnnp.bmj.com/content/85/8/833.abstract
Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions
- Nils Muhlert1,2,
- Matteo Atzori3,4,
- Enrico De Vita5,6,
- David L Thomas6,
- Rebecca S Samson1,
- Claudia A M Wheeler-Kingshott1,
- Jeroen J G Geurts7,
- David H Miller1,8,
- Alan J Thompson3,8,
- Olga Ciccarelli3,8
31 Jul, 14 | by Steve Vucic, Web Editor
Hereditary IBM is an autosomal recessive myopathy characterized by distal muscle weakness, and the absence of the classical IBM phenotype. mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene has been linked with development of this myopathy. However, there has been a paucity of genotype-phenotype correlation studies, critical for understanding disease mechanisms. In this issue of JNNP, a large Japanese group reports the mutation profile for the GNE gene and find phenotypic variability, underscoring the importance of a clinical context.
Read more at http://jnnp.bmj.com/content/85/8/914.abstract
Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy)