Acute Thyrotoxic Myopathy Combined with Neck Pain: A Case Report.

INTRODUCTION: Acute thyrotoxic myopathy (ATM) is a rare and potentially lethal complication of thyrotoxicosis. The typical clinical symptoms of ATM are characterized by bulbar paralysis. Reports of the successful treatment of ATM are sporadic due to its low incidence. However, no English literature has reported Chinese patients with ATM and neck pain. Here, we report for the first time a Chinese patient with ATM and neck pain who recovered through large doses of systemic glucocorticoids and one intrathyroidal steroid injection. CASE REPORT: A 23-year-old woman visited our hospital with a two-year history of progressive weakness of her bulbar muscles, hoarseness, cough when swallowing, dysphagia, and a one-month history of recurrent painful swelling of the thyroid gland. She was diagnosed with ATM, chronic thyrotoxic myopathy (CTM), and Graves' ophthalmopathy (GO) due to Graves' disease (GD). After she was treated with a combination of low-dose glucocorticoids, antithyroid drugs (ATDs), propranolol, and ultrasound-guided percutaneous intrathyroidal injection of glucocorticoids, her bulbar paralysis, proximal myopathy, and neck pain simultaneously improved without recurrence during follow-up. To our knowledge, this is the first case report of a patient with ATM, CTM, GD, GO and neck pain treated by administering a combination of low-dose glucocorticoids, one intrathyroidal steroid injection and antithyroid agents. CONCLUSIONS: Clinicians should consider ATM and intervene with aggressive glucocorticoid therapy, and this is the key to reversing the progression of ATM when a patient has bulbar paralysis and thyrotoxic symptoms. Our case report references the clinical diagnosis and treatment of such cases.

Benefit of high-dose oral riboflavin therapy in riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short-term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease-modifying therapies.

Herbal medicine and acupuncture relieved progressive bulbar palsy for more than 3 years: A case report.

RATIONALE: Progressive bulbar palsy (PBP) is a type of motor neuron disease (MND). The main symptoms include dysarthria, dysphagia, tongue muscle atrophy and fasciculations. This disease is generally severe and develops rapidly. Due to the lack of effective treatment, many patients with MND in China turn to traditional Chinese medicine treatment for help. We successfully relieved dysphagia and sialorrhea in a patient with PBP for 3 years with herbal medicine and acupuncture. PATIENT CONCERNS: The patient was a 68-years-old woman with PBP and suffered from severe dysphagia and sialorrhea. DIAGNOSES: Progressive bulbar palsy. INTERVENTIONS: Chinese herbal medicine and acupuncture. OUTCOMES: After 4 months of herbal medicine and acupuncture treatment, dysphagia and sialorrhea were relieved considerably. The patient's condition has been stable for more than 3 years and continues to be treated with Chinese herbal medicine and acupuncture. LESSONS: Our case suggests that alternative therapies such as herbal medicine and acupuncture may be effective in alleviating the symptoms of MND/PBP. However, standardized clinical studies are still required to verify the effectiveness and safety.

A case report of sudden-onset auditory neuropathy spectrum disorder associated with Brown-Vialetto-Van Laere syndrome (riboflavin transporter deficiency).

OBJECTIVE: The purpose of this paper is to describe a child with auditory neuropathy spectrum disorder (ANSD) associated with Brown-Vialetto-Van Laere (BVVL) syndrome, which is a rare, inherited, neurodegenerative disorder that is caused by defects in riboflavin transporter genes. DESIGN: We report the audiological and clinical profile of a child who presented with a complaint of sudden loss of speech understanding associated with an atypical form of ANSD. He was later diagnosed with BVVL. STUDY SAMPLE: An 11-year-old boy with ANSD associated with BVVL. RESULTS: The patient's severe neurological symptoms improved within a year of supplementation with high doses of riboflavin. His fluctuating hearing loss and 0% WDS remained unchanged. The patient was able to use hearing aids without any discomfort after treatment initiation, but he stopped using them again due to a lack of benefit in speech understanding. Although cochlear implantation was recommended, the patient and his family decided not to consider it for another year since they still had hope for complete recovery. CONCLUSIONS: Sudden-onset ANSD can be the earliest sign of undetected BVVL syndrome. Early detection of BVVL is crucial since all symptoms can be reversible with an early intervention of high doses of riboflavin supplementation.

Recent advances in riboflavin transporter RFVT and its genetic disease.

Riboflavin (vitamin B2) is essential for cellular growth and function. It is enzymatically converted to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which participate in the metabolic oxidation-reduction reactions of carbohydrates, amino acids, and lipids. Human riboflavin transporters RFVT1, RFVT2, and RFVT3 have been identified and characterized since 2008. They are highly specific transporters of riboflavin. RFVT3 has functional characteristics different from those of RFVT1 and RFVT2. RFVT3 contributes to absorption in the small intestine, reabsorption in the kidney, and transport to the fetus in the placenta, while RFVT2 mediates the tissue distribution of riboflavin from the blood. Several mutations in the SLC52A2 gene encoding RFVT2 and the SLC52A3 gene encoding RFVT3 were found in patients with a rare neurological disorder known as Brown-Vialetto-Van Laere syndrome. These patients commonly present with bulbar palsy, hearing loss, muscle weakness, and respiratory symptoms in infancy or later in childhood. A decrease in plasma riboflavin levels has been observed in several cases. Recent studies on knockout mice and patient-derived cells have advanced the understanding of these mechanisms. Here, we summarize novel findings on RFVT1-3 and their genetic diseases and discuss their potential as therapeutic drugs.

Riboflavin in Neurological Diseases: A Narrative Review.

Riboflavin is classified as one of the water-soluble B vitamins. It is part of the functional group of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors and is required for numerous flavoprotein-catalysed reactions. Riboflavin has important antioxidant properties, essential for correct cell functioning. It is required for the conversion of oxidised glutathione to the reduced form and for the mitochondrial respiratory chain as complexes I and II contain flavoprotein reductases and electron transferring flavoproteins. Riboflavin deficiency has been demonstrated to impair the oxidative state of the body, especially in relation to lipid peroxidation status, in both animal and human studies. In the nervous system, riboflavin is essential for the synthesis of myelin and its deficiency can determine the disruption of myelin lamellae. The inherited condition of restricted riboflavin absorption and utilisation, reported in about 10-15% of world population, warrants further investigation in relation to its association with the main neurodegenerative diseases. Several successful trials testing riboflavin for migraine prevention were performed, and this drug is currently classified as a Level B medication for migraine according to the American Academy of Neurology evidence-based rating, with evidence supporting its efficacy. Brown-Vialetto-Van Laere syndrome and Fazio-Londe diseases are now renamed as "riboflavin transporter deficiency" because these are autosomal recessive diseases caused by mutations of SLC52A2 and SLC52A3 genes that encode riboflavin transporters. High doses of riboflavin represent the mainstay of the therapy of these diseases and high doses of riboflavin should be rapidly started as soon as the diagnosis is suspected and continued lifelong. Remarkably, some mitochondrial diseases respond to supplementation with riboflavin. These include multiple acyl-CoA-dehydrogenase deficiency (which is caused by ETFDH gene mutations in the majority of the cases, or mutations in the ETFA and ETFB genes in a minority), mutations of ACAD9 gene, mutations of AIFM1 gene, mutations of the NDUFV1 and NDUFV2 genes. Therapeutic riboflavin administration has been tried in other neurological diseases, including stroke, multiple sclerosis, Friedreich's ataxia and Parkinson's disease. Unfortunately, the design of these clinical trials was not uniform, not allowing to accurately assess the real effects of this molecule on the disease course. In this review we analyse the properties of riboflavin and its possible effects on the pathogenesis of different neurological diseases, and we will review the current indications of this vitamin as a therapeutic intervention in neurology.

A juvenile ALS-like phenotype dramatically improved after high-dose riboflavin treatment.

Riboflavin transporter deficiency (RTD) was recently characterized as a cause of genetic recessive childhood-onset motor neuron disease (MND) with hearing loss, formerly described as Brown-Vialetto-Van-Lear syndrome. We describe a 18-year-old woman with probable RTD mimicking juvenile Amyotrophic Lateral Sclerosis (ALS) who presented with an inaugural respiratory failure and moderate distal four limbs weakness. Only one heterozygous SLC52A3 mutation was detected, but presence of a sub-clinical auditory neuropathy and dramatic improvement under high dose riboflavin argued for a RTD. As RTD probably has a larger phenotypic spectrum than expected, a high dose riboflavin trial should be discussed in young-onset MND.

Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation.

Brown-Vialetto-Van Laere syndrome (BVVLS) or riboflavin transporter deficiency (OMIM 211530) is a rare treatable autosomal recessive neurodegenerative disorder. This condition is associated with progressive pontobulbar palsy. We describe the clinical course of a 16-month-old boy with BVVLS and a novel homozygous mutation from Pakistan. Our patient presented with stridor and respiratory insufficiency. Hearing loss which is the most common sign of this condition was absent, making it an unusual presentation of BVVLS. His examination revealed ptosis and tongue fasciculation. His riboflavin receptor mutational analysis showed the homozygous mutation in the SLC52A3 gene. Per oral riboflavin was administered, and subsequently, he was able to be weaned off the ventilator. Now the child is improving and attaining developmental milestones.

Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown-Vialetto disease that is partially rescued by riboflavin.

Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown-Vialetto-Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell-selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy-lysosome pathway, we observed a reduced autophagic/mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVL-associated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies.

Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto-Van Laere syndrome.

The clinical diagnosis of Brown-Vialetto-Van Laere syndrome in this woman with rapidly progressive pontobulbar palsy led to empirical high-dose oral riboflavin (1200 mg/day) therapy. This resulted in a dramatic improvement in her motor function from being anarthric, dysphagic, tetraparetic and in ventilatory failure to living independently with mild dysarthria and distal limb weakness. DNA sequencing of the SLC52A3 gene found compound heterozygous C-terminus mutations, V413A1/D461Y, consistent with recent reports of mutations within the riboflavin transporter genes (SLC52A2 and SLC52A3) in this condition. Early diagnosis and empirical riboflavin therapy can lead to major motor recovery in this condition, that can be sustained with long-term maintenance therapy.

Human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy with bulbar palsy-type amyotrophic lateral sclerosis-like symptoms.

We herein report a case of Human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy with bulbar palsy-type amyotrophic lateral sclerosis-like symptoms. A 52-year-old woman developed dyslalia at approximately 40 years of age, which slowly progressed. She presented with muscular atrophy and increased tendon reflexes of the extremities as well as bulbar palsy, from which motor neuron disease was suspected. Cerebrospinal fluid (CSF) testing revealed no abnormalities except for an elevated neopterin concentration at 143.17 pmol/mL (normal ≤30 pmol/mL). Her serum and CSF anti-HTLV-I antibody titers were also high. Intravenous infusions of methylprednisolone decreased the CSF neopterin concentration to 50.33 pmol/mL. Subsequent oral prednisolone therapy was effective in alleviating the symptoms.

[A case of refractory generalized myasthenia gravis with anti-acetylcholine receptor antibodies treated with rituximab].

We report a case of a 57-year-old woman with thymoma-associated generalized myasthenia gravis (MG) showing severe bulbar and respiratory symptoms, moderate weakness of the neck muscles, and mild weakness of extremity muscles. Corticosteroid treatment with various types of immunosuppressive agents, such as cyclosporine, tacrolimus, and azathioprine, did not improve her symptoms. Plasma exchange transiently improved her symptoms, and she was required to undergo plasmapheresis every 4 weeks. At first, cyclophosphamide pulse therapy was administered, which improved her symptoms transiently. Thereafter, rituximab (RTX) was administered. Six months after RTX administration, respiratory distress and dysphagia improved gradually, and reduction in the dosage of corticosteroids from 30 mg/day to 10 mg/day did not result in symptom deterioration. Therefore, the interval between successive plasmapheresis treatments was increased from 4 to 9 weeks 19 months after the first RTX administration. During a 26-month period from the first administration of RTX, the number of CD20+ B cells in peripheral blood decreased and remained at 0% to 26% of that before RTX treatment. The titer of anti-acetylcholine receptor antibodies did not change during the first course of treatment (0.6-0.9 nmol/l). The clinical symptom worsened with the increase of the number of CD20+ B cells in peripheral blood in the 27 month after 1st RTX administration. Therefore, RTX was administered a second time, after which the patient's clinical symptoms again improved gradually. The titer of anti-acetylcholine receptor antibodies came to be stable with 0.5-0.7 nmol and low level during the 2nd course. Corticosteroids could be discontinued in the 16th month. The findings suggest that RTX can be one of the choices for pharmacological therapy in patients with intractable MG accompanied by the presence of anti-acetylcholine receptor antibodies.

Recent advances in bulbar syndromes: genetic causes and disease mechanisms.

PURPOSE OF REVIEW: With advances in next-generation gene sequencing, progress in deep phenotyping and a greater understanding of the pathogenesis of motor neuron disease, our knowledge of the progressive bulbar syndromes has significantly increased in recent years. This group of heterogeneous conditions, in which the primary disorder is focused around degeneration of the lower cranial nerves, can occur in children or adults and form a spectrum of severity, based around the common feature of bulbar dysfunction. Early genetic diagnosis may allow treatment in some bulbar syndromes. RECENT FINDINGS: Brown-Vialetto-Van Laere and Fazio-Londe syndromes are the most recent childhood forms of progressive bulbar palsy to be genetically defined. The clinical phenotype of this group of childhood disorders was first reported over 120 years ago. Recently, it was demonstrated that in a third of these patients Brown-Vialetto-Van Laere is caused by mutations in the SLC52A2 and SLC52A3 genes, both of which encode riboflavin transporters. Importantly, supplementation of riboflavin can lead to significant clinical improvement if started early in the disease process. SUMMARY: Here, we outline the clinical features, management and an update on the disease mechanisms and genetic causes of the progressive bulbar syndromes.