Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified.

Stridor in multiple system atrophy: Consensus statement on diagnosis, prognosis, and treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.

Observing movement disorders: best practice proposal in the use of video recording in clinical practice.

Clinical evaluation is of utmost importance in the semeiological description of motor disorders which often require video recording to highlight subtle signs and their subsequent evolution. After reviewing 1858 video recordings, we composed a suitable list of video-documentation maneuvers, classified semeiologically in the form of a "video recording protocol", to guarantee appropriate documentation when filming movement disorders. Aware that our proposed filming protocol is far from being exhaustive, by suggesting a more detailed documenting approach, it could help not only to achieve a better definition of some disorders, but also to guide neurologists towards the correct subsequent examinations. Moreover, it could be an important tool for the longitudinal evaluation of patients and their response to therapy. Finally, video recording is a powerful teaching tool as visual teaching highly improves educational training.

The CSF neurofilament light signature in rapidly progressive neurodegenerative dementias.

BACKGROUND: Neurofilament light chain protein (NfL) is a surrogate biomarker of neurodegeneration that has never been systematically tested, either alone or in combination with other biomarkers, in atypical/rapidly progressive neurodegenerative dementias (NDs). METHODS: Using validated, commercially available enzyme-linked immunosorbent assay kits, we measured cerebrospinal fluid (CSF) NfL, total tau (t-tau), phosphorylated tau, and ß-amyloid 42 in subjects with a neuropathological or clinical diagnosis of prion disease (n = 141), Alzheimer's disease (AD) (n = 73), dementia with Lewy bodies (DLB) (n = 35), or frontotemporal lobar degeneration (FTLD) (n = 44). Several cases with an atypical/rapidly progressive course were included in each group. We evaluated the diagnostic accuracy of every CSF biomarker and their combinations by ROC curve analyses. RESULTS: In each patient group CSF NfL showed higher levels than in control subjects, reaching the highest values in those with Creutzfeldt-Jakob disease (CJD). In the latter, NfL showed a divergent, subtype-specific correlation with t-tau, depending on the degree of subcortical involvement and disease duration. Most significantly, patients with classic sporadic CJD (sCJD) MM1 showed a significantly lower concentration of CSF NfL than those with sCJD MV2, despite the much higher t-tau levels and the more rapid clinical course. High NfL levels were also detected in most atypical CJD cases, showing a disease duration longer than 2 years and/or borderline/negative results in other CSF assays (e.g., 14-3-3, t-tau, and prion real-time quaking-induced conversion). Rapidly progressive/atypical cases showed higher NfL levels than typical patients in FTLD, but not in AD or DLB. NfL showed accuracy similar to that of t-tau in discriminating CJD from other NDs, but it had higher efficacy in differentiating atypical forms, especially in regard to Alzheimer's disease. CONCLUSIONS: The present data indicate that CSF NfL and t-tau levels reflect distinct pathophysiological mechanisms of neurodegeneration and support the clinical use of NfL as a fast screening biomarker for the differential diagnosis of atypical/rapidly progressive NDs.

Not only limbs in atypical restless legs syndrome.

Restless legs syndrome (RLS) typically affects the limbs, but the involvement of other body parts has also been reported. In this essay, we critically review all literature reports of atypical RLS cases with unusual localizations. Applying the updated diagnostic criteria of the International restless legs syndrome study group (IRLSSG), which also consider symptoms localized outside of the lower limbs, a few of these atypical cases reported in the previous literature resulted in a definitive diagnosis of RLS. We also discuss the relationship between RLS and burning mouth syndrome (BMS) or restless genital syndrome (RGS). We conclude clinical sleep specialists should be aware of unusual RLS localizations because they respond to the usual treatment for RLS. All the IRLSSG diagnostic criteria should be applied in every suspected case, in order to establish a correct diagnosis of this disabling but treatable condition.

Modulation of the Muscle Activity During Sleep in Cervical Dystonia.

Introduction: Impaired sleep has been reported as an important nonmotor feature in dystonia, but so far, self-reported complaints have never been compared with nocturnal video-polysomnographic (PSG) recording, which is the gold standard to assess sleep-related disorders. Methods: Twenty patients with idiopathic isolated cervical dystonia and 22 healthy controls (HC) underwent extensive clinical investigations, neurological examination, and questionnaire screening for excessive daytime sleepiness and sleep-related disorders. A full-night video PSG was performed in both patients and HC. An ad hoc montage, adding electromyographic leads over the muscle affected with dystonia, was used. Results: When compared to controls, patients showed significantly increased pathological values on the scale assessing self-reported complaints of impaired nocturnal sleep. Higher scores of impaired nocturnal sleep did not correlate with any clinical descriptors but for a weak correlation with higher scores on the scale for depression. On video-PSG, patients had significantly affected sleep architecture (with decreased sleep efficiency and increased sleep latency). Activity over cervical muscles disappears during all the sleep stages, reaching significantly decreased values when compared to controls both in nonrapid eye movements and rapid eye movements sleep. Conclusions: Patients with cervical dystonia reported poor sleep quality and showed impaired sleep architecture. These features however cannot be related to the persistence of muscle activity over the cervical muscles, which disappears in all the sleep stages, reaching significantly decreased values when compared to HC.

Scleral Flap-Everting Suture for Glaucoma-filtering Surgery.

PURPOSE: Most filtering surgery failures develop in the early postoperative period. The possibility to apply an everting suture to lift the flap in the postoperative period and reduce the possibility of an early failure is reported. METHODS: Surgical technique description. RESULTS: An everting suture may be applied to the scleral flap in all types of ab externo anterior filtering surgeries. It could allow the surgeon to lift the scleral flap after the removal of the releasable sutures. CONCLUSIONS: The use of an everting suture would eliminate the need to use procedures for lifting the flap that involve puncturing the conjunctiva and may cause hemorrhages and leakage and promote scarring.

Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease.

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (ΔTapmax %) and the area under the tapping effect-time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, ΔTapmax % <20% and AUCTap <1900 [(tapping/min)·min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD.

Trabeculectomy Versus EX-PRESS Shunt Versus Ahmed Valve Implant: Short-term Effects on Corneal Endothelial Cells.

PURPOSE: To evaluate short-term changes in corneal endothelial cells after trabeculectomy, EX-PRESS device implantation, and Ahmed valve implantation for the treatment of primary open-angle glaucoma. DESIGN: Prospective, interventional, comparative case series with contralateral eye control study. METHODS: We prospectively evaluated the changes in number, density, and shape of the corneal endothelium cells in 128 eyes of 64 patients divided into 3 groups depending on the treatment received. Corneal specular microscopy was performed with a noncontact specular microscope preoperatively and at 1 and 3 months after surgery. The changes at each time point were compared with those of the control group, which consisted of 32 contralateral glaucomatous eyes receiving antiglaucoma medications without any previous glaucoma surgery. RESULTS: In the subjects who underwent trabeculectomy, corneal endothelial cell density (ECD) significantly decreased by 3.5% (P = .012, paired t test) at 1 month and 4.2% (P = .007) at 3 months after surgery, compared to the baseline values. In the Ahmed valve group ECD did not change at 1 month after surgery and had a significant 3.5% decrease at 3 months (P = .04). In the patients who underwent EX-PRESS implantation and in the control group ECD did not change either at 1 month or at 3 months after surgery (P > .05). CONCLUSIONS: EX-PRESS shunt, compared to trabeculectomy and Ahmed valve, seems to be a safer procedure regarding the risk of endothelial cell loss. For this reason, it may be the treatment of choice in patients with significant low corneal ECD before surgery or other risk factors for corneal damage.

Skin biopsy and I-123 MIBG scintigraphy findings in idiopathic Parkinson's disease and parkinsonism: a comparative study.

BACKGROUND: (123) I-meta-iodobenzylguanidine ((123) I-MIBG) myocardial scintigraphy is considered reliable in differentiating idiopathic Parkinson's disease (IPD) from other parkinsonisms, but it is biased by pharmacological treatments. Skin biopsy is not influenced by therapy and has disclosed skin denervation in IPD. Our aims were to compare (123) I-MIBG scintigraphy and skin biopsy findings in IPD and parkinsonisms to (1) verify whether myocardial and skin denervations are linked; (2) explore the simultaneous extent of the autonomic dysfunction. METHODS: We studied 22 IPD and 11 parkinsonism patients by means of (123) I-MIBG scintigraphy and skin biopsies. RESULTS: In the IPD group, both (123) I-MIBG scintigraphy and skin biopsy results were abnormal in 91% of patients, showing concordance in 82% of cases. In parkinsonisms, results of both tests were normal in all patients. CONCLUSION: (1) Skin biopsy and (123) I-MIBG scintigraphy provide comparable results; (2) in IPD, autonomic dysfunctions are often simultaneously widespread at cardiac and skin branches. © 2015 International Parkinson and Movement Disorder Society.

Cardiovascular autonomic testing performed with a new integrated instrumental approach is useful in differentiating MSA-P from PD at an early stage.

OBJECTIVE: To evaluate whether a battery of cardiovascular autonomic tests (Ewing's battery, EB) performed with a new integrated instrumental approach is useful in differentiating multiple system atrophy with predominant parkinsonism (MSA-P) from Parkinson's disease (PD) at an early stage. METHODS: We retrospectively analyzed EB tests of all the patients (n = 99) with a parkinsonian syndrome referred to our clinic who performed EB during the first diagnostic workup and were subsequently evaluated at least once a year until a final diagnosis of MSA-P (n = 34) or PD (n = 65). Thirty-eight controls matched for age and sex were included. EB consisted of head-up tilt test (HUTT), Valsalva manoeuvre (VM), deep breathing, and sustained handgrip whose correct execution and results were checked and obtained automatically. Results were compared between groups. Discriminant analysis was performed to identify MSA-P or PD patients. RESULTS: Orthostatic hypotension was found in 22 MSA-P and 3 PD patients. Cardiovascular reflexes indices were significantly more affected in MSA-P compared to PD and controls. EB presented a 91% sensitivity and 94% specificity in the differentiation of MSA-P and PD. HUTT + VM presented a 91% sensitivity and 92% specificity. CONCLUSIONS: Our results suggest that EB or HUTT + VM performed with an integrated instrumental approach and analyzed with the discriminant procedure may distinguish MSA-P from PD at an early stage and might improve the accuracy of current diagnostic criteria. However, a validation in separate samples and prospective studies is needed.

Malignant glaucoma-like syndrome after EX-PRESS filtration surgery.

PURPOSE: To report a case of postsurgical shallow anterior chamber and elevated intraocular pressure (IOP) simulating malignant glaucoma. METHODS: A 20-year-old woman underwent EX-PRESS® device implant for treatment of primary open-angle glaucoma. RESULTS: Postoperative examination showed a shallow anterior chamber, the EX-PRESS® device embedded in the iris, an IOP of 28 mm Hg, and an annular detachment of the choroid ciliary body, suggesting hyperfiltration followed by EX-PRESS® blockage. The anterior chamber was restored using an ophthalmic viscoelastic and an additional suture was applied ensuring the scleral flap. The IOP progressively decreased in the following days and the anterior chamber remained deep and stable. New ocular ultrasonography showed complete resolution of the ciliary body detachment 15 days after surgery. CONCLUSIONS: After glaucoma surgery, not every patient with shallow anterior chamber and normal or high IOP necessarily has a ciliary block glaucoma. In our case, hyperfiltration led to choroidal expansion, shallow anterior chamber, obstruction of the EX-PRESS®, and secondary blockage of outflow. The differential diagnosis is important in order to avoid further invasive procedures (i.e., lensectomy or vitrectomy).

Primary familial brain calcification: Genetic analysis and clinical spectrum.

BACKGROUND: Primary familial brain calcification (PFBC) is a rare autosomal dominant disorder with bilateral calcification of basal ganglia and other cerebral regions, movement disorders, and neuropsychiatric disturbances. So far, three causative genes have been discovered: SLC20A2, PDGFRB and PDGFB, accounting for approximately 50% of cases. METHODS: Seven unrelated families with primary brain calcification were recruited to undergo clinical and genetic analysis, including Sanger sequencing of SLC20A2, PDGFRB, and PDGFB, and copy number analysis of SLC20A2. RESULTS: Mutations in SLC20A2 have been detected in three families: p.Glu368Glyfs*46, p.Ser434Trp, and p.Thr595Met. Intrafamilial phenotype variability has been observed. In spite of this, we found similar neuroimaging pattern among members of the same family. CONCLUSIONS: This molecular analysis expands the mutational spectrum of SLC20A2, which remains the major causative gene of primary familial brain calcification, and suggests the existence of disease-causing mutations in at least another, still unknown gene.

Arylsulphatase A activity in familial parkinsonism: a pathogenetic role?

Cellular mechanism leading to Parkinson Disease (PD) is still unknown, but impairment of lysosomal degradation of aberrant proteins seems to play a crucial role. The most known lysosomal disease associated with PD is Gaucher Disease. However, actually a number of different lysosomal disorders have been linked with PD. We report three families with Arylsulphatase A partial deficit in which we can find a high recurrence of parkinsonism among the siblings. The pedigree members show as well some atypical signs and symptoms among the PD spectrum features. Arylsulphatase A plays a crucial role in protein degradation. Even if a possibly casual association cannot be excluded, it can be speculated that Arylsulphatase A partial deficit can act as a cofactor for neurodegeneration in subjects with other genetic or environmental predispositions to PD or to other neurodegenerative disease.

Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease.

OBJECTIVE: To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD. METHODS: Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein. RESULTS: Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation. CONCLUSIONS: The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue?

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 ± 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype.