Update on the management of lennox-gastaut syndrome

Lennox-Gastaut syndrome is a severe childhood epilepsy disorder characterized by encephalopathy and multiple, often intractable, seizure types. The drop attack is the most frequently recognizable seizure type in this patient population, and is also the most dangerous physically, thus severely limiting quality of life. The diagnosis is confirmed by electroencephalography, for which the classic pattern is a slow 2.5 Hz generalized spike-and-wave. Newer pharmacologic treatments include rufinimide and clobazam. However, antiepileptic drugs are often exhausted in pursuit of seizure control requiring nonpharmacologic interventions. These include dietary therapies, vagus nerve stimulation, and epilepsy surgery, including corpus callosotomy and focal curative resection. Although large lobar resections are often required, very localized, discrete resections may be possible, as in symptomatic Lennox-Gastaut syndrome (specifically, hypothalamic hamartoma). We review the history of the disease and current management options.     

Update on the medical management of pituitary adenomas

The medical treatment of pituitary adenomas has changed significantly over the past decade. Pharmacologic therapy for prolactinomas in the form of dopamine agonists has been available since the 1970s, and somatostatin analogues for treatment of growth hormone (GH)-secreting adenomas were introduced in the 1980s. However, the recent introduction of long-acting forms of these agents has markedly improved efficacy. Furthermore, long-acting somatostatin analogues also have utility in treating thyrotropin adenomas and a subset of adrenocorticotroph tumors. Limited clinical studies with long-acting dopamine agonists suggest that a subset of patients with GH, adrenocorticotroph, and gonadotropin/ nonsecreting adenomas may also benefit from therapy with these agents. The introduction of a GH receptor antagonist in the 1990s has added to the pharmacologic armamentarium for treatment of acromegaly. In parallel with improved medical therapy, hormonal assays for assessing tumor activity have improved in sensitivity, necessitating new standards for treatment optimization. This article highlights some of these evolving new ideas and approaches to the pharmacologic management of pituitary adenomas.     

Update and review on the basics of pain management

This article reviews the major findings of research related to pharmacological pain therapies used in treating acute and chronic pain, it compares advantages and disadvantages of certain drugs used mainly in pain management (for example, opioids and non steroidal anti-inflammatory drugs), and others that have a secondary use in pain management (for example, skeletal muscle relaxants, antidepressants, and anticonvulsants) and their intended indications. Our goal is to present accurate up-to-date applicable data on these pharmacological choices.     

Update on the diagnosis and management of Trigemino-Autonomic Headaches

Severe shortlasting headaches are rare but very disabling conditions with a major impact on the patients’ quality of life. Following the IHS criteria, these headaches broadly divide themselves into those associated with autonomic symptoms, so called trigeminal autonomic cephalgias (TACs), and those with few autonomic symptoms. The trigeminal-autonomic cephalgias include cluster headache, paroxysmal hemicranias, and a syndrome called SUNCT (short lasting unilateral neuralgic cephalgias with conjunctival injection and tearing). In all of these syndromes, hemispheric head pain and cranial autonomic symptoms are prominent. The paroxysmal hemicranias have, unlike cluster headaches, a very robust response to indomethacin, leading to a notion of indomethacin-sensitive headaches. Although TACs are, in comparison with migraine, quite rare, it is nevertheless very important to consider the clinical factor that they are easy to diagnose and the treatment is very effective in most patients. Received in revised form: 11 May 2006     

Update on multimodal neurosurgical management of dystonias

The neurosurgical treatment of dystonia has progressed markedly since the introduction of deep brain stimulation of the globus pallidum interna. However, dystonia is not a single disorder but comprises various types and causes, and it is true that deep brain stimulation cannot cover the complex nature of dystonia. Depending on the distribution of symptoms and causes, we have to consider other surgical managements such as thalamotomy, peripheral denervation, and intrathecal baclofen. Such a multi-modal strategy has enabled us to treat and even cure many patients with dystonias. No treatment other than various neurosurgical approaches yields better results in the management of dystonias. In this sense, we are now at a stage where we should regard dystonia as a neurosurgical disorder in terms of treatment.     

Update on the pathophysiology and management of idiopathic intracranial hypertension

Idiopathic intracranial hypertension is a disease of unknown aetiology, typically affecting young obese women, producing a syndrome of increased intracranial pressure without identifiable cause. Despite a large number of hypotheses and publications over the past decade, the aetiology is still unknown. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. There continues to be no evidence based consensus or formal guidelines regarding management and treatment of the disease. Treatment studies show that the diagnostic lumbar puncture is a valuable intervention beyond its diagnostic importance, and that weight management is critical. However, many questions remain regarding the efficacy of acetazolamide, CSF shunting procedures and cerebral transverse venous sinus stenting.     

Postsynaptic block of frog neuromuscular transmission by conotoxin GI

Conotoxin GI, a peptide neurotoxin contained in the venom of the marine snail Conus geographus, was applied to the cutaneous pectoris muscle of the frog, and the effects on the postsynaptic response to acetylcholine were examined. Conotoxin GI reversibly blocked nerve-evoked muscle contractions at concentrations greater than or equal to 3 to 4 microM. Micromolar concentrations of conotoxin GI significantly reduced the amplitude of miniature endplate potentials and membrane depolarizations produced by ionophoretic application of acetylcholine, suggesting that the toxin reduced the postsynaptic sensitivity to acetylcholine. The reduction in the sensitivity of the muscle to acetylcholine was not due to changes in muscle fiber resting membrane potential or input resistance. Conotoxin GI reduced the amplitudes but did not affect the rates of decay of focal, extracellularly recorded endplate currents or miniature endplate currents, suggesting that the toxin did not affect the lifetime of ion channels opened by acetylcholine. Miniature endplate currents decay five to six times more slowly than normal when acetylcholinesterase is blocked with neostigmine methyl sulfate due to repeated binding of acetylcholine to receptors as it diffuses from the synaptic cleft. Conotoxin GI reduced the amplitude and increased the rate of decay of miniature endplate currents recorded in the presence of neostigmine methyl sulfate, suggesting that the toxin reduced the binding of acetylcholine to endplate receptors. These results are consistent with the hypothesis that conotoxin GI blocks neuromuscular transmission at the frog endplate by reducing the binding of acetylcholine to receptors.     

Update on the management of hypertension for secondary stroke prevention

High blood pressure (BP) is the strongest risk factor for stroke. It is estimated that almost 50% of strokes may be attributable to hypertension. Both diastolic and isolated systolic hypertension are important predictors of primary or recurrent strokes, and even minor decreases in BP can reduce the risk of stroke. While the primary prevention of stroke through the treatment of hypertension is well established, the issue of lowering BP after a stroke has been uncertain, particularly since this might worsen cerebral perfusion if autoregulation remains chronically damaged or severe carotid artery stenosis is present. Furthermore, there is substantial evidence to support BP lowering for prevention of a first stroke; however, few trials have focused on antihypertensive therapy for recurrent stroke prevention. In fact, currently, BP management in patients with strokes remains problematic, and questions such as the choice of antihypertensive drug and by how much to reduce BP are yet to be resolved. Recently, the American Heart Association and American Stroke Association published updated guidelines for recurrent stroke prevention, and new recommendations on BP management have been included. Our review presents the most recent evidence on the management of hypertension in patients who have had a stroke.     

Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications

Narcolepsy is a chronic, debilitating neurological disorder of sleep-wake state instability. This instability underlies all narcolepsy symptoms, including excessive daytime sleepiness (EDS), symptoms of rapid eye movement (REM) sleep dysregulation (ie, cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis), and disrupted nighttime sleep. Several neurotransmitter systems promote wakefulness, and various neural pathways are involved in regulating REM sleep-related muscle atonia, providing multiple targets for pharmacologic intervention to reduce EDS and cataplexy. Medications approved by the US Food and Drug Administration (FDA) for the treatment of EDS in narcolepsy include traditional stimulants (eg, amphetamines, methylphenidate), wake-promoting agents (eg, modafinil, armodafinil), and solriamfetol, which mainly act on dopaminergic and noradrenergic pathways. Sodium oxybate (thought to act via GABA_B receptors) is FDA-approved for the treatment of EDS and cataplexy. Pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist, is approved by the European Medicines Agency (EMA) for the treatment of narcolepsy with or without cataplexy in adults and by the FDA for the treatment of EDS in adults with narcolepsy. Pitolisant increases the synthesis and release of histamine in the brain and modulates the release of other neurotransmitters (eg, norepinephrine, dopamine). Antidepressants that inhibit reuptake of serotonin and/or norepinephrine are widely used off label to manage cataplexy. In many patients with narcolepsy, combination treatment with medications that act via different neural pathways is necessary for optimal symptom management. Mechanism of action, pharmacokinetics, and abuse potential are important considerations in treatment selection and subsequent medication adjustments to maximize efficacy and mitigate adverse effects in the treatment of patients with narcolepsy.     

Incidence and characteristics of neurotoxicity in immune checkpoint inhibitors with focus on neuromuscular events: Experience beyond the clinical trials

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune‐related NAEs in cancer patients. Medical records of ICI‐treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno‐related NAEs. A total of 1185 ICIs‐treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty‐four from the overall ICIs‐treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1‐10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain‐Barre‐like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS‐related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune‐modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune‐related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.     

Update on the management of familial central nervous system tumor syndromes

Hereditary central nervous tumor syndromes are a varied group of conditions that include neurofibromatosis type 1 and 2, tuberous sclerosis, Von Hippel-Lindau disease, and Cowden, Turcot, and Gorlin syndromes. The responsible genes have been identified in most of these disorders. These genes typically act as tumor suppressor genes, maintain normal cellular function and homeostasis, and regulate cell growth and differentiation. Familial central nervous system tumors are mostly inherited as autosomal dominant traits and involve germline mutations. Neoplastic development occurs when a somatic mutation inactivates the second allele. These patients also present unique challenges for their management. This review highlights the clinical manifestations, molecular genetics, pathophysiology, and current treatment options of these disorders with a focus on neuro-oncologic manifestations of the diseases.     

Transcutaneous electrical nerve stimulation for the management of painful conditions: focus on neuropathic pain

The management of neuropathic pain is challenging, with medication being the first-line treatment. Transcutaneous electrical nerve stimulation (TENS) is an inexpensive, noninvasive, self-administered technique that is used as an adjunct to medication. Clinical experience suggests that TENS is beneficial providing it is administered at a sufficiently strong intensity, close to the site of pain. At present, there are too few randomized controlled trials on TENS for neuropathic pain to judge effectiveness. The findings of systematic reviews of TENS for other pain syndromes are inconclusive because trials have a low fidelity associated with inadequate TENS technique and infrequent treatments of insufficient duration. The use of electrode arrays to spatially target stimulation more precisely may improve the efficacy of TENS in the future.     

Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics

Abstract:  Clinical trials indicate that over 50% of depressed patients show an inadequate response to antidepressant therapy, and that incomplete recovery from major depressive disorder (MDD) increases the risk of chronicity and recurrence. Recovery, complete remission of symptoms, and a return to baseline psychosocial function, should be the goal of therapy. Poor response to adequate antidepressant treatment has been termed treatment resistant depression (TRD). Issues such as adherence, missed diagnosis of psychotic depression, bipolar disorder, or comorbid anxiety must be investigated as reasons why patients have not responded to initial therapeutic strategies. Beyond ensuring optimal use of the index antidepressant, treatment strategies for TRD include switching to another antidepressant, and augmentation or combination with two or more agents. Since little comparative data exist it is important to consider side-effect burden, partial response, and previous medication history when deciding between strategies. In patients with TRD, adding or augmenting with lithium, tri-iodothyronine or atypical antipsychotics have demonstrated benefits. Augmentation with atypical antipsychotics, including risperidone, olanzapine, ziprasidone, and quetiapine, show promising results in terms of improving remission rates. Other interventions, including non-pharmacologic strategies and investigational physical treatments, have demonstrated some benefits, but availability and patient preference should also be considered. With today's therapeutic alternatives, full remission of depression is an attainable goal. For some patients, combination and augmentation strategies earlier in treatment may increase the likelihood of remission.     

Update on respiratory management of critically ill neurologic patients

Respiratory failure complicates a number of acute neurologic conditions, most notably neuromuscular diseases (eg, Guillain-Barré syndrome and myasthenia gravis) and stroke. In addition, pulmonary complications, particularly pneumonia and atelectasis, are fairly common in patients with these diagnoses; their prevention and early recognition are crucial to avoid detrimental consequences. This review discusses recent studies related to predictors of respiratory failure and pneumonia, strategies of respiratory care and ventilatory support, functional prognosis, and withdrawal of mechanical ventilation in patients with acute neuromuscular respiratory failure and stroke.     

Perisurgical management of patients with neuromuscular disorders

Patients with neuromuscular disorders who undergo surgical procedures are particularly predisposed to complications during the perioperative period. Such complications may arise from respiratory failure, arrhythmias,or infections, and particularly MH. It is recommended that these patients be monitored for respiratory and cardiovascular complications and receive proper respiratory toilet, physio-therapy, and incentive respirometry. Proper electrolyte balance is mandatory. They should be monitored in the ICU when necessary. Excessive sedation of these patients, and drugs that could aggravate weakness or cause MH, should be avoided. Those at risk of MH should not receive drugs that may precipitate an attack.     

Aminoglycosides and 3,4-diaminopyridine on neuromuscular block caused by botulinum type A toxin

Impulse-evoked transmitter release was greatly reduced at frog neuromuscular junctions 3-20 days after botulinum type A toxin (BoTx) poisoning. The reduction in transmitter release was accompanied by an increased variability in the latency between the presynaptic spike and the release of transmitter. The aminoglycoside antibiotics amikacin, gentamycin, and bekanamycin, when applied at concentrations within their therapeutic levels, markedly enhanced the blockade of transmitter release in BoTx-poisoned junctions. 3,4-diaminopyridine strongly antagonized the effects of BoTx at early stages of poisoning, and the combined presynaptic effects of BoTx and aminoglycoside antibiotics provided that transmitter release was not completely blocked by the toxin. The antagonism was apparent at all frequencies of stimulation. Since the aminoglycoside antibiotics enhanced the neuromuscular block caused by BoTx, these drugs should be avoided in patients suspected of poisoning by this toxin.