Autonomic function in sporadic and familial ALS type 8 Pazian Martins, Melina; González-Salazar, Carelis; de Lima, Fabricio Diniz ...
Clinical neurophysiology,
November 2023, 2023-11-00, 20231101, Volume:
155
Journal Article
Peer reviewed
•Autonomic function is impaired in fALS8 and involves parasympathetic and sympathetic divisions.•sALS and fALS8 present similar neurophysiological abnormalities but different autonomic ...complaints.•Sudomotor compromise in sALS and fALS8 is mediated by a small fiber, possibly length-dependent, autonomic neuropathy.
To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8).
We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant.
SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs.
Dysautonomia – cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group.
Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.
Amyotrophic Lateral Sclerosis (ALS) is the most relevant motor neuron disease in adults and characterized by widespread weakness. Despite frequent bulbar involvement, little is known about clinical ...and electrophysiological changes in the larynx in patients with ALS. The objective of this study was to evaluate the frequency and pattern of involvement of laryngeal muscles in ALS and its functional relevance. In addition, we assessed whether laryngeal EMG (LEMG) would increase the diagnostic sensitivity for ALS.
Fourteen ALS patients, 13 with spinal onset and 1 with bulbar onset, underwent nasofibroscopy (NF) followed by LEMG, in which a concentric needle was used to evaluate the thyroid-arytenoid (TA), lateral crico-arytenoid (CAL), posterior crico-arytenoid (CAP) and crico-thyroid (CT) muscles, at rest and during activation. After LEMG, resting and activation of the genioglossus and masseter muscles were also studied using the same concentric needle.
The mean age of the patients was 48.5 years and there were 6 women. The procedures were fast (30 min on average) and uneventful. Thirteen patients presented neurogenic changes in at least one laryngeal muscle. A single patient had entirely normal LEMG. We found a pattern compatible with chronic denervation (MUAPs remodeling and incomplete recruitment) with the following frequency: TA muscle in 11/14 patients (78.5%); CT in 10/14 patients (71.4%); CAP in 10/14 patients (71.4%) and CAL in 7/14 patients (50%). In 8 patients, there were fibrillations and/ or fasciculations associated with chronic neurogenic changes in the same muscle; of these, 4 had no alteration in the genioglossus muscle and 2 had only chronic alterations in the same muscle. NF revealed motor abnormalities in the larynx in 9 patients; in the remaining 5, NF was normal but LEMG identified signs of denervation in 4 of them.
LEMG is able to identify laryngeal denervation in patients with ALS. This procedure may increase diagnostic sensitivity for ALS by identifying bulbar involvement in patients without tongue denervation. Changes in LEMG may precede clinical involvement of the larynx in these patients.
•Autonomic dysfunction involves multiple domains in RFC1-related disorder.•This condition is characterized by a small fiber autonomic axonopathy.•Sympathetic and parasympathetic divisions are ...affected in RFC1-related disorder.
To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy.
We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson’s Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests.
In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs.
Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy.
Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.
Objective
Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) ...or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium‐dependent phospholipid‐binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11).
Methods
We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls.
Results
Clinico‐radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb‐girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP‐43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions).
Interpretation
These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239–252
Little is known about autonomic dysfunction in Friedreichs Ataxia (FRDA). Several important questions on its prevalence and severity remain unanswered. In this study we aim to determine the profile ...of autonomic manifestations in FRDA, as well as to identify possible sites of damage.
We have performed clinical and electrophysiological evaluation of 35 patients with FDRA and 21 healthy controls. We used the Friedreich’s Ataxia Rating Scale (FARS) and the Scales for Outcomes in Parkinson’s Disease: Autonomic Questionnaire-SCOPA-AUT to quantify the severity of ataxia and autonomic complaints, respectively. We also studied heart rate variability at rest, during orthostatic challenge (30:15 ratio), Valsalva maneuver (Valsalva index) and deep breathing (E:I ratio). We evaluated spectral analyses of RR intervals at rest and the quantitative sudomotor axonal reflex, Q-SWEAT test. Groups were compared using non-parametric tests and p values set at 0.05.
In the FRDA group, there were 14 Men with mean age of 32.4 ± 11.2. SCOPA-AUT score was 15.9 ± 8.9. Mean and minimum RR intervals at rest were different between patients and controls (542 × 539 ms; p = 0.039 and 479 × 601 ms, p = 0,001). The 30:15 ratio, Valsalva index, E:I ratio, low and high frequency power were all similar between the groups (p > 0.05). In contrast, 82% of the patients had abnormal sweat responses in at least one site in the body. The legs were the most frequent sites involved.
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
Limb-girdle muscular dystrophy type 2A (LGMD2A) is the most common autosomal recessive (AR) LGMD subtype worldwide. The disease is caused by homozygous pathogenic mutations in the calpain 3 gene ...(CAPN3). Although strict AR inheritance is assumed for CAPN3-related myopathies, recent reports described symptomatic patients carrying a single CAPN3 mutation.
The LGMDs share common clinical and laboratory findings such as weakness and atrophy of proximal muscles, often affecting lower extremities first; elevated creatine kinase (CK) levels; and dystrophic findings on muscle biopsy. Some clinical and imaging findings help to differentiate LGMD2A, such as asymmetric weakness and atrophy and early scapular winging. On muscle MRI, calpain deficiency characteristically reveals preferential involvement of posterior thigh muscles and the adductor magnus muscle with relative sparing of the anterior thigh muscles. There are few reports on EMG findings in patients with single CAPN3 mutations.
Two unrelated patients with LGMD and harboring single CAPN3 mutations were identified. They underwent detailed neurological evaluation, muscle biopsy, muscle MRI and electroneuromyography (ENMG).
Patient one: man, 28 years old, born from nonconsanguineous parents, presenting progressive calves atrophy since 24 years old. Genetic analysis showed the variant c.258dupT;p. (Leu87Serfs*4) at CAPN3 in heterozygosity. ENMG showed myopathic motor unit action potential (MUAP) on left gastrocnemius and pectoralis major, and on right biceps brachii, without fibs or positive sharp waves. Right gastrocnemius muscle biopsy showed moderate myopathic changes. Patient two: woman, 77 years old, born from nonconsanguineous parents, presenting progressive proximal lower limb weakness in the last 2 years. Genetic analysis revealed the heterozygous frameshift variant c.550delA; p. (Thr184Argfs*36) in the CAPN3 gene. ENMG showed moderate diffuse myopathy, with preferential involvement of posterior tigh muscles and gastrocnemius with fibs and positive sharp waves. MRI showed severe atrophy of posterior tight muscles. Right quadriceps femoris biopsy revealed minimal myopathic changes.
The typical clinical, imaging and electrophysiological findings from LGMD2A can be found in patients presenting heterozygous pathogenic mutations in CAPN3 gene, indicating that a dominantly inherited form of calpainopathy exists, but with a milder fenotype. EMG reveals a predominantly posterior leg pattern of involvement.
The distinction between sensory polyneuropathies (SP) and neuronopathies (SN) is important for etiologic investigation and for prognosis estimation. However, this task is often challenging for the ...clinical neurophysiologist. In this scenario, we hypothesize that F wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP, but not in SN. The aim of this study was to determine whether lower limb F waves are useful in the differential assessment of SP and SN.
Twenty-nine patients were selected: 8 with SP - 6 diabetic, 1 familial amyloidosis and 1 with leprosy - and 21 with SN - caused by Sjögren’s syndrome, autoimmune hepatitis, HTLV or idiopathic. We collected data on height for every subject. For each patient, we obtained 20 supramaximal distal stimuli in the peroneal and tibial nerves to record F waves using a Neuropack M1 unit (Nihon Kohden Co., Japan). The values of F wave latencies (minimum, mean and maximal) and persistence for the peroneal and tibial nerves in both groups were compared. Non-parametric tests were used and p values <0.05 were considered significant.
The mean age of patients was 52 years and there were 16 women. There were no significant between-group differences regarding ages (p = 0.191) and the F wave latencies adjusted for height (p = 0.918). The F waves persistence for the right fibular (27.5% vs 62%, p = 0.019), right tibial (69% vs 91%, p = 0.029) and left tibial nerves (72.5 vs 98%, p = 0.003 ) was significantly lower in the SP group compared to SN.
Although preliminary, these results suggest that F waves may be useful in the differential diagnosis between SP and SN. The persistence of responses seems to be the most sensitive parameter. Studies with larger series should be performed to validate these findings.
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