Abnormal dopamine transporter imaging in pure autonomic failure: a potential biomarker of central nervous system involvement.

BACKGROUND AND PURPOSE: Pure autonomic failure (PAF) is a rare progressive neurodegenerative disease characterized by neurogenic orthostatic hypotension at presentation, without other neurological abnormalities. Some patients may develop other central neurological features indicative of multiple system atrophy or a Lewy body disorder. There are currently no biomarkers to assess possible central nervous system involvement in probable PAF at an early stage. A possibility is to evaluate the nigrostriatal dopaminergic degeneration by imaging of dopamine transporter with DaTscan brain imaging. The objective was to evaluate subclinical central nervous system involvement using DaTscan in PAF. METHODS: We retreospectively reviewed pure autonomic failure patients who were evaluated at the Autonomic Unit between January 2015 and August 2021 and underwent comprehensive autonomic assessment, neurological examination, brain magnetic resonance imaging and DaTscan imaging. DaTscan imaging was performed if patients presented with atypical features which did not meet the criteria for Parkinson's disease or multiple system atrophy or other atypical parkinsonism. RESULTS: In this cohort, the median age was 49.5 years at disease onset, 57.5 years at presentation, and the median disease duration was 7.5 years. Five of 10 patients had an abnormal DaTscan without neurological features meeting the criteria of an alternative diagnosis. Patients with abnormal DaTscan were predominantly males, had shorter disease duration and had more severe genitourinary symptoms. DISCUSSION: Degeneration of nigrostriatal dopaminergic neurons measured using DaTscan imaging can present in patients with PAF without concurrent signs indicating progression to widespread α-synucleinopathy. It is advocated that DaTscan imaging should be considered as part of the workup of patients with emerging autonomic failure who are considered to have PAF.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Neurosarcoidosis with chronic cough and Horner's syndrome.

A 62-year-old man attended ophthalmology for a simple ptosis repair. He had a chronic cough, a Horner's syndrome with post-gustatory hyperhidrosis. He was referred to the respiratory and neurology teams. MR scan of his head and neck found evidence of multifocal disease at the skull base and carotid canal, and further tests identified additional deposits in the hilar lymph nodes, heart and sacrum. A transbronchial biopsy confirmed the diagnosis of sarcoidosis. His symptoms and imaging responded well to corticosteroids, but he still undergoes regular imaging. We discuss the features of Horner's syndrome, and the autonomic associations of a chronic cough.

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy.

OBJECTIVE: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. METHODS: We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. RESULTS: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. INTERPRETATION: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

Anti-N-methyl-D-aspartate receptor antibodies: a potentially treatable cause of encephalitis in the intensive care unit.

OBJECTIVE: To report the occurrence of an unusual neurologic disorder requiring admission to the intensive care unit. DESIGN: Analysis of an observational cohort study of 31 patients with encephalitis admitted over a 4-yr period. SETTING: Neurologic intensive care unit in a tertiary referral center. PATIENTS: We identified N-methyl-D-aspartate receptor antibodies in six patients (two male and four female). All seropositive patients presented with a psychiatric prodrome, before developing seizures and obtundation requiring intensive care unit admission. They exhibited limb and truncal stereotypies and orofacial dyskinesias upon weaning sedation. Two patients had ovarian tumors. INTERVENTIONS: Patients were treated with sedation, antiepileptic drugs, and immunotherapy. One patient received a magnesium infusion and ketamine. MEASUREMENTS AND MAIN RESULTS: N-methyl-D-aspartate receptor antibodies were identified in serum samples by an immunofluorescent cell-based assay. Three patients made a good but slow recovery; two were left with severe neurologic deficits; and one died after return to the referring hospital. These patients accounted for approximately 20% of all patients admitted with encephalitis to this referral center. CONCLUSIONS: N-methyl-D-aspartate receptor antibodies should be tested in patients with hyperkinetic encephalitis and neuropsychiatric prodrome admitted to the intensive care unit. The disorder is probably not rare and is potentially treatable.

Fatal autonomic failure due to premanifesting Parkinson's disease only diagnosed at autopsy.

A 46-year-old male had 11-year history of cryptic autonomic dysfunction. He developed a fatal autonomic failure with diffuse hypoxic brain injury. Histology examination of medulla oblongata and the celiac ganglion revealed many α-synuclein immunoreactive Lewy bodies confirming the diagnosis of premanifesting Parkinson's disease (PD). PNS involvement in PD is underappreciated.

Regional gray matter atrophy in early primary progressive multiple sclerosis: a voxel-based morphometry study.

BACKGROUND: Gray matter (GM) atrophy has been reported in multiple sclerosis (MS). However, little is known about its regional distribution. OBJECTIVE: To investigate the regional distribution of GM atrophy in clinically early primary progressive MS (PPMS). DESIGN AND PATIENTS: Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied. All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only. Magnetic resonance images underwent an optimized voxel-based morphometric analysis that segments magnetic resonance data volumes in a normalized space and quantifies tissue atrophy on a voxel-by-voxel basis. A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions. A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study. RESULTS: At baseline, patients with PPMS displayed bilateral thalamic atrophy compared with controls. In addition, a significant association between lesion load and decreased GM volume was found for the thalami. Loss of GM in the putamen, caudate, thalami, and cortical and infratentorial areas was observed in patients after 1 year of follow-up. CONCLUSIONS: Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to neurodegeneration. Cortical and infratentorial atrophy developed as the disease evolved.

Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study.

We have recently reported brain atrophy in the early stages of primary progressive multiple sclerosis (PPMS), affecting both grey and white matter (GM and WM). However, to date no clinical or radiological predictors of GM and WM atrophy have been identified. The aim was to investigate short-term changes in GM and WM volumes and to assess the predictive value of demographic, clinical and radiological variables in order to gain a better understanding of the pathological substrate underlying these changes. Thirty-one subjects with PPMS within 5 years of symptom onset were studied at baseline and after 1 year. At baseline, patients underwent neurological examination and were scored on the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite. They had 3D inversion-prepared fast spoiled gradient recalled (FSPGR), dual-echo and triple-dose post-contrast T1-weighted spin echo MRI scans. Proton density and enhancing lesion loads were determined. The 3DFSPGR sequence was repeated after 1 year and brain volume changes were calculated using two techniques, SPM99 (statistical parametric mapping) and SIENA (structural image evaluation, using normalization, of atrophy). Stepwise linear regression models were applied to baseline variables to identify independent predictors of atrophy development. Using SPM99, a decrease in brain parenchymal fraction (-1.03%; P < 0.001) and GM fraction (-1.49%; P < 0.001) was observed. The number of enhancing lesions independently predicted decrease in brain parenchymal fraction (P = 0.019) and decrease in WM fraction (P = 0.002). No independent predictors of GM fraction decrease were found. A mean brain volume change of -0.63% (range -4.27% to +1.18%; P = 0.002) was observed using SIENA, which was independently predicted by EDSS (P = 0.004). Global and GM atrophy can be detected over a 1-year period in early PPMS. The former may be predicted by the degree of inflammation, while the latter seems to be independent of it. SIENA and SPM-based methods appear to provide complementary information.

Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis.

OBJECTIVES: The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol. PATIENTS AND METHODS: In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent). RESULTS: By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS). CONCLUSION: We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

Amino acids in a targeted versus a non-targeted metabolomics LC-MS/MS assay. Are the results consistent?

BACKGROUND: The results of plasma amino acid patterns in samples from kidney transplant patients with good and impaired renal function using a targeted LC-MS/MS amino acid assay and a non-targeted metabolomics assay were compared. METHODS: EDTA plasma samples were prospectively collected at baseline, 1, 2, 4 and 6months post-transplant (n=116 patients, n=398 samples). Each sample was analyzed using both a commercial amino acid LC-MS/MS assay and a non-targeted metabolomics assay also based on MS/MS ion transitions. The results of both assays were independently statistically analyzed to identify amino acids associated with estimated glomerular filtration rates using correlation and partial least squares-discriminant analysis. RESULTS: Although there was overlap between the results of the targeted and non-targeted metabolomics assays (tryptophan, 1-methyl histidine), there were also substantial inconsistencies, with the non-targeted assay resulting in more "hits" than the targeted assay. Without further verification of the hits detected by the non-targeted discovery assay, this would have led to different interpretation of the results. There were also false negative results when the non-targeted assay was used (hydroxy proline). Several of said discrepancies could be explained by loss of sensitivity during analytical runs for selected amino acids (serine and threonine), retention time shifts, signals above the range of linear detector response and integration of peaks not separated from background and interferences (aspartate) when the non-targeted metabolomics assay was used. CONCLUSIONS: Whenever assessment of a specific pathway such as amino acids is the focus of interest, a targeted seems preferable to a non-targeted metabolomics assay.

Quality improvement: audio-visual tools are a valuable supplement when obtaining consent for lumbar punctures.

Neurological conditions present a challenge when obtaining consent for lumbar punctures (LPs), as patients often have -visual, hearing or cognitive impairments. The aim of this -project was to improve the quality of the consent process for LPs. Surveys of doctors and patients suggested there was scope to standardise and improve information provided during the consent process. A patient information video was -developed using online software and shown to patients using tablet -computers. Patient surveys were distributed to re-assess the quality of the process for obtaining consent. There was a -significant improvement (p=0.031) in the median response score after the video was presented to the same group of patients. The use of patient information videos -significantly improves understanding and recall of the procedure, and -satisfaction with the consent process. In conclusion, audio--visual tools are a valuable tool for standardising and -improving the process of gaining consent for LPs.

Enteric-coated mycophenolate sodium for transplant immunosuppression.

PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, monitoring, and dosage and administration of enteric-coated (EC) mycophenolate sodium are reviewed. SUMMARY: EC mycophenolate sodium is the EC salt form of mycophenolic acid (MPA), the active component of the pro-drug, mycophenolate mofetil. EC mycophenolate sodium was developed to reduce the upper-gastrointestinal (GI) effects of mycophenolate mofetil. Unlike oral mycophenolate mofetil, which releases MPA in the stomach, EC mycophenolate sodium releases MPA in the small intestine. The absolute bioavailability of EC mycophenolate sodium is 72%. MPA undergoes hepatic metabolism by glucuronyl transferase to the inactive mycophenolic acid glucuronide (MPAG), the predominant metabolite. The majority of an administered dose of EC mycophenolate sodium is found as MPAG in the urine. The mean terminal half-life of MPA ranges from 8 to 16 hours. EC mycophenolate sodium and mycophenolate mofetil have equivalent mechanisms of action and drug interaction profiles. Thus far, EC mycophenolate sodium has demonstrated similar efficacy and safety to mycophenolate mofetil in two Phase III clinical trials of adult renal transplant recipients. One study demonstrated improved health-related quality of life in patients switched from mycophenolate mofetil to EC mycophenolate sodium. Ongoing Phase IV studies are trying to further determine advantages of the EC product. CONCLUSION: EC mycophenolate sodium is a safe and effective immunosuppressive agent approved for use in the prevention of acute rejection after renal transplantation. It offers an excellent addition to the current armamentarium of immunosuppressive drugs for transplant immunosuppression.

Cyclosporine-sparing effects of daclizumab in renal allograft recipients.

PURPOSE: The safety and efficacy of reduced-dose cyclosporine in renal transplantation were studied. METHODS: Patients receiving their first renal transplant received daclizumab 1 mg/kg every 14 days for a total of five doses, mycophenolate mofetil 1 g twice daily, corticosteroids per the institution's routine protocol, and half of the institution's usual cyclosporine dosage. Trough cyclosporine concentrations targeted were half the customary goals, or 150-200 ng/mL for the first six months and 125-175 ng/mL for months 7-12. A retrospective control group included 15 matched patients who had received full-dose cyclosporine, mycophenolate mofetil, and corticosteroids without daclizumab induction therapy. RESULTS: Thirty patients were studied (15 in each group). At baseline, the control group had a significantly lower panel reactive antibody level (0.13%) than the treatment group (5.2%) (p = 0.01). Mean cyclosporine concentrations at 1, 6, and 12 months were significantly lower in the treatment group (p < 0.0001). No patient in either group had an acute rejection episode. All control patients had cyclosporine-associated adverse effects, compared with seven treatment-group patients (p = 0.0022). The treatment group had 19 infections, versus 29 in the control group (p = 0.39). Three study-group patients and eight control patients required a fine-needle aspiration or biopsy (p = 0.13). CONCLUSION: Among kidney transplant patients at low risk of acute rejection, those treated with daclizumab and low-dose cyclosporine had an identical rate of acute rejection (none) and fewer cyclosporine-associated adverse effects compared with patients in a retrospective control group who received full-dose cyclosporine without daclizumab.

Magnetic resonance imaging in primary progressive multiple sclerosis.

Ten to fifteen percent of patients with multiple sclerosis (MS) have a condition that is progressive from onset without a preceding relapsing-remitting phase: this is known as primary progressive multiple sclerosis (PPMS). Patients with PPMS tend to be older, often present with motor symptoms and, in contrast to relapsing MS, are as likely to be male as female. The conventional magnetic resonance imaging (MRI) characteristics of PPMS include a tendency to lower lesion loads and lower rate of new lesion formation. In common with relapsing MS, the relation between conventional MRI abnormalities and clinical condition is poor. Studies using newer MRI techniques, such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI), have also been carried out. These techniques are sensitive to a wider range of abnormalities within tissue, and their increased pathological specificity may be helpful in clarifying the underlying pathology of the condition.

Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis.

BACKGROUND: There is little information available on grey and white matter (GM and WM) atrophy in primary progressive multiple sclerosis (PPMS) and on their relationships with clinical and other magnetic resonance imaging (MRI) measures. AIM: To evaluate disease progression in the early phase of PPMS, focusing on axonal loss as assessed by volumetric MRI measures of WM and GM, and to determine their relationships with clinical outcomes and lesion load measures. METHODS: Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied. Three-dimensional brain scans were acquired and segmented into WM, GM, and cerebrospinal fluid (CSF) using SPM99. Brain parenchymal (BPF), WM (WMF), and GM fractions (GMF) normalized against total intracranial volumes were estimated. T2-weighted (T2) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients. RESULTS: There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores. BPF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T2 loads were only significant for BPF and WMF. CONCLUSIONS: Brain atrophy is seen in the early stages of PPMS and affects both GM and WM. WM atrophy appears more closely related to clinical outcome and WM focal damage than GM atrophy in this patient group.