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July 25, 2017; 89 (4) Article

A new potential biomarker for dementia with Lewy bodies

Skin nerve α-synuclein deposits

Vincenzo Donadio, Alex Incensi, Giovanni Rizzo, Sabina Capellari, Roberta Pantieri, Michelangelo Stanzani Maserati, Grazia Devigili, Roberto Eleopra, Giovanni Defazio, Federico Montini, Agostino Baruzzi, Rocco Liguori
First published June 30, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004146
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Abstract

Objective: To investigate whether (1) phosphorylated α-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB.

Methods: We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of α-synuclein.

Results: No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions.

Conclusions: (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms.

Classification of evidence: This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia.

GLOSSARY

AD=
Alzheimer disease;
BMDB=
brief mental deterioration battery;
DLB=
dementia with Lewy bodies;
ENF=
epidermal nerve fiber;
FTD=
frontotemporal dementia;
IPD=
idiopathic Parkinson disease;
MIBG=
iodine-123-meta-iodobenzylguanidine;
MMSE=
Mini-Mental State Examination;
NSD=
nonsynucleinopathy dementia;
OH=
orthostatic hypotension;
p-syn=
phosphorylated α-synuclein;
PAF=
pure autonomic failure;
PGP=
protein gene product;
RBD=
REM sleep behavior disorder;
SFN=
small fiber neuropathy;
TH=
tyrosine hydroxylase;
UPDRS=
Unified Parkinson's Disease Rating Scale;
VaD=
vascular dementia;
VIP=
vasoactive intestinal polypeptide

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia following Alzheimer disease (AD) dementia.1,–,4 However, ∼50% of patients with DLB remain undiagnosed, resulting in delayed treatment for their distressing symptoms because of poor sensitivity of clinical criteria when evaluated against autopsy findings in a large number of patients.5,6 The availability of a simple and reliable diagnostic biomarker would improve the rate of clinical diagnosis of patients with DLB, ensuring appropriate management, which is often difficult because of drug intolerance. Phosphorylation of α-synuclein (p-syn) at Ser 129 in skin autonomic nerves demonstrated excellent sensitivity for the in vivo diagnosis of synucleinopathies such as pure autonomic failure (PAF)7 and idiopathic Parkinson disease (IPD).8,–,10 In patients with DLB, total α-syn was mainly tested in the CSF, demonstrating a lower value when compared with different forms of dementia.11 However, other studies have not produced the same results.12 The search for p-syn in autonomic skin nerves in patients with DLB has not been reported to date, although autonomic dysfunctions and cardiac postganglionic sympathetic damage are common in this disorder.1,13,14 As skin innervation includes a large network of autonomic postganglionic nerve fibers, it may represent a useful site for finding a possible DLB biomarker.

This study aimed to investigate whether (1) p-syn deposits in skin nerves could be effective in differentiating DLB from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB.

METHODS

We studied 18 patients with well-characterized DLB fulfilling specific diagnostic criteria (table 1).1 The flow chart to select these patients comprised a clinical evaluation in tertiary university hospitals including a center for cognitive disorders. Twenty-nine patients with dementia (Mini-Mental State Examination [MMSE] corrected15 ≤24) were selected for a possible DLB diagnosis. Twenty-eight of them underwent laboratory tests such as cardiac uptake of iodine-123-meta-iodobenzylguanidine (MIBG) or nigrostriatal dopamine transporter ligand [123I]ioflupane DaTscan. These tests demonstrated cardiac postganglionic sympathetic denervation (MIBG)13 or dopaminergic nigrostriatal denervation (DaTscan)14 supporting the clinical diagnosis of DLB in 17 patients. Another patient who did not consent to these tests was also recruited for this study because of a typical clinical picture including rapid cognitive dysfunction and parkinsonism (developed within 1 year), REM sleep behavior disorder (RBD), fluctuating cognitive dysfunctions, visual hallucinations, and neurogenic orthostatic hypotension (OH) (patient 6 of table 1 reporting clinical and demographic characteristics of recruited patients). The cognitive impairment was also ascertained in all recruited patients by a brief mental deterioration battery (BMDB), a brief neuropsychological test standardized in the Italian population including the following tasks: Rey 15 words (exploring short-term and long-term memory), immediate visual memory, simple analogies, and the time of performance of the visual scanning test (Barrage). The test expresses a global cognitive impairment when the final score is negative (<0).16,17 Patients with DLB presented fluctuating cognition referred by caregivers as pronounced variations in attention and alertness (“periods of daytime drowsiness and lethargy are followed by periods in which the patient appears more wake and active”), considered a core feature of this disorder.1 Neuroleptic sensitivity, described as an acute onset or exacerbation of parkinsonism or impaired consciousness after neuroleptic treatment, characterized the majority of patients. However, these drugs were used in an early phase of the disease when the DLB diagnosis was not suspected. DLB clinical features such as fluctuating cognition, visual hallucinations, sleep disorders (RBD), and neuroleptic sensitivity were mainly anamnestic, although fluctuating cognition and visual hallucinations were confirmed during patients' continuous neurologic monitoring. In addition, 4 patients complaining of RBD underwent polysomnography that confirmed REM sleep without atonia, whereas in the remaining patients, RBD was classified as probable when the bed partner reported a history of frequent clear dream enactment, and possible when behavioral episodes did not clearly involve dream enactment or a bed partner witness was lacking (table 1). Autonomic dysfunctions included (1) neurogenic OH reported in 10 patients objectively defined by a fall in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, without affecting heart rate18 caused by a head-up tilt at 65° (9 patients) or as seen on a measurement within 3 minutes of standing measurement (one patient) or (2) impotence together with generalized sweat loss (patient 3 of table 1) ascertained by finding an absent sympathetic skin response.19 In contrast, 7 patients with DLB did not demonstrate autonomic symptoms or a fall in blood pressure after standing (table 1). None of the patients had a family history for parkinsonism or cognitive impairment.

View this table:
Table 1

Clinical and demographic data

To test the specificity of abnormal α-synuclein deposits in patients with DLB, this analysis was also performed in 23 patients with dementia of different pathogeneses assumed not to have synuclein deposits (nonsynucleinopathy dementia [NSD]). They included 13 patients fulfilling clinical diagnostic criteria for AD dementia confirmed by appropriate CSF amyloid-β1-42, total tau, and phosphorylated tau profiles,20 6 patients with frontotemporal dementia (FTD) associated with C9orf72 repeat expansion21 (4 patients), progranulin (1 patient with exon 10 c.1179+3A>G- NM_002087) or TDP43 (1 patient with exon 6, c.881G>C, p.G294A- NM_007375) mutations,22 and 4 patients with dementia resulting from a cerebrovascular etiology (i.e., vascular dementia [VaD]) such as atherosclerotic stenosis with embolization, atrial fibrillation, hypertension, or hyperlipidemia.23

Specific pharmacologic treatment of patients included l-dopa (13 patients with DLB) associated with dopamine agonists (2 patients with DLB) and a variable combination of cholinesterase inhibitors, memantine, and selective serotonin reuptake inhibitor in all patients with DLB or NSD enrolled in the study.

Serum screening for diabetes, microbiological, autoimmune, paraneoplastic, and thyroid disorders and vitamin B12 deficiency was negative, excluding predisposing causes for peripheral neuropathy. In addition, motor (bilateral tibial nerves) and sensory (bilateral sural nerves) conduction velocity studies were normal in all patients, excluding the possibility of peripheral large nerve fiber involvement. Twenty-five age-matched participants with no deficits during a neurologic examination served as healthy controls for the skin biopsy findings; 15 of these participants were reported in a previous study.9

The skin biopsy method and statistical analysis are reported in the e-Methods at Neurology.org. Skin biopsies were analyzed by 2 authors with expertise in immunofluorescent analysis (V.D. and A.I.) blinded to the clinical classification.

Standard protocol approvals, registrations, and patient consent.

The procedures used were approved by the local Human Ethics Committee and followed the Helsinki Declaration regarding international clinical research involving human beings. All participants gave their written informed consent to be included in the study.

RESULTS

Patients with DLB, patients with NSD, and healthy controls did not demonstrate any significant difference in age or sex. Patients with DLB or NSD had a similar disease duration. A global cognitive impairment was disclosed in DLB and NSD patients without significant differences by MMSE and BMDB scores (table 1). In agreement with the result of these tests, all patients enrolled in the study required a personal caregiver because the cognitive impairment interfered with normal social functions. Two patients with AD dementia and 2 patients with FTD showed slight signs of parkinsonism but as expected the Unified Parkinson’s Disease Rating Scale (UPDRS) score was higher in patients with DLB than in those with NSD (table 1). The onset symptom of DLB included dementia (12 patients) or parkinsonism (6 patients) (table 1). No participants complained of side effects during or after the skin biopsy procedure.

Phosphorylated α-synuclein deposits.

Healthy controls and patients with NSD.

No p-syn was found in any skin sample, even when considering the second skin sample.

Patients with DLB.

Abnormal α-synuclein deposits showed a proximal–distal gradient with the cervical site showing the highest level of deposition (figure 1). Considering both skin samples, the cervical site was positive for p-syn in all patients, whereas the thigh and leg were positive in 94% and 88% of patients, respectively. The first sample analyzed showed abnormal deposits in 95%, 89%, and 76% of patients (cervical, thigh, and leg, respectively) (figure 2A); overall, 75% of skin samples analyzed in the 3 skin sites (i.e., cervical, thigh, and leg) demonstrated p-syn deposition. Abnormal p-syn deposits were more frequent in adrenergic tyrosine hydroxylase (TH)–positive fibers. Accordingly, p-syn was more frequently found in skin structures innervated by adrenergic fibers (arterioles [28% of all analyzed structures], small nerve bundles usually near to arterioles in the deeper layer of dermis [32%], and the arrector pilum muscle [14%]); p-syn was less frequently found in skin structures innervated by cholinergic vasoactive intestinal polypeptide (VIP)–positive fibers, such as the sweat gland (9%). Occasionally, α-synuclein deposits were found in the subepidermal plexus (in one patient) or around hair follicles (in a different patient), whereas no abnormal deposits were found in epidermal nerve fibers.

Figure 1
Figure 1 Phosphorylated α-synuclein (p-syn) deposition in dermal annexes

Confocal microscope (×40) study of p-syn deposits in a dermal arteriole and a sweat gland in different patients with dementia with Lewy bodies. (A) Adrenergic tyrosine hydroxylase (Th)–positive fibers were found around a dermal arteriole (A.a). Most of these fibers demonstrated the presence of p-syn (A.b) as neuritic inclusions (arrowheads) shown by the merged image (A.c). P-syn staining was rarely colocalized in nonadrenergic fibers, which can be seen around arterioles (indicated by arrows). (B) A sweat tubule is encircled by cholinergic vasoactive intestinal polypeptide (VIP)–positive fibers (B.a); some of these fibers also demonstrated p-syn (B.b) deposition as shown in the merged image (B.c).

Figure 2
Figure 2 Percentage of skin samples positive for phosphorylated α-synuclein (p-syn) among different skin sites in patients with dementia with Lewy bodies (DLB)

(A) Positive p-syn staining among proximal and distal skin sites considering the first skin sample analyzed or 2 nearby skin samples. In both cases, patients with DLB showed a proximal–distal gradient with the highest positivity in the cervical site. However, 100% positivity in the cervical site was reached only when 2 nearby skin samples were also considered. (B) Positive p-syn staining among patients with DLB with and without autonomic symptoms. Patients complaining of autonomic symptoms showed 100% positivity with a homogenous distribution among different skin sites considering the 2 nearby skin samples, similar to that previously described in pure autonomic failure. In contrast, patients without autonomic symptoms presented a proximal–distal gradient with 100% positivity only in the cervical site and lower positivity in the thigh (86%) and leg (71%).

Patients with autonomic symptoms showed significantly more skin samples with p-syn deposits than patients without autonomic symptoms (97% vs 71% of analyzed skin samples; p < 0.05) with a similar distribution of affected skin structures (p > 0.1). In addition, patients with autonomic symptoms presented with a more homogenous p-syn distribution in different skin sites (considering both skin samples) than patients without these symptoms who showed a proximal–distal gradient (figure 2B).

The amount of skin samples with p-syn deposits was correlated with the UPDRS score (r = 0.5; p < 0.05) and leg arrector pilum muscle innervation rate (r = −0.6; p < 0.05), whereas no correlation was found with age at onset, disease duration, or MMSE score. Furthermore, no difference was found between patients with dementia or parkinsonism as the onset symptom or between patients receiving or not receiving l-dopa (p > 0.6).

Peripheral innervation.

Healthy controls.

Protein gene product (PGP)–immunoreactive fibers were abundant in the epidermal layer as free-ending fibers, and in the subepidermal plexus, both of which were devoid of VIP or TH fibers, confirming the nociceptive nature of these fibers (figure 3A and table 2). Dermal annexes were richly innervated by PGP fibers (figure 3, B and C, and table 2) and most these fibers were VIP or TH, suggesting they were autonomic fibers. Adrenergic TH fibers were mainly expressed around arterioles and in the arrector pilum muscle running in a longitudinal wavy pattern, whereas autonomic cholinergic VIP fibers were localized around the sweat gland, mainly encircling sweat tubules.

Figure 3
Figure 3 Confocal study of epidermal and autonomic patterns of innervation in patients with dementia with Lewy bodies (DLB) or Alzheimer disease (AD) dementia and a healthy control

Leg epidermal and autonomic innervations disclosed by confocal microscope (×20 in A.a, A.b, A.c, B.a, B.c, and B.c, and ×40 in C.a, C.b, and C.c) in an age-matched participant (A.a, B.a, and C.a) and a patient with AD dementia (A.b, B.b, and C.c) and a patient with DLB (A.c, B.c, and C.c). Nerve fibers are marked in red using a pan-neuronal marker, protein gene product (PGP) 9.5, and collagen (COLL) staining is shown in green. (A) Free-ending PGP immunoreactive epidermal fibers are evident in the epidermis of the control (A.a) whereas the patients with AD dementia (A.b) or DLB (A.c) showed a decrease in the number of such fibers. The basement membrane separating the epidermis from the dermis is marked by collagen staining and indicated with an arrow. (B) Sweat glands show abundant fibers mainly encircling the sweat tubules in the control (B.a) and patient with AD dementia (B.b), whereas a marked reduction in fiber density with an unrecognizable pattern of innervation was found in the patient with DLB (B.c). (C) Arrector pilum muscle shows a rich density of fibers running in a longitudinal and wavy pattern in the control (C.a) and patient with AD dementia (C.b). However, there is a paucity of these fibers with a deranged pattern of innervation in the patient with DLB (C.c).

View this table:
Table 2

Skin somatic and autonomic innervation scores

Patients with NSD.

Skin innervation was relatively preserved with no difference in autonomic innervation between patients and controls (figure 3, B.a and C.a, and table 2) but epidermal nerve fiber (ENF) density was decreased both in the leg (figure 3A.a) and thigh, except for patients with VaD, who demonstrated normal values (9 ± 1 and 13 ± 2/mm, respectively).

Patients with DLB.

Epidermal and autonomic skin innervations were poor, particularly in the leg (figure 3, A.b, B.b, and C.b). The leg innervation scores were decreased compared with healthy controls and patients with NSD (except for the arrector pilum muscle score). Thigh ENFs demonstrated a lower value than those of patients with NSD and healthy controls, whereas autonomic innervation of the thigh was decreased in the patients with DLB when compared with that of the control group. No significant differences between groups were found in the cervical site (table 2). Patients with autonomic symptoms displayed lower leg autonomic innervation scores than patients without autonomic symptoms, both for sweat gland (6% ± 2% vs 7% ± 2%; p = 0.1) and arrector pilum muscle (6% ± 3% vs 9% ± 2%; p = 0.05) without a difference in ENFs (5 ± 3/mm and 4 ± 1/mm; p = 0.5); innervation scores did not differ between the thigh and cervical sites of these 2 DLB subgroups. No differences were found between patients with different onset symptoms or those receiving l-dopa treatment (p > 0.3). Finally, innervation scores were not correlated with age at onset, disease duration, UPDRS, or MMSE scores.

DISCUSSION

The main results of our study indicate that (1) p-syn in autonomic skin nerves is a sensitive biomarker for DLB, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger more representative sample; (2) patients with DLB with autonomic symptoms showed widespread neuritic synuclein inclusions without any difference between different skin sites; and (3) skin autonomic neuropathy is part of the pathologic picture of DLB and may contribute to autonomic symptoms.

DLB shares common clinical and neuropsychological features with other types of dementia, such as AD dementia, making it difficult to differentiate in clinical practice. For this reason, readily available DLB biomarkers would represent an important advance.

This study used skin biopsy to explore the involvement of peripheral nerves in DLB. As skin biopsy is not expensive (the estimated cost for each skin site is ∼€50), easy to perform, and entails only minor discomfort for the patient, it could potentially become more readily accessible for the diagnosis of DLB when compared with other proposed techniques. It is a safe procedure and side effects such as bleeding or local infection are rare, as confirmed by this study. However, the staining procedure is rather complex and requires an expert technician. Deposits of p-syn, considered the pathologic form of α-synuclein,24,25 were found in autonomic skin nerve fibers in all patients with DLB but never in patients with NSD. DLB and NSD patient groups were matched for age, sex, disease duration, and MMSE score, excluding the possible influence of these factors on the results. Our data demonstrated that p-syn deposits in skin nerves are a promising and highly sensitive DLB biomarker that may accurately distinguish DLB from different dementia subtypes. Therefore our data suggest the use of skin biopsy as a diagnostic tool for in vivo DLB diagnosis, thereby helping to improve the general clinical management of this disorder. The study is rated as Class III evidence because of the case-control design requiring the absence of diagnostic uncertainty regarding the presence or absence of DLB in the patients enrolled (i.e., spectrum bias). An additional important implication of our study is the possibility to select patients for potential new synuclein-based neuroprotective treatments. As previously described in IPD,8,9 the highest p-syn deposition was found in the proximal cervical site when 2 close skin samples were analyzed. However, patients with DLB with autonomic symptoms displayed a widespread positivity without differences among different skin sites, similar to the pattern described in PAF.7 These data may have important practical implications suggesting that the choice of biopsy skin site is irrelevant in patients with DLB with autonomic symptoms. A remarkable aspect of the current data is the higher amount of p-syn in skin samples analyzed in the patients with DLB (75%) than previously reported in IPD (49%) using the same method of analysis.9 This finding suggests a more widespread involvement of autonomic nerves in DLB and explains the higher frequency of orthostatic hypotension in DLB than IPD.26 The correlation between the amount of p-syn deposition and UPDRS indicates that peripheral and motor involvement progress in a similar fashion during the course of DLB, unlike the pattern seen in IPD.8,9 Furthermore, our data show that the onset symptom of DLB (i.e., dementia vs parkinsonism) did not influence the degree of peripheral nerve involvement.

SFN involving epidermal and autonomic fibers without evidence of large nerve fiber involvement was found in the patients with DLB. The absence of acquired causes of peripheral nerve fiber damage and the correlation between p-syn deposition and leg arrector pilum muscle innervation rate suggests a pathogenetic role for abnormal α-synuclein deposits in small nerve fiber damage in DLB as previously described in IPD.8,9 Accordingly, experimental studies have shown that pathologic accumulation of α-synuclein led to selective decreases in synaptic proteins, neuronal connectivity, and neuron death.25 Furthermore, our data underlined that autonomic dysfunction was correlated with the skin autonomic denervation and more widespread p-syn deposits, suggesting that postganglionic autonomic nerve fiber involvement contributes to autonomic symptoms in DLB. Consequently, skin sympathetic activity and cardiovascular activity may be frequently affected in DLB,27 and cardiac innervation as evaluated by MIBG identifies abnormal sympathetic innervation in the majority of patients with DLB who are investigated.13 However, autonomic dysfunction may also be due to abnormalities of the central autonomic network since medullary regions controlling sympathetic output28 and baroreceptor reflex29 dysfunction have both been described in patients with DLB. It remains to be established why patients with DLB did not complain of neuropathic pain instead of decreased ENFs, which were not explained by the p-syn deposits never found in the epidermal fibers.

Interestingly, NSDs except for VaD (i.e., AD dementia and FTD) showed lower leg and thigh ENFs than in healthy controls. AD dementia and FTD are both characterized by the intraneural deposition of abnormal proteins, such as phosphorylated tau or TDP43, that demonstrate seeding properties and are involved in the pathogenetic mechanisms of these disorders.30 Thus, skin epidermal denervation may be due to the abnormal deposition of proteins other than synuclein. However, a targeted study searching for abnormal deposits in skin nerves in these disorders is needed to clarify this point.

This study presents the following limitations: (1) the lack of a definitive autopsy-based diagnosis in recruited patients. This makes it difficult to differentiate in vivo DLB from AD dementia, even in highly specialized centers,27 because of the commonly found mixed cerebral pathology between α-syn and β-amyloid. However, the accuracy of the diagnosis in our patients was supported by specific tests (i.e., MIBG, DaTscan, CSF analysis) or genetic mutations. In addition, the validity of the proposed diagnostic method was highlighted by a clear-cut difference in autonomic nerve p-syn deposits between patients with DLB and those with AD dementia or other forms of dementia instead of a possible mixed cerebral pathology31; (2) the exclusion of patients with normal laboratory tests (i.e., MIBG and DaTscan) preventing the analysis of patients with DLB with an unclear diagnosis. This approach was justified by the suboptimal specificity of the current DLB clinical diagnostic criteria,5,6,32 which may not guarantee the exclusion of different disorders in the DLB diagnosis. An additional future study aims to analyze patients with DLB with an unclear diagnosis. This only makes sense when the specificity and sensitivity of skin p-syn deposits have been established in well-defined patients with DLB; (3) many recruited patients showed atypical DLB findings, such as a longer disease duration (i.e., cases 2 and 10 of table 1), or were relatively young with a disease onset before the age of 65 years; (4) recruited patients with AD dementia did not represent a typical AD dementia population. They showed young-onset AD dementia with a mean age of 63 years. In addition, patients with diabetes were excluded because of the frequent small fiber neuropathy induced by diabetes. Additional studies are needed to establish if the results of the current study may be generalized to the AD dementia population.

AUTHOR CONTRIBUTIONS

V. Donadio: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, recruitment of patients. A. Incensi: study concept and design, drafting/revising the manuscript, analysis and interpretation of data. G. Rizzo: drafting/revising the manuscript, study concept and design, analysis and interpretation of data. S. Capellari: analysis and interpretation of data, recruitment of patients. R. Pantieri: analysis and interpretation of data, recruitment of patients. M. Stanzani Maserati: analysis and interpretation of data, recruitment of patients. G. Devigili: analysis and interpretation of data, recruitment of patients. R. Eleopra: analysis and interpretation of data, recruitment of patients. G. Defazio: analysis and interpretation of data, recruitment of patients. F. Montini: analysis and interpretation of data. A. Baruzzi: analysis and interpretation of data. R. Liguori: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, study supervision, recruitment of patients.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

V. Donadio reports a CSL Behring travel grant for the 2016 Italian Society of Neurology meeting. A. Incensi, G. Rizzo, S. Capellari, R. Pantieri, M. Stanzani Maserati, G. Devigili, R. Eleopra, G. Defazio, F. Montini, A. Baruzzi, and R. Liguori report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

ACKNOWLEDGMENT

The authors thank Anne Collins for English editing and Massimo Armaroli and Davide Cavalletti for technical collaboration.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Editorial, page 310

  • Received September 14, 2016.
  • Accepted in final form March 22, 2017.

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