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Recent eLetters

Displaying 1-10 letters out of 483 published

  1. Levodopa equivalent daily dose and the development of impulse control disorder

    We have read your paper regarding impulse control disorders (ICDs) in Parkinson's patients receiving dopamine agonist therapy with great interest. Although the stability in plasmatic levels or the route of administration of the agonist may play a role in the development of ICDs just as they might explain the occurrence of motor dyskinesias, a dose- response curve would also be expected. While the levodopa equivalent daily dose (LEDD) of rotigotine has not been delimited between those with and without ICDs, the average LEDD in the group is higher than that of patients receiving oral agonists, yet with a lower incidence of ICDs. This calls for a further review of the published equivalencies for antiparkinsonian drugs, especially those with less studies supporting the available conversion formulae.

    Conflict of Interest:

    None declared

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  2. Re:Interferon-beta and the risk of cancer in MS

    We thank Drs van der Voort and Killestein for their comments on our paper and we agree that the question of the potential role of neutralizing antibodies (Nabs) in cancer risk is an important issue. The development of Nabs could result in early discontinuation of beta-interferon (IFNB) and, if Nabs were an important mediating factor in increased cancer risk, that this could draw any potential dose response effect towards the null. It is worth emphasizing that we used 'ever vs. never IFNB' as the primary exposure and also included 'time since first IFNB' as an alternative secondary exposure measure. In addition, none of the 227 cancer cases in our study were exposed to IFNB for between 1-89 days; all 'non-exposed' cancer cases were completely unexposed. However, as Drs van der Voort and Killestein point out, the only way to answer this particular question is to investigate cancer risk specifically in people with persistent Nabs. Despite our interest in this important question,(1,2) we were unable to address this due to the lack of sufficient data on Nabs in our linked MS cohort. This continues to be an unanswered important issue that should be addressed with objective outcome data, and serially and systematically collected Nab exposure data.

    Elaine Kingwell and Helen Tremlett

    1. Gibbs E, Tremlett H, Ball N, et al. Malignant melanoma in a multiple sclerosis patient with persistent neutralizing antibodies to interferon-beta. Eur J Neurol. 2008; 15(1): e4.

    2. Kingwell E, Tremlett H. Interferons and multiple sclerosis: is it plausible that beta-IFN treatment could influence the risk of cancer among MS patients? Expert Rev Neurother. 2009; 9(9): 1263-5.

    Conflict of Interest:

    None declared

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  3. Re:How useful and how safe is a Datscan?

    We thank Dr Morrish for his letter and comments. We agree that in most cases of possible Parkinsonism, history and examination are sufficient to come to an accurate diagnosis, especially in expert hands. However, not all individuals have access to a Movement Disorders expert, and it is clear that there are more diagnostic errors early on or when signs and symptoms are unusual. The diagnosis does indeed typically become clearer over time, but in the interim, the patient may experience unnecessary disability through a delay in diagnosing Parkinson's disease (PD) or receive medications that cause adverse events with no real chance of affording benefit in a false positive diagnosis of PD. The difficulty with diagnosis of early PD has been highlighted in several recent clinical trials that included neuroimaging. In the CALM PD (pramipexole versus L dopa), REAL-PET (ropinirole versus L-dopa), and ELLDOPA (L-dopa vs placebo) studies [1-3] patients with a clinical diagnosis of early PD were enrolled by movement disorder physicians across centers in Europe and the US. All patients had functional imaging assessment at baseline (B-CIT SPECT in CALM-PD, REAL-PET, and ELLDOPA, 18F dopa in REAL-PET), after the clinical diagnosis was made and after subjects had been enrolled in the trials [1-3]. Across the 3 trials, between 4% and 15% of subjects were found to have normal imaging findings. In the ELLDOPA study of 142 subjects, 21 subjects (15%) examined by B-CIT- SPECT had normal imaging and were classified as subjects with scans without evidence of dopaminergic deficiency (SWEDDs)[3]. Marek et al followed these SWEDD patients and reported no deterioration in neurological features over time. These patients also had normal imaging results at 9 months (19/19 cases), 18 months (17/17), 36 months (12/12), and 48 months (10/10)[4]. Consensus discussion regarding these cases suggested that the original clinical diagnosis of PD was wrong[5]. A further study from Marshall et al showed an initial tendency to over- diagnose PD in uncertain parkinsonian cases at baseline: again, this was likely due to the considerable overlap in clinical features between some benign tremor cases and cases with tremulous PD[6]. These studies indicate that even the most rigorous application of the UK Brain Bank Criteria is subject to interpretation and can lead to diagnostic errors. Dr Morrish believes 6 years follow up in SWEDD cohorts is not long enough to rule out a diagnosis of PD. This might be true for the rare case of benign tremulous PD, but it is clear to those engaged in regular clinical practice, that the vast majority of PD cases will show clear progression over a few years of follow up. Furthermore, this apparent lack of clinical progression over many years would pose more of an issue for those relying on clinical diagnostic acumen alone as it would take many years of careful follow up to finally detect the clinical signs that fulfil the UK Brain Bank Criteria for PD. Whilst we agree with Dr Morrish that more work needs to be done in this area, possibly including assessment of olfaction, and response to levodopa, in a larger group of patients, current indications are that the vast majority of SWEDDs do not have PD. Although it would be ideal to know the exact false positive and false negative rate of DaTSCAN, the gold standard for diagnosis is pathology examination, and it is simply not feasible to delay evaluation of DaTSCAN in early, clinically uncertain Parkinsonism by waiting 10-30 years for pathological confirmation to emerge. Dr Morrish has further criticism over audit in DaTSCAN [7]. Although 50% participation of centres in a national audit of accuracy of read of DaTSCAN will not capture all data, it is a useful start on a rolling programme that will include more centres year on year. This programme will drive up standards of reporting and reduce error rates in the future. With regard to quantitation, beginning with its approval in the EU (2000), DaTSCAN image visual interpretation became the standard practice used by nuclear medicine physicians as an adjunct for clinical diagnosis. This is because DaTSCAN image visual interpretation results already provide a high level of sensitivity and specificity in conducted clinical trials[7]. We agree that there may be additional value for quantitative image interpretation. Soderlund et al. 2013[8] found numerical increases in inter-rater agreement (as measured by kappa scores) of three experienced readers when these readers combined visual analysis and quantitative parameters, compared to visual analysis alone. Quantification may assist in the assessment of visually borderline or difficult-to-read cases, particularly if measurements from an individual exam can be compared to measurement ranges from a normal database that allows adjustment for age- related loss of DaT receptors. Is a 1:5000 risk of cancer acceptable? Only the patient can appropriately answer this, with appropriate guidance from the clinician, and adequate pre-test counselling should always be undertaken. Alternatives to DaTSCAN include monitoring signs over time, obtaining a second opinion, and conducting medication trials. The potential pros and cons of various options should be evaluated in the context of the clinical situation. As was stressed in our article, DaTSCAN is not a replacement for clinical acumen or judgement, but provides extra data to inform that judgement. The clinician remains the best judge and arbiter of where to place the scan result in his/her final clinical view. In this regard, the use of DaTSCAN is no different from the use of surrogate imaging modalities in the work up of other complex neurodegenerative conditions, such as dementia.

    References: 1. Parkinson Study Group. Pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD Study. Clin Neuropharmacol 2000;23:34-44. 2. Whone AL, Watts RL, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET Study. Ann Neurol 2003;54:93 -101. 3. Fahn S and Parkinson Study Group. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005; (Suppl 4):252:iv37- iv42. 4. Marek K, Jennings D, et al. Long-term follow-up of patients with scans without evidence of dopaminergic deficit (SWEDD) in the ELLDOPA study. Neurology 2005;64(Suppl 1): A274(Abstract). 5. Seibyl J, Jennings D, et al. The role of neuroimaging in the early diagnosis and evaluation of Parkinson's disease. Minerva Medica 2005;96:353-64. 6. Marshall VL, Reininger CB, et al. Parkinson's disease is overdiagnosed clincally at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]-FP-CIT SPECT. Mov Disord 2009;24:500- 8. 7. Nin Bajaj, Robert A Hauser, Igor D Grachev. Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes. J Neurol Neurosurg Psychiatry 2013; 84: 1288-1295. 8. Soderlund TA, Dickson JC, Prvulovich E, Ben-Haim S, Kemp P, Booij J, et al. Value of semiquantitative analysis for clinical reporting of 123I-2-B- carbomethoxy-3B-(4-iodophenyl)-N-(3-fluoropropyl)nortropane SPECT studies. J Nucl Med. Published online March 14, 2013. doi:10.2967/jnumed.112.110106.

    Conflict of Interest:

    NB has received honoraria and a previous grant from GE Healthcare

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  4. Dopamine transporter SPECT imaging is not a useful Biomarker in the Diagnostic Workup of Corticobasal Syndrome.

    An increasing number of clinicopathological studies provides evidence against the accuracy of clinical criteria in the ante mortem diagnosis of corticobasal degeneration (CBD). Recently, Alexander and colleagues applied the new consensus criteria for the clinical diagnosis of CBD in patients with and without CBD pathology at post mortem examination and showed that the rate of misdiagnosis remains high, including false negatives (patients with CBD who were not identified) and false positives (patients fulfilling criteria for CBD but without CBD pathology, defined as CBD-mimics).[1] The authors concluded that clinical features alone are still not sufficient for precise ante mortem diagnosis and underline the need of reliable biomarkers that may help neurologists effectively in their routine clinical practice. The pathology underlying corticobasal syndrome (CBS) clinical phenotype is very heterogeneous, the most common being Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), and Alzheimer's Disease (AD). Here, I draw the attention to the most common cause misdiagnosed as CBD in the study by Alexander and colleagues,[1] that corresponds to the most common neurodegenerative disorder worlwide. Indeed, most (ten out of 14, 71%) patients among CBD-mimics had a post mortem diagnosis of AD.[1] The risk of misdiagnosis is high not only at the early stages, but also throughout the course of the disease, as focal variants of AD may maintain a CBD look -alike phenotype for several years. This occurs because it is the distribution of pathology, rather than the nature of the disease itself, that is reflected in the clinical syndrome. Now, the challenge is how to find a useful in vivo marker of AD pathology in patients presenting as CBS. Alexander and colleagues described the most recent imaging findings on this topic in a valuable effort to provide practical advice that would help clinicians in their differential diagnosis.[1] Nevertheless, to date there is still no imaging biomarker that may truly increase the diagnostic accuracy in patients presenting as CBS and currently available data should to be interpreted with caution. Firstly, although studies investigating patterns of brain metabolism or cortical atrophy have suggested that CBS- AD cases show greater abnormalities in temporoparietal regions than CBS- CBD, it still remains very difficult to translate findings from imaging research studies to the assessment of individual cases in everyday clinical practice, especially in the earliest stages. Secondly, new compounds for positron emission tomography used to investigate amyloid deposition (such as the Pittsburg compound B, PiB) have some limitations: (a) they are not widely available, (b) they do not present a typical pattern of distribution clearly differentiating between PiB-positive (supposed to be AD) and PiB negative (supposed to be CBD), (c) clinicopathological studies directly comparing the diagnostic accuracy of this in vivo technique to post-mortem examination are still lacking. Therefore, clinicians feel encouraged to search for additional biomarkers in the attempt to increase their chances of improving diagnostic accuracy. Alexander and colleagues did not mention in vivo investigation of presynaptic nigrostriatal function.[1] Current neuropathologic criteria indicate that substantia nigra pars compacta (SNc) neuronal loss characterizes CBD,[2] but not AD. As striatal dopamine transporter (DAT) imaging is a sensitive biomarker of SNc neuronal density, it would be tempting for neurologists to include DAT imaging in the diagnostic workup of CBS. In line with this belief, abnormal DAT imaging supports clinical diagnosis of Dementia with Lewy Body (DLB) according to International Consensus Criteria and, therefore, it is widely used in clinical practice to reliably differentiate it from AD. Similarly, one might expect that DAT imaging can be applied to differentiate CBD from AD. However, there are several lines of evidence supporting the fact that DAT imaging may be misleading in the diagnostic workup of CBS. We used DAT imaging to investigate in vivo SNc neuronal density in a large number of consecutive patients presenting as CBS[3]. In this cohort, DAT binding was highly variable and did not exhibit any relationship with disease-related features, such as the severity and duration of extrapiramidal motor symptoms. Normal DAT imaging was found in approximately 10% of these CBS subjects and extensive characterization of clinical features and neuropsychological profile did not reveal any difference compared to those with reduced SNc neuronal density. As neuropathology was not available, it was speculated that the mismatch between imaging findings and motor symptoms could be due to delayed reduction in SNc neuronal density in some CBD cases.[3] This hypothesis is confirmed by two recent clinicopathological reports, describing patients presenting as CBS with ante-mortem evidence of normal DAT imaging, who subsequently developed severe SNc degeneration and finally fulfilled neuropathological criteria for CBD.[4,5] Hence, normal DAT imaging in patients presenting as CBS does not exclude an underlying CBD pathology. As additional consideration, these advances broaden the spectrum of pathological heterogeneity within CBD by including 'cortical variants' without SNc neuronal loss. Some CBD patients may indeed present with predominant involvement of the cerebral cortex and subsequently display a 'cortico-to-basal' progression of neuronal degeneration in the rostro- caudal direction, finally involving the brainstem. In consistence with this hypothesis, SNc depigmentation is less evident in CBD cases presenting with cognitive rather than motor symptoms. From a clinical perspective, early dementia is now increasingly recognized as a possible presenting phenotype of CBD, while it was an exclusion criterion in previous sets of diagnostic criteria. Further study is needed to assess whether these subtypes of CBD present specific differences in clinical, neuropsychological, or natural history to deserve a separate classification, as for the other 'primary tauopathies' FTD and PSP. Finally, as SNc neuronal loss is still included among criteria for the definite diagnosis of CBD2, it might be worth considering a revision of neuropathologic criteria. In conclusion, recent research provided compelling evidence that CBD might include cases with unpredictable and delayed SNc degeneration. Consequently, DAT imaging is not a useful biomarker in the diagnostic workup of CBS, as it may potentially lead clinicians to misdiagnose AD in patients with CBD and prominent cortical involvement. Therefore, its use is inappropriate and should be firmly discouraged. Further study is needed to validate in vivo markers for CBD.

    References

    1. Alexander SK, Rittman T, Xuereb JH, Bak TH, Hodges JR, Rowe JB. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry. 2014 Feb 12. doi: 10.1136/jnnp-2013-307035. [Epub ahead of print]

    2. Dickson DW, Bergeron C, Chin SS, et al. Neuropathologic criteria for Corticobasal degeneration. J Neuropathol Exp Neurol. 2002;61(11):935- 946.

    3. Cilia R, Rossi C, Frosini D, Volterrani D, Siri C, Pagni C, et al. Dopamine Transporter SPECT Imaging in Corticobasal Syndrome. PLoS One. 2011; 6(5):e18301.

    4. Kaasinen V, Gardberg M, Roytta M, Seppanen M, Paivarinta M. Normal dopamine transporter SPECT in neuropathologically confirmed corticobasal degeneration. J Neurol. 2013; 260(5):1410-1.

    5. O'Sullivan SS, Burn DJ, Holton JL, Lees AJ. Normal dopamine transporter single photon-emission CT scan in corticobasal degeneration. Mov Disord. 2008; 23(16):2424-6.

    Conflict of Interest:

    None declared

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  5. Interferon-beta and the risk of cancer in MS

    With great interest we have read the research paper by Kingwell et al. on cancer risk with interferon-beta (IFNb) treatment in MS. The authors cautiously conclude that a possible association between IFNb usage and the occurrence of breast cancer should be investigated further. Although the authors interpret their overall finding as reassuring that overall cancer risk does not seem to be increased in IFNb users, they discuss the possibility that IFNb might indeed enhance tumour growth, as suggested by others.1

    They did not address, however, a possible role of neutralizing antibodies (NAb) to IFNb. It is well established that NAb developed during treatment with recombinant IFNb can persist for years, even after cessation of IFNb treatment.2,3 NAb are able to abolish the efficacy of IFNb treatment and have been shown to block endogenous IFNb as well.3,4 It is not implausible that persisting Nab may induce long term lack of IFNb bioactivity and thereby may increase the vulnerability to certain forms of cancer; given the anti-viral properties of IFNb probably especially those forms that are virus-induced.

    Therefore, the authors might consider to address this important issue by correlating cancer risk specifically to the occurrence of persisting anti-IFNb NAb in their large Canadian cohort of MS patients.

    Laura F van der Voort, Joep Killestein

    1 Gibbs E, Tremlett H, Ball N, et al. Malignant melanoma in a multiple sclerosis patient with persistent neutralizing antibodies to interferon-beta. Eur J Neurol 2008;15:e4.

    2 Petersen B, Bendtzen K, Koch-Henriksen N, Ravnborg M, Ross C, Sorensen PS; Danish Multiple Sclerosis Group. Persistence of neutralizing antibodies after discontinuation of IFNbeta therapy in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2006 Jun;12(3):247-52.

    3 van der Voort LF, Gilli F, Bertolotto A, Knol DL, Uitdehaag BM, Polman CH, Killestein J. Clinical effect of neutralizing antibodies to interferon-beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol 2010 April;67(4):402-7.

    4 Sominanda A, Lundkvist M, Fogdell-Hahn A, Hemmer B, Hartung HP, Hillert J, Menge T, Kieseier BC. Inhibition of endogenous interferon beta by neutralizing antibodies against recombinant interferon beta. Arch Neurol. 2010 Sep;67(9):1095-101.

    Conflict of Interest:

    J. Killestein: has received consulting fees from Merck-Serono, Teva, Biogen Idec, Genzyme and Novartis. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva.

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  6. How useful and how safe is a Datscan?

    In 2009 GE Healthcare revealed that 219,000 people had undergone the Datscan test [1]; by now it must be many more. The review article [2] by one employee of the company and two GE Healthcare sponsored clinicians considers the utility of the test. They begin by disparaging experienced clinical assessment. It is unarguable that expertise at a specialised centre doesn't extend to general practice (they cite a study from North Wales in 1999 that found that 47% of patients diagnosed did not fulfil Parkinson's Disease Brain Bank Criteria (PDBBC)} but this is a comment on education and service delivery, not the accuracy of experienced clinical diagnosis. They cite a study in which a full clinical assessment, with history and examination, was replaced by a videotape of patients with tremor. They go on to damn clinical assessment with faint praise, and I quote, "in practice clinical diagnosis is sufficient for many patients with advanced and typical manifestations of PD", thus ignoring the many years of clinical experience that tell us that in practice clinical diagnosis at symptom onset is usually correct [3] and when it isn't, then time or a second opinion often help. Patients may be happy to wait, and to allow the clinical picture to become clearer, before they decide to take medication.

    The authors then consider why between 4 and 15% of PD patients fulfilling PDBBC have a normal Datscan. I repeatedly explained to the manufacturers (then Amersham International) and many of their sponsored clinicians many years ago that, based on experience with 18Fdopa PET scanning, I was concerned that the technique showed insufficient separation between the range of values in the healthy population and that in the de-novo PD population; one could however establish the rate of false negatives in a de-novo PD population by comparing mean and standard deviation in this group with mean and standard deviation of an age-matched healthy population, the larger the sample sizes the better. They didn't listen and that study has never been carried out. In fairness to them, regulations wisely prevent the exposure of too many healthy people to radio-pharmaceuticals. My estimate in 2005, based on the limited data then available, was that the majority of the so-called SWEDD's would be false negatives [4]. The quoted long-term follow-up of SWEDD's in the ELLDOPA study (that has appeared in abstract only) was for a maximum of six years. The heterogeneity of progression in Parkinsonism (in Hoehn and Yahr's study [5] the average duration of life after diagnosis varied between one and thirty three years) means that short term follow-up has little value. Until every SWEDD has been followed up for many years, ideally to post-mortem, then the authors shouldn't imply that SWEDD's are likely to represent misdiagnoses. But the de-novo population is one in which around 90% will, by clinical assessment, have PD. In a population in which only 50% have parkinsonism as, for example, when separating PD from ET then, using the same data sources as above, Bayes theorem tells that the chance of an erroneous diagnosis may be as high as 50%.

    There are other issues to consider. The quoted national Datscan audit showed that one in twenty five Datscans were misreported in the 50% of centres that took part in the audit; we don't know the rate of misreporting in the other centres. A further problem for what is essentially an in-vivo biochemical measurement is that few human studies have been carried out with commonly used medications (for example anti- psychotics, anti-hypertensives or anti-depressants) that could affect scan results. With regard to quantitation the authors state that "the routine clinical use of quantitation...... cannot be recommended for clinical practice without a visual read". The picture we see is a colour scale interpretation of the numbers generated by the scan's detectors and computer; if quantitation can't be recommended, how can the authors recommend assessing the resulting images by eye?

    Eventually, after undermining clinical assessment and hinting loudly that the visually normal scans in patients presenting as clinical PD are explained by clinicians' diagnostic errors, the authors acknowledge that the true accuracy of the test is unknown.

    For a test to have clinical utility in helping us confidently tell a patient whether they have PD or not, we need to know the false negative and false positive rate in de-novo patients, the rate of error in image reporting in all centres, and the effect of all medications that a patient might be taking. That it has been used so extensively without this information represents a triumph of persuasive marketing over clinicians' common sense. That so many people have been exposed to radiation (one quoted author [2] has put the risk of cancer at 1 in 5000) for a test with such limitations is a worry. Instead of the 100% reliable, very safe and inexpensive test that we and our patients might want, we have false negatives (number unknown), misreading of scan images (4% in 50% of centres), possible confounding effects of medication (unknown), expense (around 800 UK pounds or 1500 US dollars per scan) and a significant risk of cancer.

    When given these facts and figures, patients will surely prefer to trust a clinician who is aware of their own limitations than a scan that has more limitations than is publicly acknowledged.

    References: 1. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM186404.pdf (accessed February 2014) 2. Bajaj N, Hauser RA and Grachev ID. Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes. J Neurol Neurosurg Psychiatry 2013; 84:1288-1295 3. De la Fuente-Feernandez R. Role of DaTSCAN and clinical diagnosis in Parkinson's disease. Neurology 2012; 78:696-701 4. Morrish PK. Controversies in Neuroimaging. 2008 Chapter 28 in Parkinson's disease; Diagnosis and Clinical Management. Demos Publishing (New York). Eds Factor and Weiner 5. Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967;17:427-42.

    Conflict of Interest:

    In 2001 I was interviewed for a job with what was then Amersham international. I used the interview to tell the company of my concerns about the test (based on my experience with 18Fdopa PET scanning). Not surprisingly I decided that I didn't want the job and they decided that they didn't want to employ me.

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  7. Misdiagnosed case of right paraspinal abscess.

    We read the article by Mackenzie et al. [1] with great interest. We would like to share our experience of an Asian patient in 20s with paraspinal abscess. The patient is a nonsmoker, nondrinker but had been active IV heroine abuser on weekends for past 5 years. He was referred to emergency services for sudden onset of right flank pain, fever (103? Fahrenheit), chills. The pain was progressive, radiated from right flank to right upper quadrant and epigastrium, 8/10 in intensity, squeezing. He denied chest pain, palpitation, weight loss or loss of appetite. Immediate physical examination showed soft abdomen but was negative for any discoloration, distention, mass, costovertebral angle tenderness, psoas sign, rovsing's sign, or obturator sign. Blood results were remarkable for WBC count 13000 cells/?L (mainly neutrophils). Initial reports of ultrasonography and CT abdomen were negative. The patient was transferred to internal medicine ward. There, I asked the patient to walk and found that he had progressive weakness 3/5 in right leg and could not walk since last 2 days ago. Reflexes at right knee and ankle were exaggerated. We ordered a repeat CT and were able to find a swelling at right paraspinal region at T-12. CT guided biopsy of the abscess was sent to pathology and was positive for staphylococcus . He was treated with vancomycin IV for 6 weeks and recovered well. This case points out to the missed diagnosis of paraspinal abscess on CT scan in surgery ward. Surgeons while suspecting abdominal pathologies should keep such a presentation in mind and look for spinal areas on imaging studies. It is also important to emphasize that physical exam is important and that is what led us here to repeat imaging.

    1 Mackenzie et al. Spinal epidural abscess: the importance of early diagnosis and treatment J. Neurol. Neurosurg. Psychiatry 1998 65:209-212.

    Conflict of Interest:

    None declared

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  8. Disconnection Vs standard anterior temporal lobectomy-which one is better?

    I read with interest the research paper by Massager et al. and the accompanying editorial by Schramm on the long term outcome of surgical disconnection of the epileptic zone in patients with medically refractory nonlesional mesial temporal lobe epilepsy (MTL) 1, 2. High functioning patients with MTL in whom WADA testing reveals bihemispheric dominance for memory frequently experience a decline in either verbal or non-verbal memory after standard anterior temporal lobectomy (ATL) with amygdalohippocampectomy (AH). Do the authors have any data to share whether their surgical disconnection technique leads to less memory dysfunction than seen after standard ATL.?

    References

    1. Massager N, Tugendhaft P, Depondt C, Coppens T, Drogba L, Benmebarek N, De Witte O, Van Bogaert P, Legros B. Long-term outcome of surgical disconnection of the epileptic zone as an alternative to resection for nonlesional mesial temporal epilepsy. J Neurol Neurosurg Psychiatry 2013; 84:1378-83.

    2. Schramm J. Disconnecting epileptogenic zone is as effective as resection. J Neurol Neurosurg Psychiatry 2013; 84:1300-1.

    Conflict of Interest:

    None declared

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  9. Re:Setting the Gold Standard

    More evidence needed before retiring the Wada test

    We thank Dr. Baxendale and colleagues for her useful comments regarding our meta-analysis and the opportunity to clarify a few points.

    The study of Janacek and colleagues provides important information on the question of validity of the Wada test and fMRI. Although at the time of submission we were not aware of this publication, we do address this issue in the beginning of the discussion , and cite studies that have shown Wada to be incorrect. We also discuss the potential caveats in fMRI that could lead to incorrect classification, such as parameter settings. Brain areas that are involved in, but are not critical for, language function are detected by fMRI but not by the Wada test. We agree that these non-critical areas may indeed have supportive function for recovery, but we believe more evidence needs to be provided before this can be stated with any certainty

    Rather than advocating the use of the Wada test as a standard, we suggest to use fMRI as standard screen, thereby reducing the number of invasive procedures. Given the potential severity of inadvertent surgery- induced deficits we believe a conservative diagnostic approach is at this point still warranted. Hence, If fMRI results are unclear, inconclusive or if they suggest atypical lateralization (which may also be caused by scan artifacts, poor task performance or poor fMRI contrast-to-noise), we recommend an additional test to evaluate laterality, such as the Wada test if that is a local standard procedure, or cortical stimulation during surgery. Novel techniques such as TMS may eventually be of use but they also require rigorous validation tests.

    We know that in some parts of the world, notably in the UK, the Wada test has already been largely replaced by fMRI. In the Netherlands, and other countries, clinical decision making still heavily relies on the Wada test, although fMRI is increasingly used as a complementary technique. fMRI may some day replace the Wada test for most cases, but we believe that complete replacement requires more evidence, indeed based on outcome research. The aim of our analysis is to encourage further steps towards routine use of non- invasive techniques.

    Conflict of Interest:

    None declared

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  10. C9ORF72 in dementia with Lewy bodies

    INTRODUCTION Recent studies have shown that a large hexanucleotide expansion in C9ORF72 is the most common cause of inherited Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND).1 In pathological terms, expansion carriers show a distinctive molecular signature within the dentate gyrus granule cells and CA4 pyramidal cells of the hippocampus and granule cells of the cerebellum characterised by TDP-43-negative, but p62-positive, neuronal cytoplasmic inclusions (NCI).2 In clinical terms, psychosis is one of the major clinical traits in patients with FTLD and/or MND who carry expansions in C9ORF72.3 Given that psychosis is also common in Dementia with Lewy bodies (DLB), we previously genetically screened 102 patients with clinically diagnosed DLB, and detected an expansion in C9ORF72 in 2 patients.4 Consequently, we immunostained tissue sections of hippocampus and cerebellum for p62 protein from a series of 53 pathologically confirmed cases of DLB in order to ascertain to what extent expansions in C9ORF72 might be present in this disorder. METHODS Brain tissues were available from a series of 53 patients with pathologically confirmed DLB within the Manchester Brain Bank. All had been obtained with full ethical permission following consent by the next of kin. Paraffin sections were cut (at a thickness of 6?m) from formalin fixed blocks of temporal cortex (with hippocampus) and cerebellar cortex and immunostained for p62 proteins (rabbit polyclonal antibody to p62-lck ligand, B D Biosciences, Oxford, UK, 1:100 dilution), involving pressure cooking the sections for antigen retrieval and employing a standard ABC Elite kit (Vector, Burlingame, CA, USA) with DAB as chromagen. Immunostained sections were assessed for presence of p62-immunoreactive NCI within the dentate gyrus and CA2/3/4 regions of the hippocampus, and within the granule cells of the cerebellum. RESULTS No p62-immunoreactive NCI were seen within the hippocampus or cerebellum in any of the 53 cases. DISCUSSION Previously, when screening a series of 102 patients fulfilling criteria for probable DLB we detected an expansion in C9ORF72 in two patients.4 Similar to expansion carriers with FTLD,3 both patients displayed psychotic features, though in neither was a previous family history of dementia recorded, nor was there pathological confirmation of DLB or other underlying neurodegenerative disease. Therefore it was possible that these 2 individuals were misdiagnosed. Indeed, a frontotemporal dementia phenotype that mimics DLB has been reported.5 We therefore investigated 53 pathologically confirmed cases of DLB for an expansion in C9ORF72, using the presence of p62-immunoreactive NCI in hippocampus and cerebellum as a surrogate marker, but did not detect any cases where relevant tissue changes were present. Although only a few of the cases had undergone formal genetic analysis for expansions in C9ORF72, and shown to be negative, evidence indicates that the presence of p62-positive NCI in these brain regions can nevertheless act robustly as a marker of the expansion in the absence of genetic analysis. From this study, we therefore conclude that expansions in C9ORF72 in confirmed cases of DLB are unlikely, and in those patients bearing expansions in clinically assessed cohorts an atypical presentation of an underlying process of frontotemporal lobar degeneration is likely to be present.

    Andrew Robinson, Yvonne Davidson, Julie S Snowden, David M A Mann

    Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.

    Correspondence to Professor David Mann, Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK; david.mann@manchester.ac.uk Contributors DMAM conceived the study, performed microscopic analyses and prepared the manuscript. AR and YD prepared tissue sections and performed immunohistochemical staining. JS assisted with clinical characterization of the cohort. Funding The work of the Manchester Brain Bank is supported by Alzheimers Research UK and Alzheimer's Society under the Brains for Dementia Research (BDR) initiative. The study was supported in part by MRC and Wellcome Trust Neuroscience Initiative MRC G0701441).

    Competing Interests None

    Ethics Approval Ethics approval was provided by Newcastle and North Tyneside 1 Local Research Ethics Committee under Generic Tissue Bank Ethical Agreement.? References

    1. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron 2011;72:257-68. 2. Mann DMA, Rollinson S, Robinson A, et al. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with Frontotemporal Lobar Degeneration and Motor Neurone Disease associated with expansions in C9ORF72. Acta Neuropathol Comm 2013;1:68. DOI: 10.1186/2051-5960-1-68. 3. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical characteristics in patients with frontotemporal dementia and C9ORF72 mutations: a study of demographics, neurology, behaviour, cognition, and histopathology. Brain 2012;135:693-708. 4. Snowden JS, Rollinson S, Lafon C, et al. Psychosis, C9ORF72 and Dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2012;83:1031-2. 5. Claasen DO, Parisi JE, Giannini C, et al. Frontotemporal dementia mimicking dementia with Lewy bodies. Cogn Behav Neurol 2008; 21:157-63.

    Conflict of Interest:

    None declared

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