Iatrogenic botulism cases after gastric and axillary application of botulinum toxin and review of literature.

INTRODUCTION: Iatrogenic botulism is a rare, serious disease that progresses with descending paralysis and develops after cosmetic or therapeutic botulinum toxin-A (BoNT-A) application. CASE PRESENTATIONS: In this case series; six cases of iatrogenic botulism followed up in our center are presented. Four of these developed after gastric BoNT-A and two after axillary BoNT-A application. RESULTS: The most important cause for the disease was the use of unlicensed products and high-dose toxin applications. The first symptoms were blurred vision, double vision, difficulty in swallowing, and hoarseness. Symptoms appeared within 4-10 days after the application of BoNT-A. Symptoms progressed in the course of descending paralysis in the following days with fatigue, weakness in extremities and respiratory distress. Diagnosis was based on patient history and clinical findings. The main principles of foodborne botulism therapy were applied in the treatment of iatrogenic botulism. If clinical worsening continued, regardless of the time elapsed after BoNT-A application, the use of botulinum antitoxin made a significant contribution to clinical improvement and was recommended. CONCLUSIONS: Routine and new indications for BoNT-A usage are increasing and, as a result, cases of iatrogenic botulism will be encountered more frequently. Physicians should be alert for iatrogenic botulism in the follow-up after BoNT-A applications and in the differential diagnosis of neurological diseases that are presented with similar findings.

Aminopyridines Restore Ventilation and Reverse Respiratory Acidosis at Late Stages of Botulism in Mice.

Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO2, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP-mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties. SIGNIFICANCE STATEMENT: There is a critical need for fast-acting treatments to reverse respiratory paralysis in patients with botulism. This study used unrestrained, whole-body plethysmography and arterial blood gas analysis to show that aminopyridines rapidly restore ventilation and respiration and reverse respiratory acidosis when administered to mice at terminal stages of botulism. In addition to supporting the use of aminopyridines as first-line treatments for botulism symptoms, these data are expected to contribute to the development of new aminopyridine derivatives with improved pharmacological properties.

Shenqi formula delayed Alzheimer's disease-like symptoms by skn-1 pathway in Caernorhabditis elegans.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenqi formula is composed of Codonopsis pilosula (Cp) and Lycium barbarum (Lb), and it is traditionally used for promoting qi and nourishing the spleen, liver and kidney. Cp and Lb have been reported to improve cognitive performance in APP/PS1 mice, prevent the accumulation of Aß, and reduce the neurotoxicity of Aß to achieve the anti-Alzheimer's disease (AD) effect. AIM OF THE STUDY: Shenqi formula was explored the therapeutic effect on Caenorhabditis elegans AD pathological model and the underlying mechanism of action. MATERIALS AND METHODS: Paralysis assay and serotonin sensitivity assay was used to detect whether Shenqi formula can alleviate AD paralysis phenotype, and then DPPH, ABTS, NBT and Fenton methods were applied to investigate the scavenging capacity to free radical, ROS, ·O2- and ·OH of Shenqi formula in vitro. H2DCF-DA and MitoSOX™ Red were employed to measure ROS and .O2- accumulation, respectively. RNAi was used to knock down the expression of skn-1 and daf-16 related to oxidative stress resistance signalling pathway. Fluorescence microscopy was used to record the expression of SOD-3::GFP, GST-4::GFP, SOD-1::YFP, and the nuclear translocation of SKN-1 and DAF-16. Western blot assay was carried out to test Aß monomers and oligomers. RESULTS: Shenqi formula delayed the AD-like pathological characteristics in C. elegans, and the complete Shenqi formula was more effective than Cp or Lb alone. The effect of Shenqi formula on delaying worm paralysis was partially eliminated by skn-1 RNAi, but not daf-16 RNAi. Shenqi formula significantly inhibited the abnormal deposition of Aß protein, decreased Aß protein monomers and oligomers. It increased the expressions of gst-4, sod-1, and sod-3 similar to paraquat, companied by rise then fall of ROS and .O2- in AD worms. CONCLUSIONS: Shenqi formula at least partially depended on SKN-1 signalling pathway to exert its anti-AD effect, and it is potential to be used as a kind of health food to prevent the progress of AD.

[Methods and results of neurosurgical treatment of cerebral palsy]. / Metody i rezul'taty neirokhirurgicheskogo lecheniya detskogo tserebral'nogo paralicha.

Treatment of spastic syndrome and muscular dystonia in patients with cerebral palsy is a complex clinical problem. Effectiveness of conservative treatment is not high enough. Modern neurosurgical techniques for spastic syndrome and dystonia are divided into destructive interventions and surgical neuromodulation. Their effectiveness is different and depends on the form of disease, severity of motor disorders and age of patients. OBJECTIVE: To evaluate the effectiveness of various methods of neurosurgical treatment of spasticity and muscular dystonia in patients with cerebral palsy. MATERIAL AND METHODS: We To evaluate the effectiveness of various methods of neurosurgical treatment of spasticity and muscular dystonia in patients with cerebral palsy.analyzed literature data in the PubMed database using the keywords «cerebral palsy¼, «spasticity¼, «dystonia¼, «selective dorsal rhizotomy¼, «selective neurotomy¼, «intrathecal baclofen therapy¼, «spinal cord stimulation¼, «deep brain stimulation¼. RESULTS: Effectiveness of neurosurgery was higher for spastic forms of cerebral palsy compared to secondary muscular dystonia. Destructive procedures were the most effective among neurosurgical operations for spastic forms. Effectiveness of chronic intrathecal baclofen therapy decreases in follow-up due to secondary drug resistance. Destructive stereotaxic interventions and deep brain stimulation are used for secondary muscular dystonia. Effectiveness of these procedures is low. CONCLUSION: Neurosurgical methods can partially reduce severity of motor disorders and expand the possibilities of rehabilitation in patients with cerebral palsy.

Telaprevir Treatment Reduces Paralysis in a Mouse Model of Enterovirus D68 Acute Flaccid Myelitis.

In 2014, 2016, and 2018, the United States experienced unprecedented spikes in pediatric cases of acute flaccid myelitis (AFM), which is a poliomyelitis-like paralytic illness. Accumulating clinical, immunological, and epidemiological evidence has identified enterovirus D68 (EV-D68) as a major causative agent of these biennial AFM outbreaks. There are currently no available FDA-approved antivirals that are effective against EV-D68, and the treatment for EV-D68-associated AFM is primarily supportive. Telaprevir is an food and drug administration (FDA)-approved protease inhibitor that irreversibly binds the EV-D68 2A protease and inhibits EV-D68 replication in vitro. Here, we utilize a murine model of EV-D68 associated AFM to show that early telaprevir treatment improves paralysis outcomes in Swiss Webster (SW) mice. Telaprevir reduces both viral titer and apoptotic activity in both muscles and spinal cords at early disease time points, which results in improved AFM outcomes in infected mice. Following intramuscular inoculation in mice, EV-D68 infection results in a stereotypic pattern of weakness that is reflected by the loss of the innervating motor neuron population, in sequential order, of the ipsilateral (injected) hindlimb, the contralateral hindlimb, and then the forelimbs. Telaprevir treatment preserved motor neuron populations and reduced weakness in limbs beyond the injected hindlimb. The effects of telaprevir were not seen when the treatment was delayed, and toxicity limited doses beyond 35 mg/kg. These studies are a proof of principle, provide the first evidence of benefit of an FDA-approved antiviral drug with which to treat AFM, and emphasize both the need to develop better tolerated therapies that remain efficacious when administered after viral infections and the development of clinical symptoms. IMPORTANCE Recent outbreaks of EV-D68 in 2014, 2016, and 2018 have resulted in over 600 cases of a paralytic illness that is known as AFM. AFM is a predominantly pediatric disease with no FDA-approved treatment, and many patients show minimal recovery from limb weakness. Telaprevir is an FDA-approved antiviral that has been shown to inhibit EV-D68 in vitro. Here, we demonstrate that a telaprevir treatment that is given concurrently with an EV-D68 infection improves AFM outcomes in mice by reducing apoptosis and viral titers at early time points. Telaprevir also protected motor neurons and improved paralysis outcomes in limbs beyond the site of viral inoculation. This study improves understanding of EV-D68 pathogenesis in the mouse model of AFM. This study serves as a proof of principle for the first FDA-approved drug that has been shown to improve AFM outcomes and have in vivo efficacy against EV-D68 as well as underlines the importance of the continued development of EV-D68 antivirals.

Bell Palsy: Rapid Evidence Review.

Bell palsy should be suspected in patients with acute onset of unilateral facial weakness or paralysis involving the forehead in the absence of other neurologic abnormalities. The overall prognosis is good. More than two-thirds of patients with typical Bell palsy have a complete spontaneous recovery. For children and pregnant women, the rate of complete recovery is up to 90%. Bell palsy is idiopathic. Laboratory testing and imaging are not required for diagnosis. When other causes of facial weakness are being considered, laboratory testing may identify a treatable cause. An oral corticosteroid regimen (prednisone, 50 to 60 mg per day for five days followed by a five-day taper) is the first-line treatment for Bell palsy. Combination therapy with an oral corticosteroid and antiviral may reduce rates of synkinesis (misdirected regrowth of facial nerve fibers manifesting as involuntary co-contraction of certain facial muscles). Recommended antivirals include valacyclovir (1 g three times per day for seven days) or acyclovir (400 mg five times per day for 10 days). Treatment with antivirals alone is ineffective and not recommended. Physical therapy may be beneficial in patients with more severe paralysis.

Thyrotoxic periodic paralysis associated with lactic metabolic acidosis: Case report of an African man and review of literature.

BACKGROUND: Thyrotoxic periodic paralysis (TPP) is a rare and most often acquired subtype of hypokalemic periodic paralysis. The association of varying degrees of muscle weakness, hyperthyroidism and hypokalemia characterizes it. The treatment requires potassium supplementation, control of hyperthyroidism and prevention measures. It is a frequent disease in Asian men, but much rare in Caucasian or African populations. This is the first report of TPP associated with lactic metabolic acidosis in an African man. CASE PRESENTATION: A 23 year-old African man, native from Morocco, with recurrent episodes of tetraparesis for eleven months, and abdominal pain, was referred for evaluation. Biochemical investigations showed severe hypokalemia associated with hyperthyroidism and lactic metabolic acidosis. His EKG showed signs of hypokalemia such as sinus tachycardia and U waves. After potassium supplementation, neurological recuperation was quick and complete. Thyroid ultrasound identified a hypoechogenic and hypervascularized goiter, associated with high levels of thyroid antibodies, in favor of Grave's disease. With antithyroid drugs and life-style changes, the patient did not have any other attack. REVIEW OF LITERATURE: In addition to the case report, this article presents an extended review of literature, from the first large study reporting the diagnosis and incidence of TPP in 1957 to nowadays. Are reported here the latest information concerning epidemiology, clinical manifestations, complementary examinations, management and genetic finding. The lactic acidosis observed initially is exceptional, never described in TPP. TPP is a diagnostic and therapeutic emergency, requiring careful potassium supplementation, in order to avoid the risk of the onset of rebound hyperkalemia, to be maintained until the etiological treatment is effective. Paraclinical assessment with emergency EKG and electromyogram are essential to assess the impact. DISCUSSION: It is essential in the face of any hypokalaemic periodic paralysis, including in non-Asian subjects, to search hyperthyroidism. CONCLUSIONS: This report demonstrates the importance of thyroid testing in case of acute muscle weakness, even in non-Asian patients in order to diagnose TPP. This is a rare but possible etiology, to be distinguished from the familial form of hypokalemic periodic paralysis. It also questions on the impact of TPP on energetic metabolism, in particular on lactic metabolism.

Recurrent hypokalemic paralysis in hypothyroidism.

Hypothyroidism, a commonly encountered thyroid disorder, usually manifests with readily recognizable typical features. However, an unusual presentation of a classic thyroid disorder may hinder accurate diagnosis in certain instances. One such rare initial presentation of hypothyroidism is recurrent hypokalemic paralysis, and existing reports in the literature are sparse. It has been more commonly reported in thyrotoxicosis. We report the case details and clinical outcomes of two middle-aged individuals (a 34-year-old male and a 37-year-old female) with recurrent episodes of hypokalemic paralysis. Their clinical examination revealed pure motor hyporeflexia quadriparesis with hypotonia and diminished deep tendon reflexes without any autonomic dysfunction. They had no significant previous medical history. Biochemical findings revealed hypokalemia in both cases (1.4 and 1.9 mEq/L, respectively) with elevated levels of thyroid­stimulating hormone and thyroid­related antibodies in both individuals, thus, confirming the diagnosis of autoimmune hypothyroidism. Immediate treatment with intravenous and oral potassium correction helped in the recovery. Thyroxine supplementation was considered a follow-up treatment, and for a one-year follow-up period there were no complaints of limb weakness reported in both individual.

Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming: Mechanisms and Proposed Standards for Clinical Assessment.

Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block.

Success rates of botulinum toxin in different types of strabismus and dose effect.

OBJECTIVE: To determine the effect of botulinum toxin in different types of strabismus and analyze its dose effect. DESIGN: This was an interventional clinical study performed in a tertiary care university hospital. METHODS: Eighty six patients treated with botulinum toxin for strabismus were included. Main outcome measures involved success of botulinum toxin, alignment change per unit of toxin, and dose effect on complications and outcomes. RESULTS: Success rates were 31% for infantile esotropia, 25% for partially accommodative esotropia, 61.5% for residual esotropia, 25% for third cranial nerve paralysis, 13.3% for sixth cranial nerve paralysis, 75% for Duane retraction syndrome, and 38.5% for nonaccomodative esotropia. Improvement in deviation size after botulinum toxin treatment was significant in patients with infantile esotropia (p = 0.001), residual esotropia (p = 0.001), and nonaccomodative esotropia (p = 0.03). Mean deviation change per 1 unit of toxin was 2.7 ± 2.4 prism diopters (PD) with a single injection and 2.1 ± 1.9 PD with multiple injections. A 3.32 PD of early deviation change with botulinum toxin corrected 1 PD of final deviation. Success rate was not correlated with age (r = 0.040, p = 0.8), sex (r = -0.083, p = 0.6), mean dose (r = -0.149, p = 0.35), or total dose (r = 0.165, p = 0.29) but was significantly correlated with deviation size (ß = -0.077, p = 0.0001). Complications were not associated with the dose of botulinum toxin (p > 0.05). CONCLUSIONS: Botulinum toxin has variable outcomes in different types of strabismus. Still, it reduces the deviation size in most patients, thus allowing for a smaller amount of subsequent muscle surgery. Early overcorrection is a more powerful indicator of better outcome than postinjection duction deficit.

Asymptomatic unilateral phrenic nerve palsy after bortezomib treatment in a newly diagnosed multiple myeloma patient.

INTRODUCTION: Bortezomib is the first chemotherapeutic agent of proteosome inhibitor class that can be used in newly diagnosed and relapsed/refractory multiple myeloma. It is well known that bortezomib has side effects such as peripheral sensory, motor, or autonomic neuropathy. In this paper, we will present our patient who developed unilateral phrenic nerve palsy as an autonomic neuropathy after six cycles of subcutaneous bortezomib treatment. This case differs from other cases in that our patient was asymptomatic. CASE REPORT: A 57-year-old male patient was admitted with back pain and gait disturbances. In the thorax computed tomography, a soft tissue mass causing compression on the spinal canal was observed in the T12 vertebra. Bone biopsy pathology report resulted in diffuse plasma cell infiltration. The patient was diagnosed with stage ISS-3, IgG kappa type multiple myeloma. MANAGEMENT AND OUTCOME: Subcutaneous bortezomib 1 × 2.2 mg (Days 1-4-8-11) + intravenous cyclophosphamide 1000 mg (Day 1) + intravenous dexamethasone 40 mg (Days 1-2-3-4) (VCD chemotherapy protocol) was started. Totally six cycles of VCD were administered. While the patient did not have any respiratory symptoms, an elevation consistent with phrenic nerve palsy was observed in the left hemidiaphragm in the thorax computed tomography that was taken during the preparation for autologous hematopoietic stem cell transplantation. DISCUSSION: Bortezomib is a frequently used chemotherapeutic agent in patients with multiple myeloma and care should be taken in terms of the risk of developing phrenic nerve palsy in patients. There are cases of autonomic neuropathy developing after bortezomib treatment.

Catatonia and Neuroleptic Malignant Syndrome in Patients With Cerebral Palsy: Two Case Reports and a Systematic Review of the Literature.

BACKGROUND: Patients with cerebral palsy, a group of movement disorders with motor, and possibly communication and behavioral features that mimic catatonic signs, may benefit from efforts to improve the detection and treatment of comorbid catatonia. Given that cerebral palsy frequently co-occurs with conditions associated with catatonia, such as autism spectrum disorder, epilepsy, intellectual disability, and mood and psychotic disorders, lifetime prevalence of catatonia in this population may be high. OBJECTIVE: This study aimed to systematically review the literature on catatonia and the related condition of neuroleptic malignant syndrome (NMS) in patients with cerebral palsy while presenting 2 additional cases of catatonia. METHODS: We used the terms "cerebral palsy" in combination with "catatoni∗," related terms for catatonia, and "neuroleptic malignant syndrome" to query Ovid MEDLINE (1948 to November 28, 2022), PsycINFO, Cumulative Index to Nursing, and Allied Health Literature, and Embase for applicable case reports. The Neuroleptic Malignant Syndrome Information Service database was also manually searched. RESULTS: In addition to our 2 catatonia reports, we identified 10 reports of catatonia in patients with cerebral palsy, as well as 8 reports of NMS. Patients with both conditions responded well, and sometimes rapidly, to treatment. Notably, of the 5 patients with catatonia and cerebral palsy who received electroconvulsive therapy, 2 developed recurrent self-limited hyperthermia posttreatment. We also identified several cases of baclofen withdrawal, which can be life threatening because of seizure risk, presenting with NMS-like features in patients with cerebral palsy who had malfunctioning intrathecal baclofen pumps for spasticity management. CONCLUSIONS: Given frequent comorbidity of conditions associated with catatonia in patients with cerebral palsy, as well as routine treatment with medications that can induce NMS, such as metoclopramide and anticholinergics, catatonia and NMS may be underreported in the cerebral palsy patient population, despite being highly treatable. Possible underdiagnosis of catatonia in patients with cerebral palsy may be because of misattribution of overlapping features between the 2 conditions to cerebral palsy. Clinicians should be aware of possible recurrent self-limited fever when using electroconvulsive therapy to treat patients with catatonia and cerebral palsy while also being vigilant for intrathecal baclofen withdrawal when encountering NMS-like features in patients with cerebral palsy.

Comparison of the onset and offset times of two available formulations of rocuronium bromide in an animal model.

Rocuronium bromide is a neuromuscular blocker in widespread use in anaesthesia, emergency and intensive care. Reports of reduced efficacy of a new different formulation of rocuronium bromide were submitted to Medsafe, the New Zealand Medicines and Medical Devices Safety Authority, in 2020. Given the requirement for rapid and predictable paralysis for patient safety the efficacy of the two available formulations of rocuronium bromide was investigated in an animal model. After ethics committee approval, 19 rats were anaesthetised and paralysis, defined as loss of tibialis anterior flexion on direct electrical stimulation of the sciatic nerve, was assessed by mechanomyography in response to ED90 doses of rocuronium.Paralysis was observed at a median of 12 seconds for the new different formulation: A, Hameln Pharma (interquartile range (IQR) 6-106 seconds) and 28 seconds for formulation B: Pfizer (IQR 12-68 seconds) P = 0.48. Offset of paralysis was observed after 293 seconds for formulation A (IQR 250-372 seconds) and 241 seconds for formulation B (IQR 220-263 seconds). While the differences observed were substantial, they were not statistically significant. Moreover, the direction of observed difference was towards a shorter median onset and longer offset for the newer formulation, a finding in the opposite direction to the initial clinical concern.Relevance to the clinical situation is indeterminate given the study was stopped at low numbers for futility and limitations around the clinical applicability of animal pharmacokinetics and dynamics. Nevertheless our findings provide some reassurance that the newly available different formulation of this critical use medication does not exhibit a substantial increase in time to onset.

Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi.

Human and veterinary filarial nematode infections are a major health concern in tropical countries. They are transmitted by biting insects and mosquitoes. Lymphatic filariasis, a group of filarial infections caused by Brugia spp. and Wucheria bancrofti affect more than 120 million people worldwide. Infected individuals develop swollen limbs and disfigurement, leading to an inability to work and ostracization from society. Control and prophylaxis for these infections involve mass drug administration combinations of anthelmintics including diethylcarbamazine (DEC). DEC has actions on microfilariae, but its effects on adult worms are less pronounced. The SLO-1 (BK) channel activator, emodepside, kills adults of many filarial species. However, the in vivo efficacy of emodepside is suboptimal against B. malayi, possibly due to reduced bioavailability in the lymphatic system. Expressing different slo-1 splice variants in B. malayi also affects sensitivity to emodepside. This study explores the potentiation of emodepside mediated paralysis by DEC in adult female B. malayi. Worminator motility measurements show that co-application of DEC and emodepside increases the potency of emodepside 4-fold. The potentiation of the emodepside effect persists even after the worms recover (desensitize) from the initial effects of DEC. RNAi knock-down demonstrates that the DEC-mediated potentiation of emodepside requires the presence of TRP-2 channels. Our study demonstrates that the addition of DEC could enhance the effect of emodepside where bioavailability or activity against a specific species may be low.

[Intrathecal Baclofen Therapy for Spastic Paralysis].

Intrathecal baclofen therapy(ITB)is a recognized treatment for spastic paralysis. Direct injection of baclofen into the intrathecal space through a catheter from a battery-loaded pump implanted in the abdomen allows effective administration of the drug at much lower doses than oral administration. ITB therapy is indicated for patients with severe spastic paraparesis that do not respond sufficiently to first-line medical therapy or in whom the side effects complicate treatment. A pump implantation is considered in cases where spasticity is improved after intrathecal infection of a small amount of baclofen. Postoperative complications include CSF leakage, infection and device malfunction. Postoperatively, the patient requires baclofen refills every 2-3 months and pump replacement surgery every 6-7 years. Currently, ITB therapy is not widespread in Japan, although further popularization is expected.

One-year-old boy with refractory Listeria monocytogenes meningitis due to persistent hypercytokinemia.

We had a case of Listeria monocytogenes (LM) meningitis complicated with hypercytokinemia and hemophagocytic lymphohistiocytosis in a healthy 22-month-old boy. He was admitted to our hospital with a fever, vomiting, mild consciousness disturbances, and extraocular muscle paralysis. Magnetic resonance imaging (MRI) revealed bilateral deep white matter lesions. After receiving ampicillin, meropenem, and gentamicin, his cerebrospinal fluid (CSF) culture results turned negative on the third day of hospitalization. However, the fever intermittently persisted, and it took approximately 40 days to completely resolve. During this period, various inflammatory cytokine levels, particularly neopterin, in the blood and CSF remained elevated. Therefore, long-term administration of corticosteroids in addition to antibiotics was required. The use of dexamethasone appeared to be effective for neurological disorders such as consciousness disturbance and extraocular muscle paralysis associated with abnormal brain MRI findings. LM meningitis may present with encephalopathy and persistent fever due to hypercytokinemia. In such cases, corticosteroid therapy should be considered.

Neutralizing Antibody Given after Paralysis Onset Reduces the Severity of Paralysis Compared to Nonspecific Antibody-Treated Controls in a Mouse Model of EV-D68-Associated Acute Flaccid Myelitis.

Enterovirus D68 (EV-D68) can cause mild to severe respiratory illness and is associated with a poliomyelitis-like paralytic syndrome called acute flaccid myelitis (AFM). Most cases of EV-D68-associated AFM occur in young children who are brought to the clinic after the onset of neurologic symptoms. There are currently no known antiviral therapies for AFM, and it is unknown whether antiviral treatments will be effective if initiated after the onset of neurologic symptoms (when patients are likely to present for medical care). We developed a "clinical treatment model" for AFM, in which individual EV-D68-infected mice are tracked and treated with an EV-D68-specific human-mouse chimeric monoclonal antibody after the onset of moderate paralysis. Mice treated with antibody had significantly better paralysis outcomes compared to nonspecific antibody-treated controls. Treatment did not reverse paralysis that was present at the time of treatment initiation but did slow the further loss of function, including progression of weakness to other limbs, as well as reducing viral titer in the muscle and spinal cords of treated animals. We observed the greatest therapeutic effect in EV-D68 isolates which were neutralized by low concentrations of antibody, and diminishing therapeutic effect in EV-D68 isolates which required higher doses of antibody for neutralization. This work supports the use of virus-specific immunotherapy for the treatment of AFM. It also suggests that patients who present with AFM should be treated as soon as possible if recent infection with EV-D68 is suspected.

A dangerous food binge: a case report of hypokalemic periodic paralysis and review of current literature.

BACKGROUND: Hypokalemic periodic paralysis is a rare neuromuscular genetic disorder due to defect of ion channels and subsequent function impairment. It belongs to a periodic paralyses group including hyperkalemic periodic paralysis (HEKPP), hypokalemic periodic paralysis (HOKPP) and Andersen-Tawil syndrome (ATS). Clinical presentations are mostly characterized by episodes of flaccid generalized weakness with transient hypo- or hyperkalemia. CASE PRESENTATION: A teenage boy presented to Emergency Department (ED) for acute weakness and no story of neurological disease, during the anamnestic interview he revealed that he had a carbohydrates-rich meal the previous evening. Through a focused diagnostic work-up the most frequent and dangerous causes of paralysis were excluded, but low serum potassium concentration and positive family history for periodic paralyses raised the diagnostic suspicion of HOKPP. After the acute management in ED, he was admitted to Pediatric Department where a potassium integration was started and the patient was counselled about avoiding daily life triggers. He was discharged in few days. Unfortunately, he presented again because of a new paralytic attack due to a sugar-rich food binge the previous evening. Again, he was admitted and treated by potassium integration. This time he was strongly made aware of the risks he may face in case of poor adherence to therapy or behavioral rules. Currently, after 15 months, the boy is fine and no new flare-ups are reported. CONCLUSION: HOKPP is a rare disease but symptoms can have a remarkable impact on patients' quality of life and can interfere with employment and educational opportunities. The treatment aims to minimize the paralysis attacks by restoring normal potassium level in order to reduce muscle excitability but it seems clear that a strong education of the patient about identification and avoidance triggering factors is essential to guarantee a benign clinical course. In our work we discuss the typical clinical presentation of these patients focusing on the key points of the diagnosis and on the challenges of therapeutic management especially in adolescence. A brief discussion of the most recent knowledge regarding this clinical condition follows.

Antidotal treatment of botulism in rats by continuous infusion with 3,4-diaminopyridine.

Botulinum neurotoxins (BoNTs) are highly potent, select agent toxins that inhibit neurotransmitter release at motor nerve terminals, causing muscle paralysis and death by asphyxiation. Other than post-exposure prophylaxis with antitoxin, the only treatment option for symptomatic botulism is intubation and supportive care until recovery, which can require weeks or longer. In previous studies, we reported the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses early botulism symptoms and prolongs survival in lethally intoxicated mice. However, the symptomatic benefits of 3,4-DAP are limited by its rapid clearance. Here we investigated whether 3,4-DAP could sustain symptomatic benefits throughout the full course of respiratory paralysis in lethally intoxicated rats. First, we confirmed serial injections of 3,4-DAP stabilized toxic signs and prolonged survival in rats challenged with 2.5 LD50 BoNT/A. Rebound of toxic signs and death occurred within hours after the final 3,4-DAP treatment, consistent with the short half-life of 3,4-DAP in rats. Based on these data, we next investigated whether the therapeutic benefits of 3,4-DAP could be sustained throughout the course of botulism by continuous infusion. To ensure administration of 3,4-DAP at clinically relevant doses, three infusion dose rates (0.5, 1.0 and 1.5 mg/kg∙h) were identified that produced steady-state serum levels of 3,4-DAP consistent with clinical dosing. We then compared dose-dependent effects of 3,4-DAP on toxic signs and survival in rats intoxicated with 2.5 LD50 BoNT/A. In contrast to saline vehicle, which resulted in 100% mortality, infusion of 3,4-DAP at ≥ 1.0 mg/kg∙h from 1 to 14 d after intoxication produced 94.4% survival and full resolution of toxic signs, without rebound of toxic signs after infusion was stopped. In contrast, withdrawal of 3,4-DAP infusion at 5 d resulted in re-emergence of toxic sign and death within 12 h, confirming antidotal outcomes require sustained 3,4-DAP treatment for longer than 5 d after intoxication. We exploited this novel survival model of lethal botulism to explore neurophysiological parameters of diaphragm paralysis and recovery. While neurotransmission was nearly eliminated at 5 d, neurotransmission was significantly improved at 21 d in 3,4-DAP-infused survivors, although still depressed compared to naïve rats. 3,4-DAP is the first small molecule to reverse systemic paralysis and promote survival in animal models of botulism, thereby meeting a critical treatment need that is not addressed by post-exposure prophylaxis with conventional antitoxin. These data contribute to a growing body of evidence supporting the use of 3,4-DAP to treat clinical botulism.

Primary cutaneous CD8+ cytotoxic T-cell lymphoma of the face with intraoral involvement, resulting in facial nerve palsy after chemotherapy.

The primary cutaneous (PC) CD8+ T-cell lymphoproliferative disorders (LPDs) comprise clinically and histopathologically heterogeneous entities including mycosis fungoides, lymphomatoid papulosis, hydroa-vacciniforme-like LPD, subcutaneous panniculitis-like T-cell lymphoma (TCL), PC acral CD8+ TCL, PC CD8+ aggressive epidermotropic cytotoxic TCL, and PC peripheral TCL, not otherwise specified (PTCL-NOS). We describe a 33-year-old man who presented with progressive facial swelling and lower lip involvement 1 year ago. Microscopy revealed an atypical small to medium-sized lymphoid proliferation exhibiting perivascular accentuation, adnexotropism, and apoptotic cell debris, without surface epithelium involvement. The tumor cells were positive for CD3, CD8, granzyme B, perforin, MUM1/IRF4, and TCR-BF1. The Ki-67 labeling index was 48%. EBER1/2 was negative. Additional studies confirmed localized disease. The diagnosis favored PC-PTCL-NOS. Two months after completing chemotherapy, right-sided facial nerve palsy was diagnosed. CD8+ T-cell LPDs should be considered in the differential diagnosis when assessing facial swelling with intraoral involvement.