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 [1]. 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 [2]. 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 [2]. 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 [3]. 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 [4]. Based on the natural course of the disease, a duration of 4 to 5 years is expected before the upper limb symptoms would start [5]. 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.

References

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.

Conflict of Interest:

None declared

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 [1]. 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 [2]. 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.

[1] 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.

[2] 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.

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:

None declared

In an editorial commentary accompanying a recent study on the prevalence of apraxia in dementia patients [1], 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 [2]), 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. [3] 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 [4], as well as neurodegenerative pathologies [5]. 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.

References

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.

Conflict of Interest:

None declared