Therapeutic Implications of Peripheral Nerve Hyperexcitability in Muscle Cramping: A Retrospective Review.

PURPOSE: Muscle cramping due to peripheral nerve hyperexcitability (PNH) is poorly characterized. This retrospective study examines the prevalence of PNH and response to treatment. METHODS: The Duke EMG Database was queried to identify patients with muscle cramping tested for PNH from 2010 to 2015. Peripheral nerve hyperexcitability was defined by compound muscle action potential after-discharges on repetitive nerve stimulation. Response to treatment was determined by the treating physician's clinical impression 6 months after diagnosis or last documented visit. RESULTS: Seventy-two patients met inclusion criteria. Twenty-three (32%) patients had electrodiagnostic evidence of PNH. Of the patients with PNH, 74% had a good response to treatment whereas 37% of treated patients in the PNH-negative group (P = 0.0258). Carbamazepine and gabapentin were the most frequently used treatments with response rates of 70% and 77%, respectively. CONCLUSION: Muscle cramps associated with PNH respond well to symptomatic treatment, particularly with carbamazepine and gabapentin.

Autoimmune dementia and encephalopathy.

Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia. It may occur as a paraneoplastic phenomenon or an idiopathic autoimmune phenomenon. The presence of a personal/family history of autoimmunity, inflammatory spinal fluid, serologic evidence of autoimmunity (neural or nonorgan-specific), or mesial temporal magnetic resonance imaging abnormalities are clues to diagnosis. Bedside cognitive assessment and/or detailed neuropsychologic testing are useful. Neural-specific autoantibodies, mostly discovered in the past two decades, may bind antigens on the cell surface (e.g., N-methyl-d-aspartate receptor autoantibodies) and are likely to be pathogenic, with treatment aimed at antibody-depleting agents often with success, while antibodies binding intracellular antigens (e.g., antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu)) are a marker of a T-cell-mediated process and treated with T-cell-depleting immunotherapies, with variable responses. Detection and treatment of cancer (when present) are essential. High-dose corticosteroids are the initial treatment in most patients and may serve as a diagnostic test when the diagnosis is uncertain. Repeat cognitive testing after immunotherapy helps document objective improvements. Maintenance immunotherapy is recommended in those at risk for relapse. Prognosis is variable, but paraneoplastic ADE with antibodies to intracellular antigens have a worse prognosis. The field is still developing and future studies should provide guidelines for diagnosis and treatments.

Morvan's syndrome and myasthenia gravis related to familial Mediterranean fever gene mutations.

BACKGROUND: We present the first case of Morvan's syndrome (MoS) and myasthenia gravis (MG) related to familial Mediterranean fever (FMF) gene mutations. CASE PRESENTATION: A 40-year-old woman with a 1-year history of bilateral ptosis and limb muscle weakness presented to our hospital. She also had memory impairment, insomnia, hyperhidrosis, and muscle twitches. Electromyography confirmed widespread myokymia, and there was evidence of temporal region dysfunction on electroencephalography. Anti-voltage-gated potassium channel complex antibodies and anti-acetylcholine receptor antibodies were both positive. Edrophonium administration was effective for bilateral ptosis and muscle weakness. She and her family experienced self-limiting febrile attacks with arthralgia, which led us to suspect FMF. Genetic analyses revealed compound heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q). From these findings, a diagnosis of MoS and MG complicated with MEFV gene mutations was made. Intravenous high-dose corticosteroids, plasma exchange, and intravenous immunoglobulin resulted in only transient, limited improvement, and frequent relapses, especially in the myasthenic symptoms. Interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α were markedly elevated in the serum, which was considered to be derived from the MEFV mutations and responsible for the resistance to immunotherapy. CONCLUSION: The present case illustrates a possible link between auto-inflammation and auto-antibody-mediated neurological diseases.

[A case of Isaacs' syndrome causing various central nervous symptoms successfully treated with high-dose intravenous methylprednisolone therapy].

A 44-year-old man with a bilateral hand tremor suffered from a decline in concentration and abnormal vision for several months. He also complained of easily falling down because of muscle stiffness and cramps in his lower limbs. On admission, he demonstrated lower limb stiffness, muscle cramps, diplopia, hyperhidrosis, left upper limb ataxia and dysesthesia in all limbs. Laboratory examination showed a marked elevation in his serum creatine kinase level (26,890 U/l), and needle electromyography demonstrated myokymic discharges in the muscles of his lower extremities. Isaacs' syndrome was diagnosed based on a positive voltage-gated potassium channel antibody titer of 1,007 pM. Administration of an anticonvulsant (phenytoin, 200 mg/day) did not resolve his symptoms; however, high-dose intravenous methylprednisolone therapy (1 g/day for 3 days) resulted in marked clinical improvement. This case suggests that high-dose intravenous methylprednisolone therapy for Isaacs' syndrome might be as effective as other immunosuppressive therapies such as plasma exchange or intravenous immunoglobulin.

Voltage-gated potassium channel antibody-associated limbic encephalitis.

We are emphasising the importance of considering a rare diagnosis, voltage-gated Potassium channel antibody-associated limbic encephalitis, in an 80-year-old gentleman who presented with memory impairment, seizure and hyponatraemia. He was found to have high titre of voltage-gated potassium channel antibodies in his serum. He was given high-dose steroids and he responded biochemically and clinically with marked improvement in symptomatology.

Agrypnia excitata.

Agrypnia (from the Greek: to chase sleep) excitata (AE) is a syndrome characterized by loss of sleep and permanent motor and autonomic hyperactivation (excitata). Disruption of the sleep-wake rhythm consists in the disappearance of spindle-delta activities, and the persistence of stage 1 non-rapid eye movement (NREM) sleep. Rapid eye movement (REM) sleep persists but fails to stabilize, appearing in short recurrent episodes, isolated, or mixed with stage 1 NREM sleep. Diurnal and nocturnal motor, autonomic and hormonal overactivity is the second hallmark of AE. Of particular interest is the finding that norepinephrine secretion is extremely elevated at all hours of the day and night whereas the nocturnal melatonin peak is lacking. Oneiric stupor is probably an exclusive sign of AE and consists in the recurrence of stereotyped gestures mimicking simple daily life activities. Agrypnia excitata aptly defines 3 different clinical conditions, fatal familial insomnia (FFI), an autosomal dominant prion disease, Morvan syndrome (MS), an autoimmune encephalitis, and delirium tremens (DT), the alcohol withdrawal syndrome. Agrypnia excitata is due to an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from cortico-limbic inhibitory control. This pathogenetic mechanism is visceral thalamus degeneration in FI, whereas it may depend on autoantibodies blocking voltage-gated potassium (VGK) channels within the limbic system in MS, and in the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in DT.

[Case of anti VGKC-complex antibody associated disorder presenting with severe pain and fasciculations predominant in unilateral upper extremity].

A 21-year-old man complained of severe pain and muscle twitching localized in his right arm. Neurological examination showed muscle fasciculations in his right forearm but no myokymia or myotonia. Needle electromyography revealed fibrillation potentials in his biceps brachii muscle and extensor carpi radialis muscle at rest but no myokymic discharges. His serum anti-voltage-gated potassium channel (VGKC)-complex antibody level was significantly high (194.2pM; controls <100pM). Although anticonvulsant therapy relieved his pain, he was readmitted to our hospital because of severe pain in his left arm and both thighs three months later. A high-dose intravenous immunoglobulin (IVIG) therapy followed by steroid pulse therapy relieved his pain. This case with neither muscle cramp nor myokymia expands the phenotype of anti VGKC-complex antibody associated disorder.

Perfil clínico-radiológico de la encefalitis límbica asociada a anticuerpos contra canales de potasio dependientes de voltaje / Clinical and immunological profile of limbic encephalitis associated with voltage-gated potassium channel antibodies

Fundamento y objetivo: La encefalitis límbica (EL) asociada a anticuerpos contra canales de potasio dependientes de voltaje (Ac-CKDV) es una entidad de reciente descripción, en general no asociada a cáncer y con buena respuesta al tratamiento inmunodepresor. Describimos las características clínicas, radiológicas y el perfil evolutivo de una serie de pacientes en nuestro medio. Pacientes y método: Análisis retrospectivo de variables demográficas, clínicas y evolutivas de una serie de pacientes con EL con Ac-CKDV y ausencia de anticuerpos onconeuronales. Resultados: En un período de 10 años se identificaron 13 pacientes; el 77% fueron varones y la mediana de edad de 67 años (extremos 50 75). La mediana de presentación fue de 10 semanas (extremos 1 24 semanas). Todos presentaron alteración de la memoria episódica, un 77% crisis epilépticas y un 77% síndrome confusional o alteración de la conducta. Un trastorno de conducta sueño-REM (TCSR) se detectó en 9 pacientes interrogados. La resonancia magnética (RM) fue anormal en el 84,6%, el electroencefalograma (EEG) en el 91%, el líquido cefalorraquídeo (LCR) en el 60% y se detectó hiponatremia en el 83% de los casos. Todos los pacientes recibieron tratamiento con inmunoglobulinas y/o glucocorticoides y el 61,5% quedó asintomático o con síntomas mínimos. Tras un seguimiento mediano de 24 meses (extremos 3 108 meses) ningún paciente desarrolló cáncer. Conclusiones: Las características demográficas y clínicas de nuestra serie son similares a las ya publicadas y se confirma que se trata de una entidad con buena respuesta al tratamiento. La presentación crónica y la normalidad de la RM no descarta el diagnóstico sindrómico y en estos casos la existencia de un TCSR, hiponatremia o un LCR inflamatorio resultan de especial ayuda diagnóstica (AU)

Background and objective: Limbic encephalitis (LE) associated with antibodies to voltage-gated potassium channels (VGKC-Ab) have recently been reported as an immunotherapy responsive encephalitis typically not associated with cancer. In the present study, we report the clinical, radiological and evolution features of LE associated with VGKC-Ab in our area. Patients and method: Retrospective analysis of clinical, radiological and evolution variables in a series of LE associated with VGKC-Ab without onconeuronal antibodies. Results: Thirteen patients were detected during a 10-years period; 77% were male and the median age was 67 years (50 75 years). The median time of presentation was 10 weeks (1 24 weeks). All patients had episodic memory impairment, 77% had epileptic seizures and 77% had confusion or behaviour disturbances. A REM-behaviour disorder (RBD) was detected in all asked patients. MRI was abnormal in the 84.6%, EEG in the 91%, CSF in 60% and hyponatraemia was detected in the 83% of cases. All cases were treated with IGIV and/or costicosteroids and 61.5% remained asymptomatic or with minimal symptoms. After a median follow-up of 24 months (3 108 months) no patient developed cancer. Conclusions: Demographic and clinical characteristics of our series are similar to those previously reported, confirming its immunotherapy-responsive condition. Chronic presentation or normal MRI does not exclude the syndromic diagnoses, and the coexistence of RBD, hyponatraemia or inflammatory CSF are especially useful to make the diagnoses in these cases (AU)

Potassium channel antibody-associated encephalitis with hypothalamic lesions and intestinal pseudo-obstruction.

A subgroup of limbic encephalitis is associated with antibodies against voltage-gated potassium channels (VGKC), and responds well to immuno-modulating therapies. Anti-VGKC antibodies are also found in Isaacs' syndrome and Morvan's syndrome, both of which are sometimes complicated by thymoma. We describe a 52-years-old man with limbic encephalitis, thymoma, and anti-VGKC antibodies, who presented with autonomic dysfunctions such as severe intestinal pseudo-obstruction, hyperhidrosis and hypertension. Thymectomy and corticosteroid therapy remarkably improved his symptoms. Brain magnetic resonance imaging showed hypothalamic lesions, in addition to the bilateral involvement of the medial temporal lobes. This patient had severe autonomic dysfunctions resembling those of Morvan's syndrome. This case may represent a subgroup of VGKC-antibody associated syndromes with a wide spectrum of symptoms, including Isaacs' syndrome, Morvan's syndrome, and limbic encephalitis.

Hypothermia in VGKC antibody-associated limbic encephalitis.

Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.

Neuromyotonia: clinical profile of twenty cases from northwest India.

OBJECTIVES: We are presenting 20 cases of the intriguing clinico-electromyographic entity, now considered a potassium channel disorder, Neuromyotonia. Our experience with the clinical manifestations, underlying abnormalities and response to various therapies is documented. MATERIALS AND METHODS: Patients with diffuse pain or undulating muscle movements, with or without stiffness were sent for electromyographic and further studies. Patients with "neuromyotonic discharges" were included after exclusion of hypocalcaemia. RESULTS: Our cases included 19 males and one female of age group 15 to 52 years, the majority being between 30 to 45 years. Undulating movements were seen in 19, of which two had focal twitching. Muscle stiffness was a complaint in five; pain was the chief presenting complaint of 19, which started in the calf in all. Irritability, insomnia and a peculiar worried pinched face were present in 12 patients. CSF was abnormal with mildly raised protein in eight. Curiously, 11 of these patients had taken ayurvedic treatment for various complaints in the preceding one month. Bell's palsy was associated in four, peripheral neuropathy in two and residual poliomyelitis in two. Electromyographic evidence of spontaneous activity in the form of "neuromyotonic discharges" was seen in all. Antibodies to voltage gated potassium channels was tested in one patient and was positive (titer was 1028 pM). Membrane stabilizers (e.g, phenytoin sodium) in our experience did not provide adequate rapid relief; we tried high-dose intravenous Methylprednisolone in 19 with significant amelioration of complaints. One patient was offered intravenous immunoglobulin, to which he responded. CONCLUSIONS: Neuromyotonia is a heterogeneous condition and can present in varied ways including diffuse nonspecific pain. This uncommon condition is potentially treatable and can be picked up with high index of suspicion.

Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study).

PURPOSE: Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation. PATIENTS AND METHODS: Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination. RESULTS: A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets. CONCLUSION: Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.

HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk.

INTRODUCTION: Direct block of I(Kr) by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current I(Kr), however. We have shown recently that two drugs in clinical use do not block hERG but produce long QT syndrome (LQTS) and TdP by inhibiting trafficking of hERG to the cell surface. To address the need for an inexpensive, rapid, and comprehensive assay to predict both types of hERG risk early in the drug development process, we have developed a novel antibody-based chemiluminescent assay called HERG-Lite. METHODS: HERG-Lite monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers. RESULTS: HERG-Lite correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition). DISCUSSION: HERG-Lite is the most comprehensive assay available for predicting drug-induced hERG risk. It accurately predicts both channel blockers and trafficking inhibitors in a rapid, cost-effective manner and is a valuable non-clinical assay for drug safety testing.