Severe and rare neurological manifestations following COVID-19 infection in children: A Malaysian tertiary centre experience.

INTRODUCTION: Since the emergence of COVID-19, we have experienced potent variants and sub-variants of the virus with non-specific neurological manifestations. We observed a surge of the Omicron variant of COVID-19 patients with neurological manifestations where less cases of multisystem inflammatory syndrome in children (MIS-C) were reported. This article describes our experience of children with severe and rare neurological manifestations following COVID-19 infection. METHODS: This is a retrospective observational case series of patients under 18 years old who fulfilled the WHO COVID-19 case definition and were referred to our paediatric neurology unit at Hospital Tunku Azizah Kuala Lumpur. Their demographic data, neurological symptoms, laboratory and supporting investigations, neuroimaging, treatment and outcomes were collected and analysed. RESULTS: There were eleven patients with neurological manifestations who fulfilled the WHO COVID-19 case definition. Nine patients presented with seizures and/or encephalopathy, one patient with eye opsoclonus and another patient with persistent limbs myokymia. Based on the history, clinical, electrophysiological and radiological findings, two of them had febrile infection-related epilepsy syndrome, two had acute disseminated encephalomyelitis, two had acute necrotising encephalopathy of childhood, one each had hemiconvulsion-hemiplegia-epilepsy syndrome, acute encephalopathy with bilateral striatal necrosis, hemi-acute encephalopathy with biphasic seizures and reduced diffusion, infection-associated opsoclonus and myokymia. CONCLUSIONS: This case series highlighted a wide spectrum of neurological manifestations of COVID-19 infection. Early recognition and prompt investigations are important to provide appropriate interventions. It is essential that these investigations should take place in a timely fashion and COVID-19 quarantine period should not hinder the confirmation of various presenting clinical syndromes.

Radiation-Induced Lumbosacral Plexopathy.

Lumbosacral plexopathy (LSP) encompasses a group of disorders affecting post-ganglionic fibers derived from the L1-S4 roots. The differential diagnosis is challenging and includes other neuropathies of medullary, radicular, or peripheral origin. Defining the etiology is equally crucial, as LSP management relies on its cause. A thorough clinical history should address potential neoplastic disease (new-onset, progression, or relapse), diabetes mellitus, lumbar or pelvic trauma, and previous exposure to radiation. This is the case of a 78-year-old male, with a history of prostatic adenocarcinoma, treated with image-guided radiation therapy and hormone therapy five years before, with no evidence of relapse on follow-up. The patient presented with bilateral weakness, numbness, and paresthesia of lower limbs, gradually progressing over a three-month period, and followed by an acute worsening with inability to stand or walk. He also referred to distal mild edema, episodic hematuria, and urinary incontinence. Physical examination revealed paraparesis affecting proximal and distal leg muscles, along with bilateral hypoesthesia, impaired deep tendon reflexes, and proprioception below knee level. Pelvic, dorsal, and lumbosacral MRI excluded neoplastic lesions but identified somatic fracture of L5 without medullary or conus medullaris compromise. These findings did not explain the clinical picture. Further neurophysiologic studies characterized sensory-motor deficits as post-ganglionic, with specific spontaneous discharges of the muscle fibers, known as myokymia. These findings were consistent with radiation-induced LSP and were supported by MRI. Radiation-induced cystitis was also documented in pelvic MRI and urethral cystoscopy. This case highlights the clinical picture and differential diagnosis of radiation-induced LSP. Despite more typical symptoms and course, a neoplastic origin should always be carefully investigated and excluded. Radiation protocol should be carefully accessed, and its complications should not be overlooked, as they might cause severe morbidity.

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy.

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel's pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Neurologic and hematologic sequalae following a timber rattlesnake (Crotalus horridus) envenomation in a dachshund.

A 2-year-old female Dachshund had a witnessed timber rattlesnake envenomation. Although rattlesnake envenomations are a common, potentially life-threatening event in companion animals, timber rattlesnake envenomations in the dog are rarely reported. This dog described in this case report had significant hematologic and neurologic clinical derangements consistent with Types A and B rattlesnake venom and a suspected hypersensitivity reaction to the venom. This patient was treated aggressively with antivenom and fully recovered without any persistent neurologic signs at follow-up.

Eyelid myokymia caused by a trigeminal schwannoma as determined by the trigeminal-evoked blink reflex.

A 57-year-old man had trigeminal schwannoma in Meckel's cave with eyelid myokymia only. The evaluation of the trigeminal-evoked blink reflex was useful for confirming eyelid myokymia and contributed to surgical decision-making. In patients with persistent eyelid myokymia, neurophysiological and imaging evaluations may be useful for determining the underlying pathophysiology.

A case report of lumbosacral plexopathy in a patient with a history of sacral chordoma and radiotherapy: Will the detection of myokymia on the EMG help to solve the case?1.

BACKGROUND: When a patient with a prior history of malignancy and radiotherapy develops progressive weakness as a presentation of plexus involvement, the differential diagnosis usually rests between radiation-induced plexopathy and invasion from recurrent tumor. The presence of myokymic discharges is helpful in differentiating radiation-induced from neoplastic plexopathy. OBJECTIVE: To present a case report of a patient with chordoma, a locally aggressive tumor, who was diagnosed with recurrent tumor accompanied by the occurrence of myokymia in needle electromyographic examination. METHOD: A 55-year-old male patient with a history of chordoma and radiotherapy presented to our outpatient clinic with complaints of foot drop, and impaired walking for two months. His latest magnetic resonance imaging (MRI) which was performed three months earlier did not show recurrence. Upon electromyographic evaluation, myokymia, the pathognomic electromyography abnormal wave for radiation plexopathy was detected supporting a diagnosis of radiation plexitis rather than recurrent neoplastic invasion. One month later he presented with more severe pain and was re-evaluated by an MRI, on which a mass was detected indicating relapse. CONCLUSION: With this case report, we would like to emphasize that the behaviour of the tumor should be considered and imaging should be repeated when tumors display aggressive or recurrent behaviour.

Botulinum Toxin Type A for the Treatment of Limb Myokymia: Experiences of Three Children.

Myokymia is a rare neuromuscular disorder and limb involvement is not common in this disease. To the best of our knowledge, isolated peroneus longus muscle myokymia was not reported before in the literature; and for that reason treatment protocols were not established. Botulinum toxin type A (BoNT-A), which is used in the treatment of a variety of neurologic disorders, was also defined as a treatment option in myokymia. Herein, we will report three cases of peroneus longus muscle myokymia in children in the absence of any other neurological findings, and the successful results of treatment with local BoNT-A injections. BoNT-A is a safe and effective treatment in myokymia when administered by an experienced clinician and should always be considered when the disorder is persistent and affecting the life of the patient.

Acetazolamide-Induced Periorbital Myokymia: A Case Report.

Acetazolamide, a carbonic anhydrase inhibitor, is primarily used in the treatment of glaucoma, due to its role in decreasing intraocular pressure by lowering the production of aqueous humor. Additionally, by lowering cerebrospinal fluid (CSF) production, it is also used in the treatment of raised intracranial pressure. Drug-induced myokymia has rarely been reported, with known triggers being clozapine, gabapentin and flunarizine, and topiramate. Acetazolamide-induced myokymia itself has only been reported once before, to the best of our knowledge, and the exact mechanism behind this occurrence remains unknown. We, therefore, report a rare case of periorbital myokymia induced by the use of acetazolamide in a patient diagnosed with idiopathic intracranial hypertension. The nature of her symptoms was significant, as they caused her considerable distress, and subsided almost immediately upon discontinuation of the drug.

Rituximab Was Effective in Relieving Symptoms of Isaacs Syndrome: A Case Report.

We presented a 23-year-old patient who had experienced neuromyotonia in his left leg. Although he tested negative for anti-LGI1 and anti-CASPR2 antibodies, we diagnosed him with Isaacs syndrome due to myokymic discharges on electromyography and symptoms being relieved by intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIg). IVMP, IVIg, plasma exchange, or cyclosporine treatment did not provide a long-term response; however, rituximab showed long-term improvement. Rituximab should be considered early in the treatment of patients with antibody-negative Isaacs syndrome who are responsive to immunotherapy, including IVMP, IVIg, and plasma exchange, and have long-term symptoms that are hard to control.

Treatment of segmental continuous hypertrophic myokymia of the limb with botulinum A toxin.

Myokymia is defined as fluctuating hyperexcitability of muscle fibers caused by repetitive spontaneous contraction of motor units. Myokymia is generally benign with self-resolution, although symptomatic treatment with benzodiazepines, anticonvulsants, and muscle relaxants can be used. Botulinum toxins can also be utilized, although they are mostly used for symptomatic facial myokymia. Here, we report two patients who developed continuous myokymia, resulting in secondary hypertrophy, stiffness, and discomfort in the affected muscles. The first patient had a history of a tethered spinal cord and developed continuous myokymia in the S1 and S2 radicular regions of the left leg. The second patient underwent radiation therapy for lung cancer and developed brachial plexopathy with abnormal activity in the muscles supplied by the musculocutaneous nerve in the right arm. Both patients experienced sleep disturbance, focal discomfort, and restlessness. The anticonvulsants and muscle relaxants were ineffective. Chemodenervation with botulinum A toxin was initiated using either onabotulinumtoxinA or abobotulinumtoxinA. Both patients experienced a substantial reduction in myokymia, with ongoing reversal of muscle hypertrophy and significant improvement in reported subjective symptoms. Treatment with botulinum toxins can be highly effective in patients with symptomatic segmental continuous hypertrophic myokymia and may be considered first-line therapy.

Facial involvement in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) can present with facial symptoms and signs, such as facial palsy, myokymia, and hemifacial spasm. Considering the importance of early diagnosis, treatment, and exclusion of causes other than MS, we aimed to assess the prevalence of these disorders in patients with MS. METHODS: MS patients who were referred to the Isfahan MS clinic from March 2021 to March 2022 were observed for facial presentations of the disease. A checklist of patients' baseline characteristics and disease features were then completed through patient interview and medical files. RESULTS: Of the total of 2260 MS patients who were assessed, 3.27% had facial palsy, 1.28% had myokymia, and 0.84% presented with hemifacial spasm. The mean age of facial symptom onset was 30.74, 29.07, and 31.37 years, respectively. No relationship was found between the type of facial presentation and factors such as age, gender, subtype of MS, affected side of face, and time of presentation. CONCLUSION: On the grounds that facial disorders can be the first presentation of MS, patients with atypical features of other common facial diseases such as Bell's palsy should therefore be carefully assessed and followed for any clues pertaining to the diagnosis of MS.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

When muscle quivers and undulates.

We describe a patient who presented with fatigue and pulling sensation in his lower limbs. He had continuous muscle contractions over his trunk (myokymia) which pointed towards the diagnosis of Isaacs syndrome which was confirmed by strongly positive CASPR2 antibodies in blood.

Morvan's syndrome Presenting with Psychiatric Manifestations - A Case Report and Review of the Literature.

The term "la chorιe fibrillare" was used by the French physician Augustine Marie Morvan to describe a syndrome showing hyperactivity features involving the central, autonomic, and peripheral nervous system. The central hyperactivity symptoms are confusion, behavioral problems, hallucinations, myoclonus, and insomnia; the autonomic hyperactivity symptoms are hyperhidrosis and variations in blood pressure; and peripheral hyperexcitability is characterized by painful cramps, myokymia, and neuromyotonia. Here, we present a case that has typical features of Morvan's syndrome and provides a brief description based on available literature.

Thymoma-associated anti-LGI1 encephalitis and myasthenia gravis: A unique combination with autoantibodies.

We report a 77-year-old woman with a thymoma, anti-LGI1antibody associated encephalitis (LGI1 encephalitis), and MG accompanied by positive anti-acetylcholine receptor antibodies (AchR Ab) and anti-titin antibodies (titin Ab). She was treated with thymomectomy followed by immunosuppressive therapy, which resulted in immediate amelioration of motor weakness and gradual improvement of cognitive impairment over the next two years. LGI1 Ab were positive at two months after thymomectomy, followed by negative conversion demonstrated on 1 year examination. The AchR Ab level had gradually decreased but titin Ab was positive on re-examination after two years, although the cognition and motor impairment symptoms had been alleviated. In patients with suspected autoimmune encephalitis, the detection of several autoantibodies including LGI1 and thymomas provides useful information for making an accurate diagnosis.

Eyelid Myokymia-a Presumed Manifestation of Coronavirus Disease 2019 (COVID-19).

The purpose of this study is to report eyelid myokymia in patients recently recovered from COVID-19 disease. A cohort of 15 patients who developed eyelid myokymia during or immediate post-recovery of systemic disease were evaluated. Demographic, clinical characteristics, effect of age, and hospitalization on the disease course were studied. The disease course was evaluated every month for 3 months period. All, except 2, patients had complete resolution of lid myokymia within 3 months of onset. Median [IQR] myokymia recovery time was 42 [31,60] days. Age and duration of hospitalization had a significant linear relationship with myokymia recovery time. Recovery was delayed by 2.64 days with every 1-year increment in age and by 6.19 days with every additional day of hospital stay. Recovery time was independent of severity of systemic disease (P = .055) and gender (P = 0.2). Eyelid myokymia can be a possible manifestation of COVID-19 recovery phase. While myokymia recovers gradually in all these patients, older age and a longer duration of hospitalization are associated with slower recovery.

Morvan's syndrome: An unusual presentation of a solid pseudopapillary pancreatic tumor.

Morvan's syndrome is a rare anti-contactin-associated protein-like 2 (CASPR2) antibody-mediated autoimmune disorder. The clinical features of this syndrome include muscular twitching, insomnia, dysautonomia, peripheral nerve hyperexcitability, and fluctuating delirium. An underlying tumor is commonly found among Morvan's syndrome cases, with thymoma being the most frequent association. We describe an unusual case of a 39-year-old female with excruciating bilateral leg pain, insomnia, hyperhidrosis, peripheral nerve hyperexcitability, serum anti-CASPR2 antibody positivity, and a solid pseudopapillary tumor of the pancreas on histopathology. Furthermore, the patient's symptoms improved after receiving intravenous immunoglobulin (0.4 g/kg per day for 5 days). To the best of our knowledge, this is the first case of Morvan syndrome associated with a solid pseudopapillary pancreatic tumor to be reported in the literature to date. Our case adds to the spectrum of malignancies that are associated with Morvan's syndrome. The recognition of this rare syndrome and its various associations are important for the neurologist, as it is a potentially treatable condition.

Post-Irradiation Facial Neuromyotonia/Myokymia: A Hemifacial Spasm Mimic.

Background: Hemifacial spasm is diagnosed on a clinical base, with certain atypical features alerting the physician for mimics. Phenomenology shown: Hemifacial neuromyotonia/myokymia characterized by tonic hemifacial contraction followed by multifocal undulating hemifacial twitches. Educational value: These features are a red flag for (post-irradiation) facial neuromyotonia/myokymia which generally responds well to low dose carbamazepine.