Episodic Neurological Dysfunction Research Articles

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Systematic review of CMTX1 patients with episodic neurological dysfunction.

ObjectiveX‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) is an inherited peripheral neuropathy caused by mutations in the gap junction beta 1 (GJB1) gene, which encodes the connexin32 protein. A small number of patients with GJB1 mutations present with episodic neurological dysfunction and reversible white matter lesions, which has not been adequately reported. Here, we aim to enable clinicians to further understand this particular situation through systematically reviewing all published relevant cases.MethodsWe conducted a comprehensive search of the PubMed electronic database for medical literature relevant to CMTX1 patients with episodic neurological dysfunction and then fully analyzed the general information, clinical manifestations, and characteristics of magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and nerve conduction study (NCS).ResultsWe identified 47 cases of CMTX1 associated with episodic central nervous system (CNS) dysfunction from 38 publications. CMTX1 patients experienced episodic CNS deficits at a young age, ranging from infancy to 26 years, and 45 (95.7%) of them were male. The CNS symptoms manifested as facial, lingual, or limb weakness in 44 (93.6%), dysarthria or dysphagia in 39 (83.0%), facial or limb numbness in 15 (31.9%), and ataxia in 10 (21.3%) patients. The duration of episodic symptoms ranged from 3 minutes to 6 months. Thirty (63.8%) CMTX1 cases have reported obvious predisposing factors, among which the most common factors were infection or fever (27.7%), travel to high altitude (12.8%), and intensive exercise (8.5%). As for brain MRI, most abnormal signals were found in bilateral deep white matter (88.9%) and corpus callosum (80.0%). In addition, most of the NCS results were abnormal, including prolonged latency, reduced amplitude, and slowed conduction velocity. The motor nerve conduction velocity (MNCV) of median nerve was the most detectable and valuable, ranging from 25 to 45 m/s.InterpretationWe have reported the most comprehensive summary of the demographic and clinical profile from 47 CMTX1 patients with episodic CNS deficits and provided new insight into the phenotype spectrum of CMTX1. We hope that our study can help clinicians make early diagnosis and implement the best prevention and treatment strategies for CMTX1 patients with episodic CNS deficits.

Sexual dysfunction among married multiple sclerosis patients in Kingdom of Saudi Arabia 2020

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions. Sexual dysfunction (SD) is a common disorder in both male and female patients complaining of multiple sclerosis (MS).Methods: A descriptive cross-sectional study was conducted including patients with MS attending Arfa MS Society in Saudi Arabia. Data were collected from participants using electronic pre-structured questionnaire. The questionnaire was uploaded online using social media platforms. Multiple sclerosis intimacy and sexuality questionnaire (MSISQ-19) was used to assess sexual dysfunction. Patient health questionnaire (PHQ-9) was used to assess patient’s psychological health and depression.Results: The study included 303 patients with multiple sclerosis whose ages ranged from 20 to 62 years old with mean age of 34.7±8.2 years old. About 75.6% took a long time to reach orgasm. Feeling sexual pleasure was reported by 73.3% of the patients and 70% reported that they had less interest or less desire for sexual activity. In general, the patients score regarding primary sexual dysfunction was 13.7 out of 25 (54.8%), 24.4 out of 45 for secondary sexual dysfunction (45.2%), and 12.6% out of 25 for tertiary sexual dysfunction (50.3%).Conclusions: In conclusion, the study revealed that sexual dysfunction in multiple sclerosis patients is not a simple process. MS was associated with high sexual dysfunction with other psychological disorders affecting male and female patients equally regardless age and educational level.

CMET-24. PLATEAU WAVE EVENTS: A COMMON, CURABLE, AND ROUTINELY MISDIAGNOSED SYNDROME IN PATIENTS WITH NEOPLASTIC MENINGITIS (NM)

Abstract INTRODUCTION NM is defined clinically by multilevel neurologic dysfunction. Seizures occur in less than 15% of patients. We describe a curable phenomenon (“plateau wave events”) that mimics and may be more common than seizures, but is not responsive to anticonvulsant medication. METHODS We queried a multinational NM registry to identify patients with episodic neurologic dysfunction suspected of having seizures. Detailed demographic, disease, treatment, and outcome data were collected. RESULTS Forty-three patients (21.2% of 203) were identified. Twenty patients (46.5% of 43) demonstrated a stereotyped constellation of symptoms including episodic severe headache and loss (19 patients) or impaired level (1 patient) of consciousness, nausea, vomiting, and gait instability lasting 30–180 seconds, with abrupt resolution and without post-ictal symptoms. Events developed a median of 74 (0–350) days following NM diagnosis. Fourteen patients (74%) were female. Median age was 54.8 [IQR 46.8, 61.6] years. Fourteen patients had solid tumors (11 breast), 5 had hematologic malignancies, and 1 had a primary brain tumor. Thirteen (68%) had ventriculomegaly. All patients demonstrated increased ICP [median 30.0 cm H2O, IQR 22.5, 30.0]. CSF cytology was positive and CSF protein was increased in 100% of patients, but no demographic, laboratory, or disease characteristic was associated with plateau wave events on multivariate analysis. Inter-ictal EEG in 8 patients showed no epileptiform activity. One intra-ictal EEG showed marked brainwave slowing and bradycardia during the clinical event. One intra-ictal ICP tracing showed an abrupt and dramatic increase in intracranial pressure during the event. Nineteen patients underwent ventriculoperitoneal shunting and experienced immediate symptom resolution. Anticonvulsant medication, initiated in 11 of these patients prior to shunting, provided no benefit. CONCLUSIONS Plateau wave events are common in patients with NM. They are frequently mistaken for seizures but are easily recognized by a constellation of defining signs and symptoms. Ventriculoperitoneal shunting is curative.

Effects of intestinal nematode treatment on CD11b activation state in an EAE mouse model of multiple sclerosis.

The experimental autoimmune encephalomyelitis (EAE) animal model of Multiple Sclerosis (MS) is characterized by episodic neurologic dysfunction arising as a consequence of perivascular mononuclear cell infiltration and demyelination in the CNS. Leukocyte integrins, which are responsible for migration through the endothelial, play key roles in the pathogenesis of autoimmune diseases and chronic inflammation. Intestinal infection of mice with Heligmosomoides polygyrus appears to target CD11b (integrin αM), which is highly expressed on myeloid cells and is critical for their migration and function. H. polygyrus infection induces suppression of ongoing experimental EAE and extensive infiltration of CD11b+ cells to the CNS. Therefore, the aim of the present study was to characterize the phenotype and activity of CD11b+ cells accompanying the tissue phase infection of L4 H. polygyrus in EAE mice. It was found that the cells displayed a CD11b+ state with a distinct phenotype characterised by the expression of co-stimulatory CD80/CD86, CD40, MHCII, F4/80 and the mannose receptor CD206. This activation state illustrates the heterogeneity of CD11b+ cells in EAE mice following nematode invasion; these may have important consequences for understanding the effects of CD11b integrin, which is involved in the downregulation of neuroinflammatory disorders.

The abnormal bifid W-waveform visual evoked potential early indicated of demyelination optic neuritis is a primary sign of multiple sclerosis disease

Objective: Multiple sclerosis (MS) is the inflammatory demyelinating process resulting in the episodic neurological dysfunction, involvement of the retinal pathway in the form of optic neuritis. These are clinical causes of ophthalmic symptoms, such as the blurring of vision, impaired of vision, and some cases are silent and the visual evoked potential (VEP) may be beneficial if there is abnormality along the optic tract.Methods: A total of 20 elected patients with MS compared with 15 healthy control groups. All groups in the present study conducted by the reversal pattern of VEP test for both eyes identify the N75-P100-N145 parameters and the percentage of the bifid W-waveform recorded in VEP.Results: The VEPs study recorded the highly significant difference in comparing between the patients and the control group; we found the significant difference (<0.005) in latency of N75, P100, N145 and N75/P100 amplitude in both eyes. The bifid W-waveform of abnormal VEP recorded in 65% of patients, 45% of the patients had bifid changes in both eyes and 20% of patients had changes in the left eye. These changes of waveform ship had a significant relationship to loss of amplitude but not related to prolong of P100 latency.Conclusion: The bifid W-shape waveform in abnormal VEP indication in early diagnosis the demyelination lesions of the optic pathway in patients with clinical and subclinical ophthalmic manifestation, a primary sign of MS diseases.

Therapeutic Application of Monoclonal Antibodies in Multiple Sclerosis.

Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disorder of the central nervous system (CNS). People with MS typically have a relapsing remitting disease course, with episodic neurological dysfunction corresponding to inflammation in the brain or spinal cord. Some relapsing patients develop a secondary progressive disease course, with accumulation of disability over time, yet other people with MS only experience a primary progressive course. Over the past 20 years, 14 immunomodulatory therapies have been approved in MS in order to reduce the frequency of inflammatory relapses and prevent CNS damage. Of the available types of therapies, the monoclonal antibodies are generally the most effective at dampening MS disease activity. In this review we will discuss the development of effective monoclonal antibody therapies coinciding with a better understanding of the complex immunopathogenesis of MS, both successes and failures, as well as targets for future development that address the mechanisms underlying progressive disease.

The syndrome of stroke-like migraine attacks after radiation therapy associated with prolonged unresponsiveness in an adult patient.

The syndrome of stroke-like migraine attacks after radiation therapy (SMART) is an extremely rare complication of cerebral irradiation. It is characterized by reversible episodic neurological dysfunction, commonly associated with headaches and occasionally with seizures, occurring years after cranial radiotherapy. Approximately a dozen cases have been reported in adult patients to date. In 1997, a 48-year-old man underwent resection of a right cerebellar metastasis from renal cell carcinoma, followed by whole-brain irradiation. Two years later he began experiencing recurrent episodes of headache associated with reversible left hemiparesis, dysphasia, visual field defects, and confusion. Over subsequent years these episodes increased in frequency, and in 2009 and 2010 the patient experienced 2 episodes associated with seizures and characterized by severe depression in level of consciousness (GCS 5); the latter of these was particularly prolonged, with neurological recovery requiring almost 6 months. Cortical and leptomeningeal gadolinium enhancement was demonstrated on magnetic resonance imaging during the second episode. Repeated electroencephalography studies did not demonstrate any epileptiform activity, and extensive workup including brain biopsy failed to identify any neoplastic, vascular, or infective pathology. The diagnosis of SMART syndrome was therefore made. Reduced level of consciousness of such severity and duration as observed here has not previously been described in SMART syndrome. This report, however, suggests that an excellent prognosis can be expected even in cases of prolonged unresponsiveness. The pathogenic mechanisms of SMART syndrome remain unclear, but may involve pathways common to both migraine and epilepsy.

Stress, caffeine and ethanol trigger transient neurological dysfunction through shared mechanisms in a mouse calcium channelopathy

Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the CaV2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in CaV2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked.

Multiple sclerosis and sexual dysfunction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions. The underlying pathogenesis of MS remains largely unclear. However, it is currently accepted as a T cell-mediated autoimmune disease. Among other clinical manifestations, sexual dysfunction (SD) is a painful but still underreported and underdiagnosed symptom of the disorder. SD in MS patients may result from a complex set of conditions and may be associated with multiple anatomic, physiologic, biologic, medical and psychological factors. SD arises primarily from lesions affecting the neural pathways involved in physiologic function. In addition, psychological factors, the side effects of medications and physical symptoms such as fatigue, muscular weakness, menstrual changes, pain and concerns about bladder and bowel incontinence may also be involved. Since MS primarily affects young people, SD secondary to MS may have a great impact on quality of life. Thus, maintaining a healthy sexual life with MS is an important priority. The treatment of SD requires multidisciplinary teamwork and cooperation among specialists, individual patients, partners and the society.

Familial Hemiplegic Migraine with Prolonged Coma and Cerebellar Atrophy: CACNA1A T666M Mutation in a Korean Family

We report the first Korean patient with familial hemiplegic migraine type 1, with clinical and multimodal imaging findings. A 43-yr-old man was admitted for right hemianopia and aphasia, followed by coma. MRI showed only cerebellar atrophy. CT angiography showed mild vasodilation of intracranial blood vessels and increased vascularity in the left hemisphere and perfusion-weighted imaging showed elevated cerebral blood flow. Gene analysis of the patient and his mother led to the identification of a heterozygous point mutation (1997C→T, T666M) in exon 16 of the CACNA1A gene. Familial hemiplegic migraine should be considered in patients with episodic neurological dysfunction with cerebellar atrophy.

Clinical Outcome of 50 Progressive Multiple Sclerosis Patients Treated with Cellular Therapy in Iraq

Multiple Sclerosis is a disease characterized by multifocal areas of demyelination in the brain and spinal cord, with associated inflammatory cell infiltrates, reactive gliosis, and axonal degeneration. It typically presents in young adults with episodic neurologic dysfunction, our aim is to find new simple method to treat multiple sclerosis by hematopoietic stem cells derived from peripheral blood. 50 patients suffering from multiple sclerosis worsening despite pharmacological treatment were treated by means of several intrathecal injections of peripheral blood cells harvested by aphaeresis after G-CSF(granulocyte colony stimulating factor) treatment. 24 patients (48% ) had a reduction of EDSS score. 8 patients had a relapse, but it was milder than usual and more easily controlled by cortisone. Since mesenchymal cells increase in the peripheral blood after G-CSF stimulation, a peripheral blood harvest seems easier and cheaper than mesenchymal cells cultivation prior to the injection. It seems a reasonable treatment for progressive multiple sclerosis.

Episodic cerebellar dysfunction in a bichon frise: a canine case of episodic ataxia?

A four-year-old neutered male bichon frise was presented for the evaluation of chronic, progressive yet episodic neurological dysfunction that was predominantly cerebellar in nature. Diagnostic testing including haematology, serum chemistry, magnetic resonance imaging, cerebrospinal fluid analysis and urine organic acid screening was normal. Trial therapies with phenobarbital, prednisone and acetazolamide were unsuccessful. Treatment with 4-aminopyridine led to complete resolution of the signs.

Advances in the Immune Pathogenesis and Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is a disorder of the central nervous system (CNS). It is characterized by episodic and progressive neurological dysfunction resulting from inflammatory and autoimmune reactions, myelin loss, conduction block, oligodendrocyte pathology, gliosis, and axonal loss in CNS. Recent years have witnessed advances in better understanding the immune pathogenesis of MS, prompted by animal models, human pathological observations and MRI studies. There have been significant changes in the therapeutic regimens in MS, with an emphasis on preventative treatment of an ongoing disease process. Agents in use and in the research pipeline have mechanisms that act on various anti-inflammatory and immunomodulatory properties, including blocking leukocyte migration into CNS and targeting chemoattraction. In addition, recent studies on the neurodegenerative components of MS have directed therapeutic trials to neuroprotection and neurorestoration. In this paper, we summarize the current understanding of the mechanisms of approved pharmacological agents and review the putative mechanisms and status of some important agents in clinical phase two or three trials in MS.

Episodic neurologic dysfunction with migraine and reversible imaging findings after radiation

Reported are three adults who developed frequent episodes of a complex neurologic syndrome years after radiation therapy for a brain tumor. MRI and [(18)F]fluorodeoxyglucose PET performed during the episodes demonstrated dramatic gyral thickening with enhancement and intense hypermetabolism in symptomatic regions that resolved on follow-up studies. EEG during episodes showed only slowing. The differential diagnosis and imaging findings are reviewed.

Noradrenergic blockade prevents attacks in a model of episodic dysfunction caused by a channelopathy

Episodic neurological dysfunction often results from ion channel gene mutations. Despite knowledge of the mutations, the factors that precipitate attacks in channelopathies are not clear. In humans, mutations of the calcium channel gene CACNA1A are associated with attacks of neurological dysfunction in familial hemiplegic migraine and episodic ataxia type-2. In tottering mice, a mutation in the same gene causes attacks resembling paroxysmal dyskinesia. Stress, a trigger associated with human episodic disorders, reliably elicits attacks in tottering mice. Because noradrenergic neurotransmission is critical to the stress response and because noradrenergic hyperinnervation is observed in tottering mice, the role of norepinephrine in stress-induced attacks was investigated. Drugs that act at alpha-adrenergic receptors to block noradrenergic transmission prevented attacks. However, agents that facilitate noradrenergic neurotransmission failed to induce attacks. These results suggest that, while noradrenergic neurotransmission may be necessary for attacks, an increase in norepinephrine is not sufficient to induce attacks.

Prevention and Treatment of Experimental Autoimmune Encephalomyelitis by CNI-1493, a Macrophage-Deactivating Agent

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by episodic neurologic dysfunction, perivascular mononuclear cell inflammation occurring mainly in white matter, and demyelination. Strong circumstantial evidence supports the conclusion that macrophage activation and local production of proinflammatory cytokines are necessary for disease induction and lesion formation. We now report that CNI-1493, a small m.w. compound, which inhibits macrophage activation and subsequent proinflammatory cytokine production, suppresses EAE induced in the genetically susceptible SJL/J mouse. Treatment with 5 mg/kg/day completely suppressed mild disease (clinical index of 1.6 +/- 0.5 in the untreated group as compared with 0.0 +/- 0.0 for the treated group) and significantly reduced acute disease (clinical index of 4.3 +/- 0.7 in the untreated group as compared with 0.5 +/- 0.3 for the treated group). Suppression of clinical manifestations of the disease correlated with a significant decrease in histopathology and proinflammatory cytokine expression at the lesion site. Moreover, drug treatment during the chronic phase resulted in amelioration of clinical signs. The data presented here should prove useful in developing novel chemotherapeutic approaches for the treatment of MS.

脳幹, 脊髄の海綿状血管腫

The case histories of five patients with cavernous angiomas are presented in this paper. Two of the lesions were located in the brain stem and three in the spinal cord. Three men and two women experienced episodic brain stem or spinal cord dysfunction, ranging in duration from one month to 17 years. Total removal was performed in four patients and biopsy and evacuation of the hematoma were performed in one. Neurological function improved in two patients, was unchanged in two and worsened in one.Magnetic resonance imaging (MRI) is invaluable in the diagnosis of cavernous angiomas, particularly in the brain stem and spinal cord. The combination of a reticulated core of mixed signal intensity with a surrounding rim of decreased intensity strongly suggests the diagnosis of a cavernous angioma.The management of cavernous angiomas in the brain stem and spinal cord is controversial. In recent years an increasing number of successful removals of these lesions has been reported. Surgical treatment is indicated in patients with progressive or episodic neurological dysfunction due to recurrent hemorrhages. In such cases complete removal of the lesion is feasible because a gliotic margin provides an adequate cleavage plane.