Rhythmic Jaw Movements in Amyotrophic Lateral Sclerosis: Is It Clonus or Tremor?

Background: Jaw clonus refers to involuntary, rhythmic jaw contractions induced by a hyperactive trigeminal nerve stretch reflex; however, the movements, when triggered without a stretch, can be confused with a tremor. Phenomenology Shown: This video demonstrates a patient with amyotrophic lateral sclerosis presenting with rapid rhythmic jaw movements seen at rest, alongside a power spectrum analysis revealing a narrow high-frequency peak of 10 Hz. Educational Value: Rhythmic jaw movements are seen in many disorders such as Parkinson's disease, essential tremor, tardive syndromes, and cranial myorhythmias; however, a high-frequency movement, regardless of clonus or tremor, can indicate amyotrophic lateral sclerosis when accompanied by typical upper and lower motor neuron signs. Highlights: The presented video abstract shows a patient with amyotrophic lateral sclerosis with rhythmic jaw movements seen at rest. A power spectrum analysis of the rhythmic movements revealed a 10 Hz peak, a frequency higher than those seen in patients with Parkinson's disease, essential tremor, myorhythmia, and tardive syndromes.

[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

Roussy-Lévy Syndrome: Pes Cavus, Tendon Areflexia, Amyotrophy, Gait Ataxia, and Upper Limb Tremor in a Patient with CMT Neuropathy.

Background: Roussy-Lévy syndrome (RLS) is characterized by postural hand tremor seen in patients with familial autosomal dominant Charcot-Marie-Tooth (CMT) neuropathy. Phenomenology Shown: This video demonstrates irregular, jerky bilateral kinetic, postural, rest tremor affecting the right > left hand, along with pes cavus and gait ataxia in a patient with CMT disease. Educational Value: Pes cavus, tendon areflexia, sensory ataxia, and upper limb tremor should prompt consideration of CMT neuropathy. Highlights: This video abstract depicts a bilateral hand tremor characteristic of Roussy-Lévy syndrome seen in patients with Charcot-Marie-Tooth disease neuropathy. The significance of the abstract lies in the phenomenology and the physiology of the tremor seen in patients with genetically confirmed duplication of PMP22 gene.

MRI of the Spine in Patients who Toe Walk: Is There a Role?

BACKGROUND: Little is known about the prevalence of intraspinal pathology in children who toe walk, but magnetic resonance imaging (MRI) may be part of the diagnostic workup. The purpose of this study was to examine the role of MRI for children who toe walk with a focus on the rate of positive findings and associated neurosurgical interventions performed for children with said MRI findings. METHODS: A single-center tertiary hospital database was queried to identify a cohort of 118 subjects with a diagnosis of toe walking who underwent spinal MRI during a 5-year period. Patient and MRI characteristics were summarized and compared between subjects with a major abnormality, minor abnormality, or no abnormality on MRI using multivariable logistic regression. Major MRI abnormalities included those with a clear spinal etiology, such as fatty filum, tethered cord, syrinx, and Chiari malformation, while minor abnormalities had unclear associations with toe walking. RESULTS: The most common primary indications for MRI were failure to improve with conservative treatment, severe contracture, and abnormal reflexes. The prevalence of major MRI abnormalities was 25% (30/118), minor MRI abnormalities was 19% (22/118), and normal MRI was 56% (66/118). Patients with delayed onset of toe walking were significantly more likely to have a major abnormality on MRI ( P =0.009). The presence of abnormal reflexes, severe contracture, back pain, bladder incontinence, and failure to improve with conservative treatment were not significantly associated with an increased likelihood of major abnormality on MRI. Twenty-nine (25%) subjects underwent tendon lengthening, and 5 (4%) underwent neurosurgical intervention, the most frequent of which was detethering and sectioning of fatty filum. CONCLUSIONS: Spinal MRI in patients who toe walk has a high rate of major positive findings, some of which require neurosurgical intervention. The most significant predictor of intraspinal pathology was the late onset of toe walking after the child had initiated walking. MRI of the spine should be considered by pediatric orthopedic surgeons in patients with toe walking who present late with an abnormal clinical course. LEVEL OF EVIDENCE: Level III Retrospective Comparative Study.

Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats.

Spasticity, affecting ∼75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms, and cocontractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 cotransporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons. We successfully transduced lumbar motoneurons in adult rats with SCI using intrathecal administration of adeno-associated virus vector serotype 6, carrying a shRNA sequence against calpain1. This approach significantly reduced calpain1 expression in transduced motoneurons, leading to a noticeable decrease in spasticity symptoms, including hyperreflexia, muscle spasms, and cocontractions in hindlimb muscles, which are particularly evident in the second month post-SCI. In addition, this decrease, which prevented the escalation of spasticity to a severe grade, paralleled the restoration of KCC2 levels in transduced motoneurons, suggesting a reduced proteolytic activity of calpain1. These findings demonstrate that inhibiting calpain1 in motoneurons is a promising strategy for alleviating spasticity in SCI patients.

Epidural Spinal Cord Stimulation for Spasticity: a Systematic Review of the Literature.

OBJECTIVE: Spasticity is a form of muscle hypertonia secondary to various diseases, including traumatic brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis. Medical treatments are available; however, these often result in insufficient clinical response. This review evaluates the role of epidural spinal cord stimulation (SCS) in the treatment of spasticity and associated functional outcomes. METHODS: A systematic review of the literature was performed using the Embase, CENTRAL, and MEDLINE databases. We included studies that used epidural SCS to treat spasticity. Studies investigating functional electric stimulation, transcutaneous SCS, and animal models of spasticity were excluded. We also excluded studies that used SCS to treat other symptoms such as pain. RESULTS: Thirty-four studies were included in the final analysis. The pooled rate of subjective improvement in spasticity was 78% (95% confidence interval, 64%-91%; I2 = 77%), 40% (95% confidence interval, 7%-73%; I2 = 88%) for increased H-reflex threshold or decreased Hoffman reflex/muscle response wave ratio, and 73% (65%-80%; I2 = 50%) for improved ambulation. Patients with spinal causes had better outcomes compared with patients with cerebral causes. Up to 10% of patients experienced complications including infections and hardware malfunction. CONCLUSIONS: Our review of the literature suggests that SCS may be a safe and useful tool for the management of spasticity; however, there is significant heterogeneity among studies. The quality of studies is also low. Further studies are needed to fully evaluate the usefulness of this technology, including various stimulation paradigms across different causes of spasticity.

Chronic chemogenetic inhibition of TRPV1 bladder afferent promotes micturition recovery post SCI.

Spinal cord injury often results in chronic loss of micturition control, which is featured by bladder hyperreflexia and detrusor sphincter dyssynergia. Previous studies showed that treatment of capsaicin reduces non-voiding bladder contractions in multiple animal injury models and human patients. However, its underlying neural mechanisms remain largely unknown. Here, by injecting a RetroAAV into the bladder wall, we specifically targeted TRPV1+, a capsaicin receptor, bladder afferent neurons. Morphometric analysis revealed borderline increase of the soma size and significant spinal axon sprouting of TRPV1+ bladder afferent neurons post a complete T8 spinal cord crush. We further demonstrated that chronic chemogenetic inhibition of these DRG neurons improved micturition recovery after SCI by increasing voiding efficiency and alleviating bladder hyperreflexia, along with reduced morphological changes caused by injury. Our study provided novel insights into the structural and functional changes of TRPV1+ bladder afferent post SCI and further supports the clinical use of capsaicin as an effective treatment to improve bladder functions in patients with SCI.

Marcus-Gunn jaw winking syndrome: case series study and management algorithm.

PURPOSE: To identify a rationale for treatment of patients with Marcus Gunn jaw winking syndrome (MGJWS). METHODS: Retrospective review of 38 consecutive patients with MGJWS referred to a single tertiary institution. Clinical data included visual acuity, ocular motility, side of jaw-wink, presence or absence of ptosis, levator function, clinical photographs, and management undertaken. Thirty-two patients were operated on with customized surgery by a senior surgeon (FQL). RESULTS: Cases with no ptosis or mild ptosis were managed conservatively. Levator advancement (LA) was successful in case of moderate ptosis and negligible synkynesis but resulted in a more evident synkinesis. Levator resection (LR) in patients with severe ptosis was associated with high rate of ptosis recurrence. Ptosis was adequately corrected in all patients submitted to uni- or bilateral levator excision (LE) and bilateral frontalis suspension (FS) or unilateral frontalis flap (FF). Jaw winking resolved in all patients submitted to LE but recurred in three cases at a later stage. Strabismus surgery was performed simultaneously in case of associated esotropia or hypotropia. CONCLUSIONS: Moderate ptosis can be corrected with LA, but success is not related to levator function and synkinesis becomes more evident postoperatively. In severe ptosis, LR showed unpredictable results. In case of severe ptosis and severe synkinesis, uni- or bilateral LE and bilateral FS are recommended; unilateral FF is an alternative in patients who refuse bilateral treatment, as the cosmetic outcome is usually better than after unilateral FS.

Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury.

Spasticity is a hyperexcitability disorder that adversely impacts functional recovery and rehabilitative efforts after spinal cord injury (SCI). The loss of evoked rate-dependent depression (RDD) of the monosynaptic H-reflex is indicative of hyperreflexia, a physiological sign of spasticity. Given the intimate relationship between astrocytes and neurons, that is, the tripartite synapse, we hypothesized that astrocytes might have a significant role in post-injury hyperreflexia and plasticity of neighboring neuronal synaptic dendritic spines. Here, we investigated the effect of selective Rac1KO in astrocytes (i.e., adult male and female mice, transgenic cre-flox system) on SCI-induced spasticity. Three weeks after a mild contusion SCI, control Rac1wt animals displayed a loss of H-reflex RDD, that is, hyperreflexia. In contrast, transgenic animals with astrocytic Rac1KO demonstrated near-normal H-reflex RDD similar to pre-injury levels. Reduced hyperreflexia in astrocytic Rac1KO animals was accompanied by a loss of thin-shaped dendritic spine density on α-motor neurons in the ventral horn. In SCI-Rac1wt animals, as expected, we observed the development of dendritic spine dysgenesis on α-motor neurons associated with spasticity. As compared with WT animals, SCI animals with astrocytic Rac1KO expressed increased levels of the glial-specific glutamate transporter, glutamate transporter-1 in the ventral spinal cord, potentially enhancing glutamate clearance from the synaptic cleft and reducing hyperreflexia in astrocytic Rac1KO animals. Taken together, our findings show for the first time that Rac1 activity in astrocytes can contribute to hyperreflexia underlying spasticity following SCI. These results reveal an opportunity to target cell-specific molecular regulators of H-reflex excitability to manage spasticity after SCI.Significance Statement Spinal cord injury leads to stretch reflex hyperexcitability, which underlies the clinical symptom of spasticity. This study shows for the first time that astrocytic Rac1 contributes to the development of hyperreflexia after SCI. Specifically, astrocytic Rac1KO reduced SCI-related H-reflex hyperexcitability, decreased dendritic spine dysgenesis on α-motor neurons, and elevated the expression of the astrocytic glutamate transporter-1 (GLT-1). Overall, this study supports a distinct role for astrocytic Rac1 signaling within the spinal reflex circuit and the development of SCI-related spasticity.

Can CANVAS due to RFC1 biallelic expansions present with pure ataxia?

BACKGROUND: Biallelic expansion of AAGGG in the replication factor complex subunit 1 (RFC1) was identified as a major cause of cerebellar ataxia, neuropathy (sensory ganglionopathy, or SG) and vestibular areflexia syndrome (CANVAS). We wanted to clarify if RFC1 expansions can present with pure ataxia and if such expansions could be responsible for some cases where an alternative diagnosis had been made. METHODS: We identified patients with a combination of ataxia and SG and no other cause found, patients where an alternative diagnosis had been made, and patients with pure ataxia. Testing for RFC1 expansions was done using established methodology. RESULTS: Among 54 patients with otherwise idiopathic sporadic ataxia without SG, none was found to have RFC1 expansions. Among 38 patients with cerebellar ataxia and SG in which all other causes were excluded, 71% had RFC1 expansions. Among 27 patients with cerebellar ataxia and SG diagnosed with coeliac disease or gluten sensitivity, 15% had RFC1 expansions. CONCLUSIONS: Isolated cerebellar ataxia without SG makes the diagnosis of CANVAS due to RFC1 expansions highly improbable, but CANVAS is frequently the cause of the combination of idiopathic cerebellar ataxia with SG. It is important to screen patients diagnosed with other causes of acquired ataxia and SG as a small percentage were found to have RFC1 expansions.

Management of Complications after Levator Resection for Ptosis.

OBJECTIVE: To analyse the complications after external levator resection (ELR) for ptosis, and their management. STUDY DESIGN: Observational Study. Place and Duration of the Study: Mughal Eye Hospital Trust, Lahore, from June 2018 to December 2022. METHODOLOGY: A total of 256 eyes were operated for ptosis cases having good levator function who were treated by ELR. The exclusion criteria was any history of operation of lids or orbits or poor levator function, Marcus Gunn jaw-winking phenomenon, and neurogenic ptosis. The frequency of complications and their management was documented. RESULTS: Age ranged from 6 to 65 years. The follow-up ranged from 8 weeks to 3 years. Eleven (4.3%) cases developed complications. Two cases had mild undercorrection and did not require any treatment. In moderate overcorrection encountered in one eye, pulling the lid down for a few times daily improved lid level in four weeks. Four eyes had severe overcorrection, 2 patients required one operation and the other two patients required two operations each. These included hang-back sutures in two eyes (with 5/O Ethibond in one eye and 6/O Vicryl sutures in another eye) and simple incision in the levator (disinserting it partially from the tarsal plate) in two eyes. Lagophthalmos in two eyes improved with conservative treatment. Notching in two eyes improved with partial disinsertion of levator by cutting one Vicryl suture attaching levator to the tarsal plate and leaving 2 Vicryl sutures connecting levator to the tarsal plate. CONCLUSION: Ptosis correction by ELR is a low-complication procedure with good corrective results. KEY WORDS: Ptosis, Good levator function, Overcorrection after ptosis operation, Hang-back sutures, Partial levator disinsertion.

Thyrotoxic periodic paralysis presenting with quadriparesis and hyperreflexia.

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism that manifests as painless flaccid paralysis. An East Asian man in his late 20s presented to the emergency department with an acute onset of quadriparesis associated with hypertonia and hyperreflexia. His initial symptoms and signs suggested involvement of the brain and spinal cord; however, MRI of the neuroaxis was normal. His serum potassium concentration was low, and thyroid test results were consistent with hyperthyroidism. The patient was diagnosed with TPP associated with Graves' disease and was treated with potassium supplementation, propranolol and methimazole. Motor strength improved to his baseline level of power; bulk was normal, and tone was increased. Although flaccid paralysis is a typical presentation of TPP, brisk reflexes and muscle spasticity cannot rule out this condition. This case highlights the importance of considering TPP as a possible diagnosis in patients presenting with acute quadriparesis.

Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia.

Spasticity is a chronic neurological complication associated with spinal cord injury (SCI), characterized by increased muscle tone and stiffness. A physiological sign of spasticity is hyperreflexia, evident by the loss of evoked rate-dependent depression (RDD) in the H-reflex. Although previous work has shown that SCI-induced astrogliosis contributes to hyperexcitability disorders, including neuropathic pain and spasticity, it is unclear how reactive astrocytes can modulate synaptic transmission within the injured spinal cord. To study astrocytes' role in post-SCI hyperreflexia, we examined glutamate transporter-1 (GLT-1) and postsynaptic density protein 95 (PSD-95) proteins in astrocytes and neurons, respectively, within the ventral horn (lamina IX) below the level of injury (spinal segment L4-5). The close juxtaposition of GLT-1 and PSD-95 markers is a molecular correlate of tripartite synapses and is thought to be a key element in the astrocyte-induced plasticity of neuronal synapses. Our study compared animals with and without SCI-induced hyperreflexia and spasticity and investigated potential synaptic abnormalities associated with astrocyte involvement. As expected, 4 wk after SCI, we observed a loss in evoked H-reflex RDD in hindlimb electromyogram recordings, i.e., hyperreflexia, in contrast to uninjured sham. Importantly, our main findings show a significant increase in the presence of GLT-1-PSD-95 tripartite synapses in the ventral spinal cord motor regions of animals exhibiting SCI-induced hyperreflexia. Taken together, our study suggests the involvement of astrocyte-neuron synaptic complexes in the plasticity-driven progression of chronic spasticity.NEW & NOTEWORTHY The role of astrocytes in H-reflex hyperexcitability following SCI remains understudied. Our findings establish a relationship between GLT-1 expression, its proximity to neuronal PSD-95 in the spinal cord ventral horn, and the loss of H-reflex RDD, i.e., hyperreflexia. Our findings provide a new perspective on synaptic alterations and the development of SCI-related spasticity.

Effect of electroacupuncture on urodynamics and Raf/MEK/ERK signaling pathway in spinal cord tissue of rats with detrusor hyperreflexia after suprasacral spinal cord injury. / ç”µé’ˆå¯¹éª¶ä¸Šè„Šé«“æŸä¼¤åŽé€¼å°¿è‚Œåå°„äº¢è¿›åž‹å¤§é¼ å°¿æµåŠ¨åŠ›å­¦åŠè„Šé«“Raf/MEK/ERK信号通路的影响.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on urodynamics and Raf/MEK/ERK signaling pathway in spine cord tissue of rats after suprasacral spinal cord injury (SSCI), so as to explore its possible mechanism in improving bladder function in rats with detrusor hyperreflexia after SSCI. METHODS: Female SD rats were randomly divided into blank, sham operation, model, EA and EA+PD98059 groups, with 12 rats in each group. Thorax (T) 10 spinal cord transection was performed by surgery. Rats in the EA group were given EA (10 Hz/50 Hz, 20 min) at "Ciliao" (BL32), "Zhongji" (CV3), "Sanyinjiao" (SP6) and "Dazhui" (GV14) once daily for 7 d. Rats of the EA+PD98059 group received intraperitoneal injection of PD98059 (5 mg/kg) 2 h before EA intervention. The urodyna-mics was used to measure the base pressure, leak point pressure, maximum pressure, maximum capacity and comp-liance of bladder, and the morphology of bladder detrusor tissue was observed with HE staining. The TUNEL staining was used to detect the cell apoptosis of the spinal cord tissue. The expression levels of exchange protein directly activated by cAMP 2 (Epac2), Rap, phosphorylated rapidly accelerated fibrosarcoma (p-Raf), phosphorylated mitogen-activated extracellular signal-regulated kinase (p-MEK), phosphorylated extracellular signal regulated kinase 1 and 2 (p-ERK1/2), B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X protein (Bax) were determined by Western blot. RESULTS: Compared with the sham operation group, the base pressure, leak point pressure and maximum pressure of bladder were significantly increased (P<0.01), the maximum bladder capacity and bladder compliance were decreased (P<0.01), the cell apoptosis rate of spinal cord tissue was increased (P<0.01), and the expression levels of Epac2, Rap, p-Raf, p-MEK, p-ERK1/2, and Bcl-2 protein in spinal cord tissue were decreased (P<0.01), while the expression level of Bax protein was increased (P<0.01) in the model group. After the treatment and compared with the model group, the base pressure, leak point pressure and maximum pressure of bladder, the cell apoptosis rate of spinal cord tissue, the expression level of Bax protein were decreased (P<0.05) in the EA group, while the maximum bladder capacity and bladder compliance, the expression levels of Epac2, Rap, p-Raf, p-MEK, p-ERK1/2, and Bcl-2 protein in spinal cord tissue were all increased (P<0.05, P<0.01). In comparison with the EA group, the base pressure, leak point pressure and maximum pressure of bladder, the cell apoptosis rate, the expression level of Bax protein were significantly increased (P<0.05), whereas the maximum bladder capacity, bladder compliance, and the expression levels of p-MEK, p-ERK1/2, and Bcl-2 protein were decreased (P<0.05) in the EA+PD98059 group. Results of HE staining showed disordered transitional epithelial cells and destroyed lamina propria in bladder detrusor tissue, with the infiltration of monocytes in the model group, which was obviously milder in both EA and EA+PD98059 groups, especially in the EA group. CONCLUSIONS: EA can improve the bladder function in detrusor hyperreflexia rats after SSCI, which may be related to its effect in up-regulating Epac2 and Rap, activating the Raf-MEK-ERK pathway, and reducing the cell apoptosis of spinal cord tissue.

Non-Hodgkin's Lymphoma with Intraspinal Involvement Mimics Bilateral Thoracolumbar Plexopath.

PURPOSE: Non-Hodgkin lymphoma (NHL) is the most common type of lymphoma, and its extranodal manifestation is rare. Skeletal muscle involvement is noted in only 1.1% of patients with NHL. Here, we present a case of high-grade B-cell lymphoma (HGBL); it infiltrated the left neural foramina from the left psoas muscle before encroaching on the whole spinal canal and subsequently invading the contralateral neural foramina from T12 to L3. CASE REPORT: A 43-year-old man with HGBL who could function independently presented with numbness and weakness of the left thigh 2 months after a diagnosis of infiltrative lymphoma in the left psoas muscle. His symptoms were urine incontinence and unsteady gait. A neurological examination revealed weakness in the left psoas and quadriceps with hyporeflexia and hypesthesia. Lumbar spine magnetic resonance imaging (MRI) revealed intraspinal extradural invasion from T12 to L3 with multiple left-sided root compression despite the resolution of primary psoas lymphoma. At 6 weeks after symptom onset, his symptoms progressed to weakness, numbness, and hyporeflexia of the bilateral lower extremities with preserved anal sensation. Follow- up MRI revealed the progression of intraspinal invasion, which spread through the spinal canal and invaded the contralateral neural foramina from T12 to L3. The patient was finally bound to a wheelchair. CONCLUSION: Clinicians must check for possible intraspinal involvement in patients with HGBL, particularly patients with known paraspinal soft-tissue involvement. The resolved infiltration of the soft tissue does not preclude the possibility of further neurological involvement. Additionally, MRI may provide higher resolution findings for clarifying the structure of the neural foramina and thecal sac. Keyword: Non-Hodgkin's Lymphoma, high-grade B-cell lymphoma, plexopathy.

Ross syndrome with chronic cough and RF positivity: a case report.

Ross syndrome is a rare disorder of unknown etiology, characterized by the triad of segmental anhidrosis, tonic pupil, and areflexia/hyporeflexia. Ross syndrome is thought to be a limited and selective ganglioneuropathy. Its etiology has not been fully elucidated. Autonomic findings may also accompany. We wanted to present our 25-year-old patient who was diagnosed with Ross syndrome and presented with complaints of inability to sweat, heat intolerance, headache, diarrhea and chronic cough. Keyword: cough, tonic pupil, anhidrosis, compensatory.

Dysfunctional neuro-muscular mechanisms explain gradual gait changes in prodromal spastic paraplegia.

BACKGROUND: In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperreflexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes - depicted by digital gait recording - are related to disease severity in prodromal and early-to-moderate manifest SPG4 participants. METHODS: We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperreflexia and muscle weakness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 participants. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor reflex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. RESULTS: By increasing hyperreflexia of plantarflexor and dorsiflexor muscles, we found gradual muscular and kinematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 participants. CONCLUSIONS: Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 participants by gradual alterations of sensory-motor reflex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions.

Frequency and Phenotype of RFC1 Repeat Expansions in Bilateral Vestibulopathy.

BACKGROUND AND OBJECTIVES: Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP. METHODS: The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification). RESULTS: Biallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34-72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6-8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease. DISCUSSION: This study identifies RFC1 as the first-and frequent-monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution of RFC1 spectrum disease, with implications for designing natural history studies and future treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1 repeat expansions cause BVP.

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.