Posted in Journal Reviews on 12th Mar 2013
Beware old friends
When I started in epilepsy, two eminent epileptologists held a debate, in which one argued that all patients should be give valproate from the outset and see what happens, as it is a broad spectrum drug effective against a range of epilepsies and only change to something else if necessary. Whilst he was adopting a position for the purposes of debate, it is a salutary lesson that this drug is rapidly becoming the spaghetti bologneighs of the AED world and that this is happening forty years after the launch of the drug. Whilst data collection is better than it was, I am also reminded of the fall from grace of vigabatrin, several years after marketing as a result of visual disturbances that were really very common. This highlights an issue that very long term use of new drugs requires a different mindset from that which we use for many drugs. Absence of proof of long term effects is not proof of their absence and vigilance is required for many years. Two more nails in the coffin of valproate, at least for women of childbearing age, have been hammered into place recently. Bromley et al show that neurodevelopmental disorders including autism and ADHD are up to ten times commoner in children born to women taking the drug than to those taking carbamazepine, lamotrigine or controls. Valproate is still one of the most profitable AED, but that is largely through its role in psychiatry. Do psychiatrists know about these problems? Meador et al provided data at six years of age for children born to women taking AED. They found that children born to mothers taking valproate had lower scores across a range of function, including verbal, non verbal, and executive function than compared to those on lamotrigine, carbamazepine or phenytoin, with some subtle variations. There was a clear difference between women above the median dose of 1000mg and those below and preconception folate improved function in all groups. So, for my patients for whom nothing apart from valproate works, and they are not such a tiny number, is it better to give low dose valproate and something else or high dose valproate on its own? I veer to the former, in that there seems to be something in the mechanism of valproate that is not shared by other drugs, which predisposes to this problem, but I should be interested to hear if others disagree. – MM
Bromley RL, Mawer GE, Briggs M, et al. On Behalf of the Liverpool and Manchester Neurodevelopment Group. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J NEUROL NEUROSURG PSYCHIATRY. 2013 Jan 31. doi:10.1136/jnnp-2012-304270. [Epub ahead of print]
Meador KJ, Baker GA, Browning N, et al.NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcome at age 6 years (NEAD study): a prospective observational study. LANCET NEUROL 2013 Mar;12(3):244-52. doi: 10.1016/S1474-4422(12)70323-X. [Epub ahead of print]
Warts on the brain
I am never quite sure whether honest ignorance or disingenuous reassurance works better for patients. Overall, my ignorance being so all-encompassing, I find it easier to share it than to try and make something up. I have colleagues however, who never let a patient out of the clinic without a diagnostic label. Of course you could call it idiopathic, which as my Professor of Medicine, Oliver Wrong at UCH, sadly deceased last year, taught me means ‘the idiots do not know the pathology’. Over the years, however, I have learned to be very suspicious of claims of: “don’t worry it’s only a virus”. Of course, finding out that something may be due to a virus, particularly one for which we have a vaccine is very exciting. So it was with great interest that I learned that all of 50 specimens of Taylor type focal cortical dysplasia with balloon cells, otherwise known as FCDIIB, “robustly” expressed human papilloma virus HPV16 DNA. The DNA was not present in control areas from the same brains or from control brains. HPV16 is the virus associated with cervical cancer and some forms of oropharyngeal cancer. The virus induces a protein called HPV16 oncoprotein, which activates signalling of mammalian target of rapamycin complex (mTORC1). This is already recognised to be a player in animal studies of epilepsy and in association with tuberose sclerosis where its activity is increased. An inhibitor, everolimus, has already been used in the treatment of malignantly transformed TS lesions. Will the next generation of children born to girls immunised against HPV16 suffer with less FCDIIB? – MM
Chen J, Tsai V, Parker WE et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. ANNALS OF NEUROLOGY. 2012 Dec;72(6):881-92. doi: 10.1002/ana.23795.
Leukotriene receptor agonists for brain repair?
The interaction between neuroinflammation and neurodegeneration, or their co-existence, generally is considered to be a bad thing. Zebrafish seem to possess the innate ability to regenerate neurons in response to injury, and Kyritsis et al. from Michael Brand’s group in Dresden, take advantage of this property and demonstrate a mechanism that links inflammation and repair. Kyritsis et al. first inject the fungal derivative zymosan A into zebrafish telencephalons and demonstrate a similar upregulation of macrophages and leukocytes, subsequent upregulation of radial glial cells and neurogenesis (measured by bromodeoxyuridine labelling), as seen with traumatic brain lesioning. They show that dexamethasone suppresses neurogenesis in the lesioned but not control fish. Through analysis of a transcriptome comparison, they show that cysteinyl leukotriene receptor 1 (cysltr1) is upregulated after injury (locally and in the ventricular zone), and blocking its signalling with Pranlukast inhibits neurogenesis. Use of a leukotriene agonist of the cystltr1 enhances neurogenesis. A further round of experiments with gata3 signalling supports the conclusion that this injury evoked repair is injury-specific. Reconciling this with the prevailing view that inflammation, through promotion of glial scarring and other effects, is deleterious to repair in mammals, is difficult but probably valid, and the work does reveal a potential target for clinical trials. – MZ
Kyritsis N, Kizil C, Zocher S et al. Acute Inflammation Initiates the Regenerative Response in the Adult Zebrafish Brain. SCIENCE 2012 Dec 7;338(6112):1353-6. doi: 10.1126/science.1228773.
Saji and colleagues from Niigata, Japan combine a neuropsychometric study with a smaller and more intriguing neuropathological one, declaring prevalent cognitive impairment in neuromyelitis optica, but also widespread cortical inflammation in the absence of demyelination. In the first study, Rao’s Brief Repeatable Battery of Neuropsychological Tests, which includes the PASAT test and others of attention, verbal and visual memory and language, was applied to 5 patients with NMO (all AQ4 antibody positive) and 9 with limited NMO (cord or optic nerve, but all had AQ4 antibodies). Patients with NMO were compared to unspecified healthy controls and the degree of matching and subsequent analysis is hard to interpret, suffice to say that a large proportion of NMO patients and 17 MS patients were defined as cognitively impaired (57% and 47% respectively), of which a large part may just reflect disease activity and medications. The authors then examined 6 NMO brains in comparison with control brains, and demonstrate increased meningeal inflammation, with no evidence of B-cell follicle-like structures, and cortical neuronal loss with microglial activation without cortical demyelination or lymphocytic infiltration. Whether there is primary or secondary cortical involvement, the results are interesting and need replication. This is clearly a controversial area, with other authors, for example Calabrese et al. using neuroimaging, claiming no cortical involvement in NMO. – MZ
– Saji E, Arakawa M, Yanagawa K, et al. Cognitive impairment and cortical degeneration in neuromyelitis optica. ANNALS NEUROLOGY. 2013 Jan;73(1):65-76. doi: 10.1002/ana.23721.
Calabrese M, Oh MS, Favaretto A et al. No MRI evidence of cortical lesions in neuromyelitis optica. Neurology. 2012 Oct 16;79(16):1671-6.