Concurrence of Hyperhidrosis and Hypohidrosis in Ross Syndrome.

Ross Syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and abnormal segmental sweating. The pathophysiology of the disease remains unclear, with either hypohidrosis or hyperhidrosis reported in individual patients. We present the case of a man, aged 57 years, who presented with hyperhidrosis in his right extremities, anhidrosis in the left extremities, and changes in his pupils. The disease was not associated with markers of autoimmune disease, which supports recent research findings on the role of neurodegeneration. The patient's son was exhibiting similar symptoms, which implicates genetic inheritance in the process. A multidisciplinary approach is crucial for the diagnosis and ultimate management of patients with Ross Syndrome.

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

[Neuropathological Findings in Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome].

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by neuropathological changes such as loss of Purkinje cells and degeneration of the posterior column of the spinal cord. In the peripheral nervous system, CANVAS is associated with loss of ganglion cells in the dorsal root and vestibular ganglia. Some patients may show degeneration of the inferior olivary nucleus, corticospinal tracts, and the facial and trigeminal ganglia. Further research is warranted to determine whether differences in lesion distribution are attributable to differences in genetic abnormalities and their combinations. To date, aggregates of abnormal proteins such as intranuclear inclusion bodies characteristic of this disease have not been identified in the nervous system.

Effect of Long-Term Classical Ballet Dance Training on Postactivation Depression of the Soleus Hoffmann-Reflex.

Classical ballet dancing is a good model for studying the long-term activity-dependent plasticity of the central nervous system in humans, as it requires unique ankle movements to maintain ballet postures. The purpose of this study was to investigate whether postactivation depression is changed through long-term specific motor training. Eight ballet dancers and eight sedentary subjects participated in this study. The soleus Hoffmann reflexes were elicited at after the completion of a slow, passive dorsiflexion of the ankle. The results demonstrated that the depression of the soleus Hoffmann reflex (i.e., postactivation depression) was larger in classical ballet dancers than in sedentary subjects at two poststretch intervals. This suggests that the plastic change through long-term specific motor training is also expressed in postactivation depression of the soleus Hoffmann reflex. Increased postactivation depression would strengthen the supraspinal control of the plantarflexors and may contribute to fine ankle movements in classical ballet dancers.

Motor neuron pathology in CANVAS due to RFC1 expansions.

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (P < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Reflexive Eye Closure in Response to Cone and Melanopsin Stimulation: A Study of Implicit Measures of Light Sensitivity in Migraine.

BACKGROUND AND OBJECTIVES: To quantify interictal photophobia in migraine with and without aura using reflexive eye closure as an implicit measure of light sensitivity and to assess the contribution of melanopsin and cone signals to these responses. METHODS: Participants were screened to meet criteria for 1 of 3 groups: headache-free (HF) controls, migraine without aura (MO), and migraine with visual aura (MA). MO and MA participants were included if they endorsed ictal and interictal photophobia. Exclusion criteria included impaired vision, inability to collect usable pupillometry, and history of either head trauma or seizure. Participants viewed light pulses that selectively targeted melanopsin, the cones, or their combination during recording of orbicularis oculi EMG (OO-EMG) and blinking activity. RESULTS: We studied 20 participants in each group. MA and MO groups reported increased visual discomfort to light stimuli (discomfort rating, 400% contrast, MA: 4.84 [95% confidence interval 0.33, 9.35]; MO: 5.23 [0.96, 9.50]) as compared to HF controls (2.71 [0, 6.47]). Time course analysis of OO-EMG and blinking activity demonstrated that reflexive eye closure was tightly coupled to the light pulses. The MA group had greater OO-EMG and blinking activity in response to these stimuli (EMG activity, 400% contrast: 42.9%Δ [28.4, 57.4]; blink activity, 400% contrast: 11.2% [8.8, 13.6]) as compared to the MO (EMG activity, 400% contrast: 9.9%Δ [5.8, 14.0]; blink activity, 400% contrast: 4.7% [3.5, 5.9]) and HF control (EMG activity, 400% contrast: 13.2%Δ [7.1, 19.3]; blink activity, 400% contrast: 4.5% [3.1, 5.9]) groups. DISCUSSION: Our findings suggest that the intrinsically photosensitive retinal ganglion cells (ipRGCs), which integrate melanopsin and cone signals, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Moreover, we find a dissociation between implicit and explicit measures of interictal photophobia depending on a history of visual aura in migraine. This implies distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which the amplification of ipRGC signals elicits implicit and explicit signs of visual discomfort.

Assessment of sacral spinal excitability using stimulus-response curves of the bulbocavernosus reflex.

OBJECTIVE: To analyze and quantify sacral spinal excitability through bulbocavernosus reflex (BCR) stimulus-response curves. METHODS: Thirty subjects with upper motor neuron lesions (UMN) and nine controls were included in this prospective, monocentric study. Sacral spinal excitability was assessed using stimulus-response curves of the BCR, modeled at different bladder filling volumes relative to the desire to void (as defined by the International Continence Society) during a cystometry. Variations in α (i.e. the slope of the stimulus-response curve) were considered as an indicator of the modulation of sacral spinal excitability. RESULTS: In all subjects, α increased during bladder filling suggesting the modulation of spinal sacral excitability during the filling phase. This increase was over 30% in 96.7% of neurological subjects and 88.9% of controls. The increase was higher before the first sensation to void in the neurological population (163.15%), compared to controls, (29.91%), p < 0.001. CONCLUSIONS: We showed the possibility of using BCR stimulus-response curves to characterize sacral spinal response with an amplification of this response during bladder filling as well as a difference in this response amplification in patients with UMN in comparison with a control group. SIGNIFICANCE: BCR, through stimulus-response curves, might be an indicator of pelvic-perineal exaggerated reflex response and possibly a tool for evaluating treatment effectiveness.

Changes of Blink Reflex in Type 2 Diabetes Mellitus.

Blink reflex provides an objective assessment of the cranial and central nervous systems. However, the relationships between body mass index, dizziness, and BR have not been explored in patients with type 2 diabetes mellitus (T2DM). Moreover, R2 duration, one of the parameters of the blink reflex, has not been studied to date. In the present study, we aimed to investigate the characteristics and influencing factors of blink reflex in patients with T2DM. We included 45 healthy subjects and 105 hospitalized patients with T2DM. The relationships between these parameters and sex, age, body mass index, duration of T2DM, hemoglobin A1c, distal symmetrical polyneuropathy (DSPN), and dizziness symptoms were analyzed. The results showed that blink reflex latencies (including R1, ipsilateral R2, and contralateral R2 latency) were negatively associated with body mass index but were positively correlated with the duration of T2DM. There were no correlations between blink reflex parameters and sex, age, and hemoglobin A1c. Patients with DSPN had longer blink reflex latencies and shorter R2 durations than those without DSPN. Patients with dizziness had longer latencies (including R1, ipsilateral R2, and contralateral R2 latencies) and shorter R2 durations (including ipsilateral R2 and contralateral R2 durations) than those without dizziness. R2 duration was also a predictive factor for blink reflex abnormality. R2 latency was the most sensitive factor and the optimal predictor of dizziness. These results demonstrate that patients with T2DM with low body mass index, longer duration of T2DM, DSPN, and dizziness-related symptoms had more abnormal blink reflex parameters, indicating more serious injuries to the cranial nerves or the central nervous system.

Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure.

INTRODUCTION: Angiotensin II (ANG II) and vasopressin (VP) interact in several physiological mechanisms, playing a role in arterial hypertension and congestive heart failure. Aim and Methods of Search: To overview the primary mechanism involved in the regulation of cardiovascular function, PubMed/Medline was searched, and authors selected original articles and reviews written in English. RESULTS: Angiotensin II (ANG II) and vasopressin (VP) are involved in several physiological mechanisms. ANG II stimulates VP release via angiotensin receptor 1. ANG II and VP stimulate aldosterone synthesis and secretion and enhance its action at the renal collecting duct level. VP is also involved in the cardiovascular reflex control of the sympathetic nervous system (SNS). Also, VP potentiates vasoconstriction and cardiac contractility, enhancing the effect of ANG II on sympathetic tone and arterial pressure. On the other hand, ANG II and VP act antagonistically in regulating baroreflex control of the SNS. There is evidence that high VP plasma levels increase baroreflex sympatho-inhibitory responses, and the arterial baroreflex response is shifted to lower pressure. This cardiovascular reflex control is mediated mainly in the brain, specifically in the circumventricular organ area postrema (AP). The modulation of cardiovascular reflex control induced by VP is abolished after lesions of the AP. VP modulation of baroreflex function is also under the control of α2-adrenergic pathway arising from the nucleus of the solitary tract (NTS) and synapsing on VP-ergic neurons of supraoptic and paraventricular nuclei. Presynaptic α2-adrenergic stimulation within the NTS inhibits VP release induced by hypovolemia and the effects of VP and AP on baroreflex control of SNS, thus showing baroreceptor afferent inputs are processed within the NTS and contribute to the increased baroreflex sympatho-inhibitory responses. DISCUSSION: In patients with congestive heart failure (CHF), plasma VP levels are elevated, inducing an up-regulation of aquaporin 2 water channel expression in renal collecting duct (CD) cells provoking exaggerated water retention and dilutional hyponatremia. Antagonists of VP and ANG II receptors reduce edema, body weight, and dyspnea in CHF patients. CONCLUSION: Hormonal imbalance between ANG II, VP, and SNS may induce hypertension and impaired water-electrolyte balance in cardiovascular diseases.

The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation.

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

Complex Movement Disorders in Ataxia with Oculomotor Apraxia Type 1: Beyond the Cerebellar Syndrome.

Background: Ataxia with oculomotor apraxia (AOA1) is characterized by early-onset progressive cerebellar ataxia with peripheral neuropathy, oculomotor apraxia and hypoalbuminemia and hypercholesterolemia. Case Report: A 23-year-old previously healthy woman presented with slowly-progressive gait impairment since the age of six years. Neurological examination revealed profound areflexia, chorea, generalized dystonia and oculomotor apraxia. Brain MRI revealed mild cerebellar atrophy and needle EMG showed axonal sensorimotor neuropathy. Whole exome sequencing revealed a mutation in the aprataxin gene. Discussion: AOA1 can present with choreoathetosis mixed with dystonic features, resembling ataxia-telangiectasia. This case is instructive since mixed and complex movement disorders is not very common in AOA1. Highlights: Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by early-onset ataxia and oculomotor apraxia caused by variants in the APTX gene.Ataxia is usually not the sole movement abnormality in AOA1.Hyperkinetic movement disorders, especially chorea and dystonia, may occur.Mixed and complex movement disorders is not very common in AOA1.Patients with early-onset ataxia associated with mixed movement disorders should also be investigated for AOA1.

Neurological Development, Epilepsy, and the Pharmacotherapy Approach in Children with Congenital Zika Syndrome: Results from a Two-Year Follow-up Study.

Clinical outcomes related to congenital Zika syndrome (CZS) include microcephaly accompanied by specific brain injuries. Among several CZS outcomes that have been described, epilepsy and motor impairments are present in most cases. Pharmacological treatment for seizures resulting from epilepsy is performed with anticonvulsant drugs, which in the long term are related to impairments in the child's neuropsychomotor development. Here, we describe the results from a two-year follow-up of a cohort of children diagnosed with CZS related to the growth of the head circumference and some neurological and motor outcomes, including the pharmacological approach, and its results in the treatment of epileptic seizures. This paper is part of a prospective cohort study carried out in the state of Mato Grosso Sul, Brazil, based on a Zika virus (ZIKV)-exposed child population. Our data were focused on the assessment of head circumference growth and some neurological and motor findings, including the description of seizure conditions and pharmacological management in two periods. Among the 11 children evaluated, 8 had severe microcephaly associated with motor impairment and/or epilepsy. Seven children were diagnosed with epilepsy. Of these, 3 had West syndrome. In four children with other forms of epilepsy, there was no pharmacological control.

Rectus femoris hyperreflexia contributes to Stiff-Knee gait after stroke.

BACKGROUND: Stiff-Knee gait (SKG) after stroke is often accompanied by decreased knee flexion angle during the swing phase. The decreased knee flexion has been hypothesized to originate from excessive quadriceps activation. However, it is unclear whether hyperreflexia plays a role in this activation. The goal of this study was to establish the relationship between quadriceps hyperreflexia and knee flexion angle during walking in post-stroke SKG. METHODS: The rectus femoris (RF) H-reflex was recorded in 10 participants with post-stroke SKG and 10 healthy controls during standing and walking at the pre-swing phase. In order to attribute the pathological neuromodulation to quadriceps muscle hyperreflexia and activation, healthy individuals voluntarily increased quadriceps activity using electromyographic (EMG) feedback during standing and pre-swing upon RF H-reflex elicitation. RESULTS: We observed a negative correlation (R = - 0.92, p = 0.001) between knee flexion angle and RF H-reflex amplitude in post-stroke SKG. In contrast, H-reflex amplitude in healthy individuals in presence (R = 0.47, p = 0.23) or absence (R = - 0.17, p = 0.46) of increased RF muscle activity was not correlated with knee flexion angle. We observed a body position-dependent RF H-reflex modulation between standing and walking in healthy individuals with voluntarily increased RF activity (d = 2.86, p = 0.007), but such modulation was absent post-stroke (d = 0.73, p = 0.296). CONCLUSIONS: RF reflex modulation is impaired in post-stroke SKG. The strong correlation between RF hyperreflexia and knee flexion angle indicates a possible regulatory role of spinal reflex excitability in post-stroke SKG. Interventions targeting quadriceps hyperreflexia could help elucidate the causal role of hyperreflexia on knee joint function in post-stroke SKG.

Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington's Disease.

In the BACHD mouse model of Huntington's disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered -but differentially so- in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31 -but not Q97- MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model.

Understanding hyper-reflexia in acute motor axonal neuropathy (AMAN).

Hyper-reflexia is occasionally seen in acute motor axonal neuropathy (AMAN), but its pathophysiology is unclear. We report a patient with AMAN following Campylobacter jejuni enteritis, who showed generalized hyper-reflexia, bilateral Hoffmann sign and right Babinski sign. MRI and transcranial magnetic stimulation of the motor cortex disclosed no corticospinal tract involvement. An extensive electrophysiological investigation documented α-motoneuron hyperexcitability and dysfunction of the interneuronal inhibitory circuits in the spinal anterior horn. We propose an immune-mediated damage of the spinal inhibitory interneuronal network as possible mechanism inducing hyper-reflexia in AMAN.