7 Oct, 16 | by Dr Jose Manuel Matamala, JNNP web editor.
In the current issue of JNNP, Gonçalves and colleagues have published a randomized control trial (RCT) comparing melatonin, amitriptyline and placebo for migraine prevention.
Migraine is a chronic neurological disease and has been ranked as the sixth disabling condition by World Health Organization (WHO). The goals of migraine prophylaxis are to reduce migraine attacks, limit the need for analgesic intake and improve the quality of life. However, despite the different pharmacological treatments available, only a small fraction of patients receive adequate preventive treatment, which amongst other reasons is related to unfavourable drug security profile.
In this study, after randomizing 196 patients into melatonin (3 mg), amitriptyline (25 mg) or placebo (randomization ratio 1:1:1) and following up for 12 weeks, the authors reported a significant reduction in the number of migraine headache days per month with melatonin or amitriptyline versus placebo. Even though melatonin and amitriptyline were equally effective for the primary endpoint, the number of patients with greater than 50% reduction in migraine headache days was significantly higher in the melatonin group. Moreover, the number of adverse effects was also significantly lower in this group compared with amitriptyline. These results support the efficacy and tolerability of melatonin as a prophylaxis therapy for migraine.
Melatonin a new therapeutic option for the treatment of migraine patients
Melatonin is a hormone produced mainly in the pineal gland, and it plays an essential role as an endogenous synchronizer of internal circadian rhythms. Melatonin has demonstrated efficacy and safety in the treatment of nociceptive and neuropathic pain in several studies. Specifically in migraine, melatonin receptors have been described in the nuclei of the trigeminal nerve, suggesting that may decrease trigeminovascular nociception. Moreover, melatonin levels have been described to be reduced in migraine patients. Regarding the security profile, melatonin is remarkably well tolerated and it only has minor side effects such as daytime sleepiness, dizziness, and stomach pain. These features make melatonin a good candidate for migraine prophylaxis.
In short, this is an interesting article that has clear and immediate clinical application.
Read more at http://jnnp.bmj.com/content/87/10/1127.full.pdf
29 Aug, 16 | by Dr Jose Manuel Matamala, JNNP web editor.
In the current issue of JNNP, Iwadate and colleagues investigated the correlation between the changes in 11C-methionine positron emission tomography (PET) and the 1p/19q status in oligodendroglial tumours.
Gliomas are the most common primary brain tumour in adults. Typically, based in the histological classification, gliomas have been classified into two major subgroups: (i) astrocytic tumours and (ii) oligodendroglial tumours. This differentiation is not trivial given that oligodendroglial tumours are more sensitive to radiotherapy and chemotherapy and are associated with better prognosis. Among the new molecular biomarkers used in the stratification of gliomas, the chromosome 1p/19q deletion has been established as a prognostic and predictive marker in oligodendroglial tumours.
In this study, the authors retrospectively reviewed 66 cases with grade II or III oligodendroglioma or oligoastrocytoma that were studied by 11C-methionine PET and fluorescence in situ hybridisation to defined the 1p/19q status. The tissue uptake of 11C-methionine was expressed as a ratio of tumour to normal tissue (T/N) of the standardized uptake values (SUV). The T/N ratio was higher in grade III oligodendroglial tumours than in grade II tumours. The mean T/N ratio was significantly higher in the 1p/19q non-deleted tumours than the tumours with the deletion in grade II and grade III oligodendroglial tumours. These changes were not associated with cell density or Ki-67 labelling index. The authors conclude that among suspected oligodendroglial tumours 11C-methionine PET could be helpful to stratify preoperatively tumours with and without 1p/19q deletion.
1p/19q status in oligodendroglial tumours with 11C-methionine PET. In this study, tissue uptake of 11C-methionine was significantly higher in the 1p/19q non-deleted tumours than the tumours with the deletion.
This article contributes to the non-invasive and preoperative characterization of biological biomarkers for oligodendroglial tumours. The knowledge of the molecular signature in gliomas stratification is more crucial than ever. The WHO Classification of Tumours of the Central Nervous System has been recently modified1. For the first time, the WHO classification uses molecular parameters in addition to histopathological features to define brain tumours. Now the diagnosis of oligodendroglioma and anaplastic oligodendroglioma thus involves the demonstration of both an IDH mutation and the 1p/19q deletion.
Clearly, the knowledge of the molecular fingerprint of oligodendroglial tumours using non-invasive imaging techniques could improve the planning of neuro-oncological treatments and may help define future pre-surgical therapeutics options in tumours with specific molecular markers.
Read more at http://jnnp.bmj.com/content/87/9/1016.full.pdf
- Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20.
28 Jul, 16 | by Dr Jose Manuel Matamala, JNNP web editor.
In the current issue of JNNP, Watanabe and colleagues published a genome-wide association study (GWAS) in ALS to explore the effects of genetic variants in the disease course of sporadic ALS patients.
ALS is an incurable neurodegenerative disease that affects the motor neurons in the cortex, brainstem, and spinal cord, typically resulting in death within 2 – 3 years. Even though enormous advances in the comprehension of the disease have been achieved during the last decade, the huge clinical and genetic heterogeneity of the disease have hindered the development of new disease-modifying treatments. With the aim to explore the heterogeneity across ALS spectrum, a number of GWAS using large-scale genotyping of single nucleotide polymorphisms (SNPs) have failed to generate consistent results and reported associations were not strong enough to develop suitable disease models.
In the study, Watanabe and colleagues explore the impact of genetic variants (SNPs) in different patterns of functional decline in patients with sporadic ALS. A total of 465 ALS patients were clustered according to the longitudinal functional score (ALSFRS-R) in four groups: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. Amongst the 572.983 SNPs studied using genome-wide analysis, seven SNPs were associated with the rapid decline cluster (odds ratio: 5.5 to 5.84). Specifically, homozygosity for the minor alleles of the seven SNPs (linkage disequilibrium block) was associated with decreased expression of TNN (the gene that encodes Titin, a sarcomere protein). Finally, the authors described down-regulation of Titin in immortalised lymphocytes lines from such patients with ALS.
Titin associated SNPs and rapid functional decline in patients with ALS. In this GWAS study, seven SNPs were associated with the rapid functional decline cluster. These SPNs are linked to decreased expression of Tilin, a sarcomere protein that plays important roles in muscle function.
The studying of the genetic factors that influence the clinical course of ALS is extremely valuable in the design of new clinical trials. This study is the first that identifies genetic factors associated with rapid functional decline in sporadic ALS patients. The seven SNPs related to functional decline were associated to decreased Titin expression, an essential sarcomere protein. These results may suggest that Titin determines ALS disease progression through its role in muscle function. Previous studies have related Titin with different myopathies (e.g. limb-girdle muscle dystrophy). Given that there are not previous studies of Titin in ALS, these results represent a new opportunity to explore the role of Titin in ALS pathogenesis. From a clinical point of view, the impact of Tinin on the clinical disease course must be confirmed in future prospective studies, which must explore these genetic variants in ALS patients with different genetic backgrounds.
Finally, it is clear that this study provides a new candidate that might help to understand the complex heterogeneity behind the ALS spectrum.
Read more at http://jnnp.bmj.com/content/87/8/851.full.pdf
9 Jul, 16 | by Dr Jose Manuel Matamala, JNNP web editor.
In the current issue of JNNP, Vanli-Yavuz and colleagues published the largest systematic screening study of neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Of relevance to the study, epilepsy is a prevalent neurological disorder affecting over 50 million people worldwide. Despite all the advances in this field, it is estimated that around 30% of all patients with epilepsy are refractory to antiepileptic treatment, MTLE-HS being one of the major causes of intractable epilepsy. Different mechanisms have been related to the development of this disease including a possible autoimmune dysfunction among others.
Returning to the study by Vanli-Yavuz and colleagues, the authors studied the prevalence of different neuronal autoantibodies in a large series of 111 patients with MTLE-HS and compared with 80 control subjects (30 healthy subjects and 50 patient with relapsing-remitting multiple sclerosis) (http://jnnp.bmj.com/content/87/7/684.full). Interestingly, they found the presence of neuronal autoantibodies in 22.5% of MTLE-HS patients principally against the VGKC-complex. The healthy and disease control group did not show any neuronal autoantibodies. The presence of neuronal autoantibodies was associated with a history of status epilepticus, diagnosis of psychosis, and involvement of temporal and extra-temporal regions on PET/SPECT studies. In addition, specifically, the VGKC-complex patient’s subgroup also was associated with cognitive dysfunction. Surprisingly, unexplained remission (either spontaneous or following antiepileptic drugs) was significantly more frequent in the seropositive group (28% vs 3.5%). Finally, the authors reported the absence of inflammatory activity in brain tissue from 7 operated seropositive patients.
Neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). In this study, approximately one-fourth of the patients showed seropositivity to neuronal autoantibodies, principally against the VGKC-complex.
Given the prevalence and the complex treatment approaches to MTLE-HS, the findings in this article seem highly relevant in the future consideration of immunomodulatory therapies in these patients. However, before this can happen, there are still many questions that need to be critically addressed. For instance, What is the role of these neuronal autoantibodies in MTLE-HS pathogenesis? Are they pathogenic or are they the consequence of neuronal destruction? Why are these neuronal autoantibodies associated with patients with unexplained remission?. Clearly, further studies will be needed to answer some of these questions. Nevertheless, this study provides hope to improve our understanding of this disease and suggest a new skyline for this neurological disease.
Well worth the read!!
21 Apr, 16 | by Arun Krishnan, Web Editor
Arun Krishnan and Steve Vucic, Neurologists and JNNP web editors, discuss recent data on possible Zika virus-induced neurological disease.
There has been considerable worldwide coverage documenting the impact of the recent Zika virus epidemic which spread through South America and more recently the Carribean. While infection with Zika is of little consequence in most people but there have been major concerns with infection in pregnant women and most of the interest has focussed on the nervous system. The most marked congenital neurological abnormality has been the development of microcephaly in newborns and this was most clearly brought out in the large spike in cases of microcephaly in Brazil in 2016. There have however been concerns about attributing causality based on epidemiological data alone and a recent paper in the New England Journal of Medicine noted that there were methodological concerns in some of the studies and that it may be premature to invoke causality . A more recent report in the same journal has laid out the case for and against a causal effect . In this paper, the authors test current scientific knowledge concerning Zika against accepted criteria for proof of human teratogenicity. Interestingly, the case for causality appears strong when assessed in this manner. Of note, the spike in cases of microcephaly in South America was not the first time that it has been associated with a Zika outbreak: a previous Zika epidemic in French Polynesia in 2013-2014 was also associated with an increase in microcephaly. In both South America and French Polynesia, the Zika outbreak preceded the spike in microcephaly cases and neonates who were affected also manifested other signs that are consistent with Zika exposure. The authors also provide references to studies that have outlined the mechanisms of Zika-induced neurotoxicity, with changes noted in neural progenitor cells that are exposed to the virus, providing evidence of biological plausibility.
In addition to the neonatal neurological manifestations, Zika virus infections have been associated with the occurrence of Guillain Barre Syndrome (GBS) [3-7], an acute immune-mediatied polyradiculoneuropathy with a heterogeneous phenotype, that causes acute weakness and impaired sensation. The first case of ZIKA related GBS was reported in 2013 in a French Polynesian lady, clinically presenting as global tetraparesis, facial paralysis, and autonomic nervous system dysfunction. Subsequently, a further 42 GBS cases secondary to Zika virus infection have been reported, with Zika virus infection preceding the onset of GBS by 6 days . Most patients exhibited a rapid disease course, severe tetraparesis and bilateral facial weakness, with an elevated CSF protein level. Respiratory dysfunction, requiring intensive care management, was evident in 38% of patients, although all responded to therapy with intravenous immunoglobulin or plasmapheresis. Importantly, no patients died as a result of Zika virus infection related GBS, and over half the patients exhibited good clinical recovery at 3 months post infection. Neurophysiological studies disclosed a predominantly distal demyelinating motor neuropathy which improved on follow-up . The pathophysiological mechanisms by which Zika virus infection underlies the development of GBS remains to be fully elucidated, although antigenic mimicry against yet to be identified axonal targets, or direct viral infection of nerves has been invoked. Given the rapid reversal of clinical and neurophysiological findings, the possibility of an antibody-mediated blockade of nodal Na+ channels leading to failure of distal neurotransmission, should also be explored.
In conclusion, Zika virus infections can lead to severe neurological syndromes including neonatal microcephaly and GBS. Since the Zika virus infection is spreading rapidly across the South America countries, physicians need to be vigilant about the possibility of neurological sequalae and resources need to be allocated to the management of neurological complications of Zika virus infection.
- Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, et al. Zika Virus as a Cause of Neurologic Disorders. The New England journal of medicine. 2016. Epub 2016/03/10. doi: 10.1056/NEJMp1602708. PubMed PMID: 26959308.
- Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects – Reviewing the Evidence for Causality. The New England journal of medicine. 2016. Epub 2016/04/14. doi: 10.1056/NEJMsr1604338. PubMed PMID: 27074377.
- Roze B, Najioullah F, Ferge JL, Apetse K, Brouste Y, Cesaire R, et al. Zika virus detection in urine from patients with Guillain-Barre syndrome on Martinique, January 2016. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2016;21(9). Epub 2016/03/12. doi: 10.2807/1560-7917.es.2016.21.9.30154. PubMed PMID: 26967758.
- Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika virus infection complicated by Guillain-Barre syndrome–case report, French Polynesia, December 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2014;19(9). Epub 2014/03/15. PubMed PMID: 24626205.
- Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016. Epub 2016/03/08. doi: 10.1016/s0140-6736(16)00562-6. PubMed PMID: 26948433.
- Anaya JM, Ramirez-Santana C, Salgado-Castaneda I, Chang C, Ansari A, Gershwin ME. Zika virus and neurologic autoimmunity: the putative role of gangliosides. BMC medicine. 2016;14(1):49. Epub 2016/03/24. doi: 10.1186/s12916-016-0601-y. PubMed PMID: 27001187; PubMed Central PMCID: PMCPmc4802632.
- Araujo LM, Ferreira ML, Nascimento OJ. Guillain-Barre syndrome associated with the Zika virus outbreak in Brazil. Arq Neuropsiquiatr. 2016;74(3):253-5. Epub 2016/04/07. doi: 10.1590/0004-282×20160035. PubMed PMID: 27050856.
- Vucic S, Kiernan MC, Cornblath DR. Guillain-Barre syndrome: an update. J Clin Neurosci. 2009;16(6):733-41. Epub 2009/04/10. doi: S0967-5868(08)00527-4 [pii]10.1016/j.jocn.2008.08.033 [doi]. PubMed PMID: 19356935.
9 Sep, 15 | by Arun Krishnan, Web Editor
Confusion is a common enough symptom in clinical practice. Often, it can be attributed to systemic conditions, such as medication side effects or infection. Occasionally however, one can be caught out in a situation where a patient develops confusion that is due to a more sinister and rare cause. Encephalitis is a rare cause of confusion but it is important to recognise as early treatment is the key to preventing disability. While viral forms of encephalitis are well recognised, more recently the possibility of immune-mediated encephalitis due to circulating antibodies has begun to emerge as an important cause of encephalitis. Often these disorders occur in the presence of a remote malignancy, such as lung or ovarian cancer and often the neurological diagnosis is the first sign of the malignancy.
In the present issue of JNNP, Onugoren and colleagues have published a series of cases of encephalitis due to unusual antibodies http://jnnp.bmj.com/content/86/9/965.abstract . In their series, patients developed a form of encephalitis known as limbic encephalitis, due to GABA and AMPA receptor antibodies. Lung cancer was subsequently diagnosed in a number of their patients. Interestingly, immune treatments led to improvements in the neurological status of a number of these patients.
This is an interesting paper on a rare but emerging form of encephalitis. The diagnostic and treatment insights are particularly interesting for neurologists everywhere.
29 Jul, 15 | by Arun Krishnan, Web Editor
Some readers will no doubt have watched the 1990 movie, Awakenings starring Robin Williams and Robert de Niro, about a group of patients who had suffered a form of encephalitis and survived, only to be permanently in a state of reduced awareness and responsiveness. The movie was based on a book by the famous neurologist, Oliver Sacks, and explores the potential use of a new treatment for these patients. In his memoir of the same name, Sacks was referring to the possible beneficial effects of L-DOPA, a medication that is first-line treatment for Parkinson’s Disease. That book was written 40 years ago, so what have we learnt since then about this condition?
In this issue of JNNP, Wijemanne and Jankovic have reviewed this topic and have provided an insightful update on this condition http://jnnp.bmj.com/content/86/8/825.full . As noted in their review, catatonia can occur in numerous conditions, both neurological and psychiatric, and it is no longer regarded purely as a form of schizophrenia. In addition, there are a number of systemic conditions in which it can occur including cardiovascular, renal and connective tissue disorders. It can also occur as an adverse reaction to numerous medications.
While the exact pathophysiology remains unclear, the role of changes in GABA neurotransmission have been explored in depth and Zolpidem, a GABA-agonist, has been suggested as a possible treatment. Electroconvulsive therapy (ECT) remains a very potent treatment for this condition and neuroleptic medications are also trialled in some patients. However, as noted in their review, the question of why this occurs remains unresolved and is a question for future research.
3 Jul, 15 | by Arun Krishnan, Web Editor
Infectious diseases of the nervous system are an evolving and extremely interesting area of neurology. There always seems to be a new infection on the horizon and this means that neurologists constantly need to stay up-to-date on how these infections present clinically. Importantly, many are treatable and this means that you have to be on the ball to ensure that patients can receive early treatment with a reduction in long-term disability.
In this issue of JNNP, Misra et al from Lucknow in India have presented a comprehensive analysis of patients admitted to their institution in 2012-2013 who had been diagnosed with Scrub Typhus, a condition transmitted by a rickettsial organism that is usually spread by ticks, lice and fleas http://jnnp.bmj.com/content/86/7/761.abstract. There are certain areas of the world where this organism is endemic, including India, Pakistan, Russia, Japan and Australia.
Amazingly, the authors identified 38 cases in this short period of time and have provided a wonderful overview of how these patients present. Meningitis and encephalitis are common presentations with patients often experiencing headache, fever and disorientation. The condition can also be life-threatening and some patients in this series were admitted to intensive care units with lung involvement or kidney failure. The most important aspect of this paper is that ~90% had a good response to antibiotic treatment with doxycycline. As suggested by the authors, scrub typhus should be included in a list of conditions that can cause encephalopathy with fever, particularly in patients who live in or who have travelled to areas where this condition is endemic.
15 Jun, 15 | by Arun Krishnan, Web Editor
Over the weekend, the Sydney Morning Herald wrote of the ‘heavy cost’ of obesity to the Australian health system http://www.smh.com.au/nsw/the-heavy-cost-of-obesity-and-how-nsw-health-workers-are-responding-20150613-ghmxbu.html . The article featured a quote that “the new normal is to be overweight or obese”. The epidemic of obesity has presented major health challenges that are not just faced by the developed world but which are now increasingly also becoming part of the health dilemmas facing developing countries.
There are groups of obese patients however who do not seem to encounter the health problems that one might expect and these patients have been called the ‘obese well’ http://www.ncbi.nlm.nih.gov/pubmed/23491523 The reasons for why these people remain free of health problems remains unclear although a number of theories have been put forward including reduced inflammatory mediators in this group of patients. Accordingly, the possibility that anti-inflammatory drugs may improve outcomes such as glucose control and diabetes risk is an ongoing area of research.
In the current issue of JNNP, Kim and colleagues from Seoul have demonstrated that mild-moderate elevations of body mass index (BMI) are associated with reduced stroke severity http://jnnp.bmj.com/content/86/7/743.abstract . This backs up previous studies that have shown lower risk of mortality in obese patients who suffer haemorrhagic or ischaemic stroke. The importance of these observations is that it lays the foundation for further studies that may be able to address why this group is relatively protected from severe long-term disability. This will help in drilling down on the potential ways of improving outcomes in all stroke patients, regardless of BMI.
3 Jun, 15 | by Arun Krishnan, Web Editor
For most clinicians, having to tell a patient that they have motor neuron disease/amyotrophic lateral sclerosis (ALS) is a difficult and challenging dilemma. In the community, it is one of the few remaining conditions that are inseparably linked with severe physical disability resulting in loss of independence and eventually loss of life. On a more optimistic note, the pace of research in this field provides hope for a cure or at the least for treatments that may slow the progression of the condition.
ALS was first described by Jean-Martin Charcot, the father of modern Neurology and in the current issue of JNNP, Turner and Swash http://jnnp.bmj.com/content/86/6/667.abstract chart the historical journey that commenced with Charcot’s initial descriptions of the condition, which largely remain true and accurate to the present day. In addition, the authors have also managed to provide a state-of-the-art review of where we are at in terms of genetic contributions to this condition and provide a thorough analysis on the potential cause of ALS.
In addition to the obvious question of who is likely to develop ALS, they also touch on another intriguing question of whether there are individuals who are likely to never develop ALS.
In short, this is a highly recommended review.