Displaying 1-10 letters out of 536 published
Re: A Val30Met sporadic familial amyloid polyneuropathy case with atypical presentation: Upper limp onset of symptoms
Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant disorder caused by the mutations of the transthyretin (TTR) gene. The mutant amyloidogenic TTR protein causes systemic accumulation of amyloid fibrils that result in organ dysfunction . Over 100 mutations in TTR gene are associated with the disease but still, the first identified Val30Met mutation make up 50% of the cases worldwide. In the three main regions in which TTR-FAP is endemic (Portugal, Sweden and Japan), the Val30Met mutation is the predominant genetic cause. However, in non-endemic regions genetic features are more heterogeneous . Clinical presentation is highly variable due to the interplay between several factors consisting of genotype, geographical origin of the patient, regional variation, penetrance of gene mutation and age at onset of symptoms . Length dependent axonal sensory-motor and autonomic polyneuropathy is the hallmark feature of TTR-FAP hence, lower limb sensory symptoms are generally the initial manifestations. Yet, Koike et al reported that 5 of 50 patients presented with upper limb sensory symptoms . Herein, we describe a patient with Val30Met mutation presented with asymmetrical upper limb symptoms which was not previously reported in non-endemic regions. A 66-year-old male patient was admitted with 3-year history of progressive numbness and pain in right hand. He progressively deteriorated and his symptoms have spread to his left hand in several months. He was diagnosed as bilateral carpal tunnel syndrome and underwent bilateral surgical carpal tunnel ligament release. However, he gradually worsened with tingling and numbness spreading to his forearms followed by weakness in both hands without any significant lower limb symptoms. He has had recurrent constipation, orthostatism and impotence, which are suggestive of autonomic involvement, for three years. Two years after the onset of the upper limb symptoms he developed numbness in footpad, followed by pain and weakness in both legs. He was diagnosed chronic inflammatory demyelinating polyneuropathy two years ago and treated with prednisolone for six months. His past medical history was significant for systemic hypertension and a myocardial infarction four years prior. His grandfather, father and uncle had died from unknown cardiac cause. In his initial examination, he had bilateral miosis, distal muscle weakness predominantly in upper and left-side with absent deep tendon reflexes, stocking and glove type hypoaesthesia and hypoalgesia, diminished vibration sensation. Nerve conduction studies revealed a demyelinating sensory and motor polyneuropathy syndrome accompanied by the signs of axonal loss. These findings were accompanied by sympathetic autonomic involvement. His cerebrospinal fluid (CSF) examination revealed increased protein level (75 mg/dl) with normal cytological examination. Urinalysis results showed microalbuminuria but urinary tract ultrasonography was normal. Because of the positive family history of unknown cardiac deaths, echocardiograpy was performed which revealed secondary changes in the myocardium associated with amyloid deposition. His cardiac magnetic resonance imaging results correlated with the findings of echocardiogram. In his rhythm holter monitoring, baseline rhythm was sinus with the average heart rate of 62/min (lowest heart rate: 47/min, highest heart rate: 78/min). No signs of arrythmia or conduction blocks were detected. With those findings, we assumed that the patient had amyloid associated neuropathy. Minor salivary gland biopsy was performed and amyloid infiltration of the blood vessel wall and periductal field was observed. Molecular analysis of TTR gene revealed heterozygous Val30Met (c.148G>A) mutation in exon 2. Tafamidis 20 mg/day treatment was initiated right after the patient was diagnosed. TTR-FAP is a multisystemic and increasingly popular disease but still very difficult to recognize especially in non-endemic regions. Various clinic presentations, negative family history and the clinicians' lack of awareness are most common causes of misdiagnosis. Upper limb onset axonal polyneuropathy is a rare presentation in general practice and was not reported in TTR-FAP patients in non-endemic regions . Based on the natural course of the disease, a duration of 4 to 5 years is expected before the upper limb symptoms would start . On the other hand, in a previous analysis of late-onset cases with Val30Met mutation, 10% of the patients had upper limb symptoms as the initial presentation. Among those patients, the mean age at upper limb onset was 66.3 ? 5.8 whereas lower limb symptoms occured at 66.5 ? 6.2 years of age. Although age at disease onset was nearly similar in our case, duration between the upper limb and the lower limb symptoms was slightly longer than the latter report. In conclusion, we emphasize the heterogenous clinical presentation of late -onset FAP in non -endemic regions. Careful examination and clinical suspicion is mandatory for reducing the misdiagnosis of the atypical cases.
1. Andrade, C., A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain, 1952. 75(3): p. 408-27.
2. Parman, Y., et al., Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol, 2016. 29 Suppl 1: p. S3-13. 3.
3. Koike, H., et al., Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non- endemic areas. J Neurol Neurosurg Psychiatry, 2012. 83(2): p. 152-8. 4.
4. Durmus-Tekce, H., et al., Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. Neuromuscul Disord, 2016. 26(7): p. 441-6. 5.
5. Conceicao, I., et al., "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst, 2016. 21(1): p. 5- 9.
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Accumulation of MRI Markers of Cerebral Small Vessel Disease in Depression
In a study published in J Neurol Neurosurg Psychiatry, Xu et al.1 aimed to investigate the relation between microbleeds (CMBs) and Neuropsychiatric symptoms (NPS) in an elderly population, through a cross- sectional study related to 802 participants. Interestingly, they found a statistically significant increment of the incidence of depression, with the presence of multiple CMBs, in particular lobar CMBs. This finding is in line with the previous research by Tang et al..2 However, a recent study by Zhang et al.3 did not find the similar increment trend in deep CMBs in patients with post-stroke depression, indicating that the presence of lobar CMBs, not deep CMBs, was a potential predictor maker of depression. While CMBs is one of the MRI biomarkers of cerebral small vessel disease (cSVD) and was often accompanied by other cSVD-related brain changes, such as lacunar infarcts, white matter lesions, and enlarged perivascular spaces.
The available evidence suggests that cSVD was a principal determinant in the pathogenesis and development of post-stroke depression,4 and depression in patients with a prevalence of cerebrovascular disease burden may be related more to cumulative vascular pathology than to the location and severity of a single risk factor. Investigating the role of a total MRI burden of cSVD in its pathogenesis may help to understand this disease better. As the previously mentioned, Zhang et al. found that higher total MRI burden of cSVD was an independent predictor of depression, even without detecting an apparent association between deep CMBs and depression. Similar to the study by Zhang et al., a recent research investigated total MRI burden of cSVD in cerebral amyloid angiopathy (CAA), in univariable analysis, total cSVD score was associated with the presence of CAA-related changes on pathologic analysis and CAA presentation with ICH, but none of the different MRI markers comprising the score were individually linked to vasculopathic changes in univariable or multivariable logistic regression analyses.5 These suggest that an assessment of total MRI burden of cSVD has several potential advantages because it avoids overreliance on any one individual marker of small vessel disease.5 Hence, a complete evaluation of the total MRI burden of cSVD may be important to understand the effect of cSVD on clinical outcomes, such as depression.
Conflict of Interest Disclosures: None. Reference: 1. Xu X, Chan QL, Hilal S, et al. Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort. Journal of neurology, neurosurgery, and psychiatry 2017;88(1):7-11. doi: 10.1136/jnnp -2016-313271 2. Tang WK, Chen Y, Liang H, et al. Cerebral microbleeds as a predictor of 1-year outcome of poststroke depression. Stroke; a journal of cerebral circulation 2014;45(1):77-81. doi: 10.1161/STROKEAHA.113.002686 3. Zhang X, Tang Y, Xie Y, et al. Total magnetic resonance imaging burden of cerebral small-vessel disease is associated with post-stroke depression in patients with acute lacunar stroke. Eur J Neurol 2016 doi: 10.1111/ene.13213 4. Pavlovic AM, Pekmezovic T, Zidverc Trajkovic J, et al. Baseline characteristic of patients presenting with lacunar stroke and cerebral small vessel disease may predict future development of depression. Int J Geriatr Psychiatry 2016;31(1):58-65. doi: 10.1002/gps.4289 5. Charidimou A, Martinez-Ramirez S, Reijmer YD, et al. Total Magnetic Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid Angiopathy: An Imaging-Pathologic Study of Concept Validation. JAMA neurology 2016;73(8):994-1001. doi: 10.1001/jamaneurol.2016.0832
Conflict of Interest:
Re:Deep brain stimulation as a feedback control system
We are very grateful to Dr Keller for his comments and support for the feedback control approach to deep brain stimulation for Parkinson's disease. As he points out, "reducing or turning off the stimulation current when it is not needed conforms to the clinical axiom if it ain't broke, don't fix it". This is further borne out by a publication currently in press in this journal in which we show that feedback-controlled deep brain stimulation has the potential to avoid the speech side-effects of stimulation sometimes experienced by patients with Parkinson's disease . A case report from an independent group provides evidence that this approach may also limit the dyskinesias that can be experienced by patients receiving deep brain stimulation in combination with levodopa . Feedback-controlled deep brain stimulation is an exciting area of development, but it still remains unclear whether the superior acute efficacy and selectivity of such stimulation over conventional continuous deep brain stimulation will be carried over in to the chronic state.
 Little S, Tripoliti E, Beudel M, Pogosyan A, Cagnan H, Herz D, Bestmann S, Fitzgerald J, Aziz T, Cheeran B, Zrinzo Z, Hariz M, Hyam J, Limousin P, Foltynie T, Brown P. Speech side effects are ameliorated in by adaptive compared to conventional deep brain stimulation for in Parkinson's disease. Journal of Neurology, Neurosurgery and Psychiatry, In Press.
 Rosa M, Arlotti M, Ardolino G, Cogiamanian F, Marceglia S, Di Fonzo A, Cortese F, Rampini PM, Priori A. Adaptive deep brain stimulation in a freely moving Parkinsonian patient. Mov Disord. 2015 30:1003-5.
Conflict of Interest:
SL has been a participant in a DBS teaching course funded by Medtronic. PB has received fees and non-financial support from Medtronic and personal fees from Boston scientific.
It is mentioned that Sherrington introduced the term Synapse. In fact the word synapse was introduced By Macheal Foster,then Professor of Physiology at Cambridge along with his mentor Arthur Woodllgar Verrall coined the word Synapse,meaning Clasp.Thus Sherrington made no such discovery,and is ti be credited only with having solicited the name. As he was working on Reflexes,he has advocated the physiological concept of Synapses. Even Sigmund Freud, has visualized the gap between the nerve cells,before Sherrington and called it "Contact barrier". His sketch is published. With the fact mentioned above, why the contributions were not recognized,by the scientific community? Their contributions has gone un-noticed for a long time by the community,it should not happen for ever.Soceity will loose faith in the scientific community for ever. By this we do not undermine Sherrington 's contributions, he shared the Nobel Prize in 1932 along with Edgar Douglas (Lord) Adrian. Hence the credit should be given to Macheal Foster, Arthue Woodllgar and Sigmund Freud. If down,scientific community is justified.
D. Narayan Rao PhD( Neurophysiology) P
Conflict of Interest:
Deep brain stimulation as a feedback control system
As a physician with Parkinson's disease, and as a former Bell Labs electrical engineer, I recognize that Professor Brown's group is pursuing an important and fundamental improvement to deep brain stimulation. The theory of electronic feedback control systems has been extensively studied and applied in areas such as aircraft and missile guidance; Brown's work may expand the existing theoretical domain of control systems, as well as find new application for established theorems.
The concept of "on demand" stimulation makes intuitive biological sense. Reducing or turning off the stimulation current when it is not needed conforms to the clinical axiom "if it ain't broke, don't fix it". DBS, like other therapeutic interventions, should be applied to the point of maximum benefit but not beyond, in order to limit side-effects. Feedback control is the ideal way to accomplish this.
Will the DBS leads currently being implanted in Parkinson's patients require replacement with leads optimized for sensing the feedback signal as well as stimulation? If so, this may be a consideration for patients with milder symptoms who might wish to wait for the availability of adaptive DBS, to avoid the need for lead replacement.
Conflict of Interest:
profound benefits for melatonin
We physicians are trained to push Rx medicines but increasingly we find that supplements are efficacious and safer. That melatonin is associated with weight loss is news to me. This paper does an excellent job summarizing the clinical implications and cautions in using melatonin. The dosage information is helpful as well.
Conflict of Interest:
Also patients with dementia need motor examination, but do we need more examination tools?
In an editorial commentary accompanying a recent study on the prevalence of apraxia in dementia patients , Bak emphasizes two facts: 1) research in cognitive neuroscience is contributing to increase the awareness of a close relationship between cognitive and motor functions and, by extension, cognitive and motor disorders in clinical populations; 2) despite so, the examination of motor functions in patients with cognitive disorders is not part of the routine clinical evaluation. Apraxia is a disorder in executing voluntary motor programming, in the absence of deficits in primary motor or sensory processes, comprehension of task instructions, object recognition or frontal inertia. Bak identifies apraxia as the critical disorder to address in routine clinical evaluation of patients with cognitive symptoms, as "it is exactly at the intersection between both [movement and cognition]". In Bak's view, a major obstacle to the improvement of clinical practice in this direction, is the absolute lack of tests for apraxia, practical and fast to use as part of routine evaluation. The Edinburgh Motor Assessment, in preparation by Bak and colleagues, is thus introduced as the first tool to respond to this urge. We could not agree more with the importance of considering apraxia in the routine clinical evaluation of cognitive functions in neurological patients, including those with dementia. Apraxia is indeed a cognitive deficit, affecting the higher-order mechanisms that govern purposeful motor production. However, if poverty or absence of tools is the problem, then we might not have a problem. Researchers have long since recognized apraxia as a cognitive disorder (with consequences on motor production). Moreover, efforts have been made to offer handy, standardized tests of praxis functions (e.g., the test TULIA ), based on models of apraxia, whose anatomo-functional correlates have been extensively studied in brain- damaged patients and in healthy individuals, with neuroimaging research. A problem with most previous tests, evaluating gesture recognition, identification and production in great detail, is the administration time, usually so long as to advise their use in a post-screening phase (i.e., after the patient received a diagnosis of apraxia). Addressing this problem, Tessari et al.  have developed STIMA (short test for ideomotor apraxia), a standardized test for an accurate but quick diagnosis of apraxia. The test, also usable for bedside screening, requires the patient to imitate 36 gestures that form eight subscales. The test and each individual subscale are accompanied by tables to correct raw-scores for age and education, and convert raw-scores into equivalent scores (useful for clinicians to estimate deficit severity) and percentiles (more often used for diagnosis in research). Different subscales test for different praxic impairments. In particular, STIMA emphasizes the distinctions between: 1) imitation errors indicative of cortical damage (e.g., sequence errors or unrecognizable gestures) versus subcortical damage (e.g., postural or timing errors); 2) producing distal (fingers/hand) versus proximal (arm) components of gesture; 3) producing known gestures, which recruits semantic structures in the left temporo-parietal cortex, versus producing novel gestures, which relies on a bilateral cortical network, to transform the visual input (the seen gesture) in a motor act. The evaluation of novel gestures is also crucial to detect praxis deficits in patients who can properly use objects and tools in their domestic context. Evaluation of praxis solely based on execution or reports of daily activities may leave those cases unnoticed. STIMA has been used and proven sensitive to apraxic deficits in patients with stroke , as well as neurodegenerative pathologies . Our short (and non-exhaustive) overview of available standardized tests of apraxia shows a scenario brighter than the total absence of suitable tools depicted by Bak, and does justice to the numerous research teams in cognitive neuropsychology and neuroscience, who have paid more attention than Bak fears, to the clinical scopes of their activity and the constraints of the clinical setting (i.e., time pressure). Since the Edinburgh Motor Assessment by Bak et al. comes after recent and less recent attempts to provide clinicians with a fast and accurate test of apraxia, one may ask: do we really need this new tool? Perhaps, the Edinburgh Motor Assessment introduces features that make it more suitable to dementia patients, than other tests; or it relates to a model of apraxia, not represented in the other tests. Presenting the Edinburgh Motor Assessment as the first step toward an apraxia test for clinical practice precludes the possibility to clarify those or other potentially important aspects of that test. Considering its relation to extant tools rather appears as a good method to provide clear indications about which tool one (e.g., a clinician) should select in which case. This may help reducing the noise in the exchange between researchers and clinical practitioners as well as within our research field.
1. Ahmed S, Baker I, Thompson S et al. Utility of testing for apraxia and associated features in dementia. J Neurol Neurosurg Psychiatry 2016; doi:10.1136/jnnp-2015-312945
2. Vanbellingen T, Kersten B, Van Hemelrijk B et al. Comprehensive assessment of gesture production: a new test of upper limb apraxia (TULIA). Eur J Neurol 2010;17:59-66.
3. Tessari A, Toraldo A, Lunardelli A, et al. STIMA: a short screening test for ideo-motor apraxia, selective for action meaning and bodily district. Neurol Sci 2015;36: 977-984.
4. Mengotti P, Corradi-Dell'Acqua C, Negri GA, et al. Selective imitation impairments differentially interact with language processing. Brain 2013;136:2602-2618
5. Papeo L, Cecchetto C, Mazzon G et al. The processing of actions and action-words in amyotrophic lateral sclerosis patients. Cortex 2015; 64:136-147.
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REPLY TO: "RETINAL NERVE FIBRE LAYER THINNING IS ASSOCIATED WITH DRUG RESISTANCE IN EPILEPSY: PROMISING YET OPEN ENDED"
Sir, We thank Kumar et al. for their interest in our recent article on retinal nerve fibre layer thickness (RNFL) in people with epilepsy. In their letter they raise a few points that we would like to address.
1. Comparison between people with epilepsy and healthy controls. They suggest that a comparison between people with drug-resistant versus non- resistant epilepsy might have been more appropriate. However, as described in the paper itself, in Methods - Statistics, we first compared cases versus controls and then tested for differences in the distribution of average RNFL thickness as a continuous variable according to each demographic and clinical factor, including drug-resistance. The results of this comparison are presented in Results - Average RNFL thickness across all quadrants and exposure to AEDs or non-medical treatments, and showed thinner average RNFL in people with drug-resistant epilepsy compared with non-resistant epilepsy.
2) Kumar et al. state that the aetiological spectrum of epilepsy is not described. We report the epilepsy aetiology in Supplementary material, Table S2, classified according to the "Commission on Classification and Terminology of the International League Against Epilepsy, 1989". We also tested for difference in the distribution of RNFL thickness according to the epilepsy type (see Results - Average RNFL thickness and clinical characteristics--univariate associations). This information was all present in the publication.
3) We agree with the fact that age is a major factor determining the RNFL thickness. We analysed correlation of average RNFL thickness with age in both cases and controls. We included only epilepsy duration in the regression models because of high collinearity with age. We did not consider age group distribution as this would have significantly limited the sample size.
4) We recognise that refractive errors may affect RNFL thickness. For this reason, we excluded people with a distance refractive error of >4.50 dioptres mean sphere/>2.5 dioptres cylinder.
5) We attempted to account for all known factors known to be associated with changes in RNFL (exposure to vigabatrin, diabetes, glaucoma or other known ocular disease, concurrent diagnosis of multiple sclerosis, history of trauma or surgery to the eye or orbit, refractive errors, brain MRI evidence of visual pathway involvement), as stated in Methods, Participants.
The points raised by Kumar et al. were therefore all already addressed in the original paper.
Conflict of Interest:
RETINAL NERVE FIBRE LAYER THINNING IS ASSOCIATED WITH DRUG RESISTANCE IN EPILEPSY: PROMISING YET OPEN ENDED
Sir, The recently published article titled "Retinal nerve fibre layer thinning is associated with drug resistance in epilepsy" by Balestrini S et al has been a refreshing approach into a common menace - refractory epilepsy. 30 to 40% of patients with seizure are classified as persistent seizures under AEDs among which refractory epilepsy is included. (1) Retinal nerve fibre layer (RNFL) thinning is an easy and non invasive analysis which would point towards possible refractory epilepsy leading to shortening of lead time to diagnosis. The present paper opens a whole new arena of thought process for evaluation of refractory epilepsy but leaves the promise open ended. Few points we would like to point out are mentioned below (1) Study groups: This retrospective case control analysis based on hospital records compares two groups including those with epilepsy as the case group and healthy individuals as controls. This comparison has its flaws in comparing two different groups with inherent differences in itself. The case group (epileptics) includes both refractory and non- refractory epileptics, with the control groups being healthy controls. Comparing the case group (patients of refractory epilepsy) with non refractory epileptics might have been more prudent. (2) Etiology of refractory epilepsy and its implications: Effectiveness of AEDs in management of epilepsies is heavily weighted on the underlying etiology. The present study has not mentioned the etiological spectrum of epilepsy which would have further helped in enumerating subgroups adding to strength and validity. Over reliance on the retrospective data for delineating refractory epilepsy takes out the possibility of fixing an appropriate etiology for refractoriness (3) Variation in RNFL among the study population: Age group distribution among the study group has not been mentioned. Literature points the role of age as a major factor in determining the RNFL thickness. (2) Even refractive errors has been noted to have an effect on RNFL thickness. (3) The study excludes only few obvious factors noted to be associated with reduction in RNFL thickness namely multiple sclerosis, Alzheimer's disease, previous optic neuritis and angle closure glaucoma. References 1. Beleza P. Refractory epilepsy: a clinically oriented review. Eur Neurol. 2009;62(2):65-71. 2. Celebi AR, Mirza GE. Age-related change in retinal nerve fiber layer thickness measured with spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54(13):8095-103. 3. Pawar N, Maheshwari D, Ravindran M, Ramakrishnan R. Retinal nerve fiber layer thickness in normal Indian pediatric population measured with optical coherence tomography. Indian J Ophthalmol. 2014;62(4):412-8.
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Short Montreal Cognitive Assessment (s-MOCA): validation study
Roalf et al. describe a short form of the Montreal Cognitive Assessment (s-MOCA) comprising 8 items (score range 0-16) from the original MoCA.
Data from a historical cohort administered the MoCA (n = 150)1 were examined to extract s-MoCA scores. There was high correlation between s- MoCA scores and MoCA and MMSE scores (0.94, 0.80 respectively).
s-MoCA scores differed significantly (null hypothesis rejected) between dementia and mild cognitive impairment (MCI), and between MCI (t = 2.6, p = 0.01) and subjective memory complaint (SMC; t = 6.6, p < 0.001).
Using the specified s-MoCA cutoff of <12/16, the test was very sensitive (0.94) but not specific (0.25) for diagnosis of dementia versus MCI, with a better balance for diagnosis of MCI versus SMC (sensitivity 0.75, specificity 0.66).
Effect sizes (Cohen's d) were medium for diagnosis of dementia versus MCI (0.65) but large (1.19) for diagnosis of MCI versus SMC. All outcome measures were similar to those for the MoCA.
This retrospective study suggests s-MoCA has utility as a cognitive screening instrument for diagnosis of dementia and MCI in a dedicated cognitive disorders clinic. Validation of s-MoCA in a prospective cohort from this clinic (n > 200) is now being examined.
1. Larner AJ. Screening utility of the Montreal Cognitive Assessment (MoCA): in place of - or as well as - the MMSE? Int Psychogeriatr 2012;24:391-6.
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