Controversies In Neurology Research Articles

Abstracts from the 17th World Congress on Controversies in Neurology, March 23-25, 2023, in Dubrovnik, Croatia.

Abstracts from the 17th World Congress on Controversies in Neurology, March 23-25, 2023, in Dubrovnik, Croatia.

COVID-19 and the World Congress on Controversies in Neurology

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ABN News Feb 2019

![Graphic][1] ### 21–23 May 2019, EICC Edinburgh Registration is now open for the ABN 2019 annual scientific meeting which will be held in Edinburgh. The programme will cover a range...

Neuro-Behçet’s Disease – Clinical Features, Diagnosis and Differential Diagnosis

Background:Behçet’s disease is a relatively uncommon, inflammatory disorder with characteristic mucocutaneous lesions and multisystem involvement, of unknown aetiology; presumably a vascular autoinflammatory syndrome that develops under combined environmental and genetic influences. As neuro-Behçet’s disease affects the central nervous system in about 10% of cases and in ways that can mimic other neuroinflammatory conditions, awareness of its manifestations, significance, and management is important for neurologists. In March 2017, a mini-symposium at the 11th Congress of Controversies in Neurology in Athens, Greece, was dedicated to specific aspects of Behçet’s and neuro-Behçet’s disease. These included an introduction to Behçet’s disease, pathogenesis and treatment, an overview of its neurological manifestations (neuro-Behçet’s disease) and the differential diagnosis from other neuroinflammatory conditions. Illustrative case reports were used.Objectives:To provide a brief overview of neuro-Behçet’s disease that is informative for clinical neurological practice and that follows the structure of the 2017 mini-symposium.Data sources:Relevant recent comprehensive reviews of the subject and relevant original articles and case reports were provided by each speaker at the mini-symposium. This article contains some of these sources and some additions where necessary to emphasise specific points. References are also provided for more comprehensive recent reviews.Limitations:The mini-symposium was an opportunity for providing a brief update and overview of neuro-Behçet’s disease and to exchange ideas and experience among neurologists. As such, it was found to be helpful, but also limited in scope. This resultant article refers to comprehensive reviews on the topic but is not in itself a comprehensive systematic review.Conclusions:Neuro-Bechet’s disease comprises largely two forms, parenchymal and a non-parenchymal. These manifestations seldom overlap in the same individual and may reflect different pathogenetic mechanisms. The principles of treatment largely follow the principles of treating Bechet’s disease in general, with the mainstay being corticosteroids for exacerbations and immunosuppressive treatments for prevention of exacerbations. One notable exception is cyclosporine, which is typically avoided in neuro-Bechet’s disease. Anti-tumour necrosis factor biologicals play an increasing role in treatment. Distinguishing neuro-Behçet’s disease from other neuroinflammatory conditions, such as multiple sclerosis, is essential for both management and prognostic reasons.

CONy 2016: Controversies in Neurology were ignited in Lisbon and acknowledged in the International Journal of Clinical Neurosciences and Mental Health

CONy 2016: Controversies in Neurology were ignited in Lisbon and acknowledged in the International Journal of Clinical Neurosciences and Mental Health

A Report From the World Congress On Controversies in Neurology

The 6th World Congress on Controversies in Neurology, held in Vienna, Austria, in March 2012, provided a forum for clinicians and neuroscientists to discuss the advantages and disadvantages of a large spectrum of neurological and neuropsychiatric disorders. With 35 sessions, 65 debates (in four parallel sessions), two satellite symposia and poster sessions, the meeting highlighted the current diagnostic and management criteria across many areas of clinical neurology, with a wide range from multiple sclerosis, neuroimmunology, dementia, brain injury, neuro-oncology, neurogenesis, stroke, epilepsy, neurorehabilitation, movement disorders and neuropsychiatry. With a multidisciplinary approach, the conference aimed to clarify a myriad of controversial aspects in the pathogenesis, diagnosis, treatment and prevention of major neurological and neuropsychiatric diseases, in order to gain new insights into essential problems and to develop new treatment options for these disorders.

Controversies in Neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease

BackgroundEarly initiation of pharmacotherapy in Parkinson's disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease.DiscussionIn multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease.SummaryMAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

Mark A. Smith: The Scientist, the Man

Alzheimer disease (AD) research suffered a devastating loss with the death of Mark A. Smith on 19 December 2010. In addition to being the most prolific and fifth most cited AD author, Mark had a keen eye for innovation and quality of execution. Investigations into oxidative stress, cell cycle reentry, gonadotropins, mitochondria, metal homoeostasis and other novel ideas owe much of their origin and all of their continued influence to Mark’s unparalleled energy, as well as a progressiveness and generosity that enabled him to share his intellectual achievements and promote his colleagues and trainees. Mark was initially drawn to oxidative stress as a means of understanding the biology of AD and the necessity, in his view, of maintaining a fidelity to evolutionary adaptation for successful ageing. So at a time, when virtually all others were embracing classical notions of gain-of-function toxicity, Mark brought oxidative stress to the forefront with his first studies, one demonstrating glycation and another induction of heme oxygenase 1, in human AD in vivo. As a result, investigation into oxidative stress comprises 5% of the total AD research output and has continued to rise; something that was inconceivable only 20 years ago. In a short period of time, Mark became convinced that oxidation must be part of a programme of changes that surface at the initiation of AD if not sooner. Further demonstrating cell cycle reentry in neurons at risk of death in AD was the first success of his thought process, leading to the ‘two-hit’ hypothesis, in which he proposed that oxidative stress as well as cell cycle conspire to initiate non-apoptotic cell death. As data began to accumulate that the amyloid cascade hypothesis was fundamentally upside down, and the neuroscience community, in the quiet of private reflection, began to see the need for a paradigm shift, Mark’s call for objectivity, both in the literature and with his booming baritone voice in lectures all over the world, was a welcome instillation of courage and inspiration. Perhaps more than Mark realized, he was a voice of strength and scientific values that were badly needed in the face of a peer review system and granting agencies that, in Mark’s words, was caught in a game of ‘follow the leader’. In essence, by questioning the amyloid cascade hypothesis, Mark ushered the return of scientific values, the necessity for objectivity and the necessity to always question, for numerous colleagues thirsting for such a return. Yet questioning the amyloid cascade hypothesis was also a natural continuation of his efforts, and the extension of his experimental evidence and intuition. The notoriety of numerous debates, including the last this past October (Controversies in Neurology, Barcelona, Spain, October 2010), and over a decade of articles claiming analogy to protective responses were simply a continuation of Mark’s inclination towards objective appraisal of the evidence at hand. INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY Int. J. Exp. Path. (2011), 92, 297–298

Controversies in neurology: asymptomatic carotid stenosis—intervention or just stick to medical therapy. The argument for carotid endarterectomy

Patients with a significant carotid stenosis are at an increased risk of suffering from a potentially fatal or disabling stroke. The current management strategies available to a patient with an asymptomatic carotid stenosis are either medical therapy alone, or in combination with either carotid endarterectomy, or carotid angioplasty and stenting. Medical therapy alone can reduce the incidence of stroke in general, but whether there is any reduction in stroke attributable to a significant carotid stenosis is less clear. Carotid endarterectomy, on the other hand, has been shown to reduce the incidence of ipsilateral ischaemic stroke in both symptomatic and asymptomatic patients, with the benefits extending into the long-term. Carotid angioplasty and stenting is a newer technique with the benefit of being minimally invasive. The results of trials comparing the technique to endarterectomy have had conflicting results, and the results of large multi-centre trials are awaited. Currently the safest strategy for a patient with a significant asymptomatic carotid stenosis consists of optimal medical therapy with carotid endarterectomy for those less than 75years of age, who are suitable for surgery.

CONy: a new perspective for readers of JNT

The way knowledge advances is by finding new truths, and by discarding old beliefs. There is more than one way to progress, but the basic one is to question previously held views. The Jewish Talmudic scholars, just as the Greek sophists and, more importantly, the Socratic dialect followers, headed and developed this method. This method is invaluable in science, as well as in medicine. Debates are frequently used by scientists, but having meetings specifically for this purpose is a new concept. Controversies in Neurology (CONy) is an annual meeting dedicated just to that. The CONy Congress functions as a unique forum for international experts to share and compare experiences, in order to outline appropriate diagnostic methods and treatments for neurological disorders. It is embarked upon primarily to facilitate effective debates on unresolved clinical and therapeutic dilemmas, supported by evidence-based medicine and the opinions of experts. These congresses have attracted much attention over the years with thousands of clinicians who not only learned, but also enjoyed the programs. Our four meetings so far in Berlin, Athens, Prague and Barcelona, and future ones in Beijing and Vienna, deserve a wider audience and we are delighted to launch this new section of the Journal of Neural Transmission (JNT) which will be devoted to debates emanating from our congresses. We begin with the debate ‘‘AED discontinuation may not be dangerous in seizure-free patients’’ (E. Beghi and D. Schmidt), while future issues of the JNT will have debates on ‘‘Asymptomatic carotid stenosis: Intervention or just stick to medical therapy (G. Chrysant, L. Hirt and J. Streifler), ‘‘Substantia nigra hyperecogenicity is a risk marker for PD’’ (D. Berg and U. Walter), ‘‘The origin of migraine attacks’’ (L. Vecsei and E. Shevel), ‘‘What is the best treatment for advanced fluctuating PD’’ (S. Chabardes and R. Hilker) and hopefully many more. We are grateful to the eminent neurologists who have contributed to CONy and now agree to present their views and experiences in articles for you, the readers of JNT.

Diagnosis and management of multiple sclerosis

A handful of patience is worth more than a bushel of brains — Dutch proverb Controversy exists concerning almost every aspect of the diagnosis and management of multiple sclerosis (MS), the most common nontraumatic cause of neurologic disability in young adults. Although authoritative guidelines for diagnosis, such as those of the McDonald Committee, are available, a high rate of false positive attribution of MS has been observed in clinical practice.1 On the other hand, data from the North American Research Committee on Multiple Sclerosis registry demonstrate that the ascertainment time (from first symptom to diagnosis) is currently very brief, indicating that false negative attribution of MS is rare or transient.2 Currently, overdiagnosis in suspected MS is the most common diagnostic error and has been ascribed to uncritical reliance on MRI and hasty workup.1,3 Management of MS is controversial, both in terms of the general role of disease-modifying treatment (DMT) and the merits of specific DMTs. A recent “Controversies in Neurology” in the Archives of Neurology featured opposing reviews by MS specialists either favoring or questioning universal institution of DMT once MS or a MS-like clinically isolated syndrome is diagnosed.4,5 Experts on both sides of this dispute agree with the authoritative Cochrane reviewers …

2nd World Congress on Controversies in Neurology

Controversies in Neurology (CONy) is an international congress dedicated to debates in several areas of neurology. Its second annual meeting was held in Athens, Greece, in October 2008, with an attendance of over 1200 participants. Several debates were held between opposing leaders in the fields of multiple sclerosis, stroke, Parkinson’s disease, dementia, epilepsy and headache.

Announcement: The First World Congress on Controversies in Neurology (CONy)

Announcement: The First World Congress on Controversies in Neurology (CONy)

Clinical profile of solitary seizures

Background: Solitary seizure is one of the controversies in neurology. This study was taken up to study the clinical profile of solitary seizure and the factors related to seizure recurrence with a view to evolve guidelines for management. Methods: We studied 150 cases of solitary seizure. All our patients were males. The age varied from 18–52 years. The diagnosis of seizure was confirmed with history. Apart from clinical neurological examination, blood counts, urinalysis and screening investigations to exclude possible underlying metabolic disorders were done. Inter-ictal EEG and contrast enhanced CT scan were done. Results: CT scan was abnormal in 28 cases. EEG was abnormal in 33; clinical abnormality was noted in 15 cases. Median follow up duration was 1.2 years. 18 patients had seizure recurrence. Type of seizure, EEG findings (normal or abnormal) and treatment with antiepileptic drugs did not have any effect on seizure recurrence. Seizure recurrence was less common in presence of CT scan abnormality though it was not significant statistically. Routine laboratory tests of blood count, blood sugar and urinalysis were normal in all cases. Conclusion: In cases of solitary seizure, type of seizure, results of EEG and CT scan findings are not likely to predict seizure recurrence. Treatment with antiepileptic drugs does not prevent seizure recurrence. Laboratory investigations like blood counts, urinalysis and blood sugar estimation are unlikely to be of value in routine work-up of these cases.

New Controversy Section

Where knowledge fails, controversies flare. Well-chosen controversies focus, educate, and encourage further research. Sixteen years of controversies in neurology did not dampen the interest in such …

The significance of neutralizing antibodies in patients with multiple sclerosis treated with interferon beta.

T HE DEVELOPMENT of neutralizing antibodies(NABs)against interferons is well described in patients with viral hepatitis and with some cancers that are treated with interferon. In patients with hepatitis or cancer, thedevelopmentofNABshas been associated with reduction of interferon-relatedadverseeffects (eg, fever, chills, and myalgia) and with the recurrence of disease activity. TreatmentfailureduetoNABsinsuch patientshasbeenmucheasier to identify, by measuring the more sensitive diseaseactivitymarkers(eg,transaminase levels in patients with hepatitis ortumorortumormarkers inpatients with cancer). The development of NABs in patients with multiple sclerosis (MS) treated with interferons is a more recent observation, which has generated substantial controversy. Approximately one third of patients treated with interferon beta-1b developed NABs in the pivotal trial of that agent. The NABs were identified by neutralization of a standard dose of interferon in a virus plaque assay and by the reduction of interferon induction of the MxA protein in cell culture. Disease activity markers, barring the use of magnetic resonance imaging (MRI), are not yet available in MS. Measurement of the clinical effect of NABs has generally depended on measuring attacks or disability in periods subsequent to the development of a positive titer. Interferon-treated patients with MS who develop NABs generally do so in the second half of the first year of treatment. Many clinical trials have not been powered to show an effect of the NAB after this period. Furthermore, pursuing the identification of a deleterious effect of such antibodies has not been a leading corporate interest. It appears that all interferons are capable of inducing the formation of NABs and that interferon NABs are generally cross-reactive. It is difficult to compare the data from the pivotal trials of the 3 major interferons: interferon beta-1b (Betaseron) and 2 types of interferon beta-1a (Avonex and Rebif). The antibody titers were derived from different assays, and the definitions of positive titers were different. From studies of the development of NABs outside clinical trials, it has been noted that interferon beta-1b is more immunogenic than interferon beta-1a and that the subcutaneous route of administration might increase this risk, compared with intramuscular administration. In the study of interferon beta1b, the development of NABs appeared to be associated with loss of efficacy, especially in the observation period between 18 and 24 months. Patients who were positive for NABs experienced an attack rate in this time frame approximating that of placebo-treated patients. This clinical observation was also supported by parallel changes in the MRI studies and by reduction of interferon adverse effects. For example, skin necrosis occurred only in patients without NABs. The NABs that developed in 22% of the longest-treated (104week subset) patients in the trial of interferon beta-1a (Avonex) were not shown to significantly alter attack rates, although an effect was seen on MRI activity and on the induction of neopterin. In the most recent study of interferon beta-1a (Avonex) in which the drug was used after the first attack, NABs developed in fewer than 1% of patients. Why the rates of NAB positivity keep decreasing with each successive observation from this group remains enigmatic. An effect of NABs was not identified in the PRISMS Study of interferon beta-1a (Rebif) at 2 years, but extension of this study for another 2 years revealed definite differences between attack, disability, and MRI outcome measures in favor of the patients who remained NAB negative. According to the findings of studies of adequate duration, there appears to be a convincing effect of NABs on primary outcome measures, by which the efficacy of these drugs has been shown. Is all interferon efficacy lost after NAB development? Earlier studies of interferon treatment in hepatitis and cancer suggested a reduction but not total abrogation of efficacy. There is also some suggestion that disease progression might be less likely in NABpositive patients with MS, but this observation requires corroboration. Observations over the shortterm had suggested that NABs could disappear in a substantial proportion of patients. Of interest, in the pivotal trial with interferon beta1b, 60% of the patients who had a NAB titer were subsequently shown to have a negative NAB titer. In a cohort of patients studied with frequent MRI analyses, approximately 50% of the patients who met the definitions for NABs ultimately From the Multiple Sclerosis Clinic, University of Western Ontario, London. CONTROVERSIES IN NEUROLOGY

Treatment of ocular myasthenia with corticosteroids: yes.

O CULAR findings often represent the first, and sometimes the sole manifestation of acquired MG. Ocular MG, with weakness restricted to the ocular muscles, is generally considered a mild subtype of MG. Nonetheless, the diagnosis and management of purely ocular MG may be particularly challenging and frustrating. Diplopia and ptosis, resulting from dysfunction of neuromuscular junctions (NMJs) of extraocular skeletal muscles and levator palpebral muscles in ocular MG, often impair vision sufficiently to interfere with work and quality of life. Whereas ocular symptoms are often the presenting symptoms of MG, they also tend to be the symptoms most refractory to treatment. Response to anticholinesterases is often incomplete, and pharmacological suppression of the NMJ immune attack or thymectomy is often required for resolution of symptoms. The judicious use of corticosteroids represents a key component of management of individual patients with ocular MG. A second consideration is that half the patients with MG, with weakness restricted to ocular muscles clinically, reveal decrement on repetitive nerve stimulation in extremity muscles. Furthermore, most patients with purely clinical ocular MG at the onset of disease develop generalized weakness, especially within the first year. This represents a subgroup of patients with ocular MG at risk for rapid deterioration. Myasthenic crisis is better prevented than treated. In this context, immune treatment is warranted in individual patients with ocular MG and electrophysiological evidence of generalized MG. A third consideration arises from recent observations suggesting that withholding immune treatment in mild ocular MG may predispose to severe disease. Myasthenia gravis commences with ocular symptoms in 75% of patients, a susceptibility that may be related to antigenic structure and/or a reduced safety factor at the ocular muscles. Generalized MG may result from increased antibody production and expansion of antigenic molecular targets. Patients treated with immune intervention early in the course of ocular MG are less likely to develop generalized disease. The duration of the initial period of NMJ immune attack may be an important determinant for subsequent severity of disease. Correlation of increased duration and severity of subsequent disease with the duration of the initial immune attack occurs in other autoimmune conditions, including relapsing experimental autoimmune encephalomyelitis. It is possible that an unchecked immune response in ocular MG leads to structural changes in selfantigens at the NMJ and destruction of the NMJ architecture. In turn, exposure of novel antigens may potentiate the autoimmune attack, leading to disease persistence and increased disease severity. Symptomatic treatment with anticholinesterases may improve clinical symptoms but mask ongoing autoimmune damage. Abrogation of the immune attack would limit end organ damage and resultant long-term immune stimulation,constitutinganadditional reason to support the use of immune treatments in selected patients early in the course of the disease. Patients with MG treated with corticosteroids require close supervision.Optimally, corticosteroidsare used to help induce and maintain a clinical remission. Remission induction generally requires high oral doses for a period of 2 to 3 months. Potential complications include MG worsening during the first 2 weeks of therapy, asepticbonenecrosis,hyperglycemia,hypertension,osteoporosis, immune compromise, psychological disturbance, growth retardation inchildren, cataracts, glaucoma, proximalmyopathy,anddysmorphic soft tissue changes. Complications are to be identified and treated early; they are best prevented. Ancillary treatmentssuchaselandronatetoprevent osteoporosis are useful. Most steroid complications correlate with cumulativedose.Animportantmeans to prevent complications in patients receiving steroids is to limit the totalsteroiddose.Thismaybeachieved, and relapses kept to a minimum, by dose reduction in a slow, monitored fashionoverseveralmonths.Alternateday therapy reduces hypothalamicpituitary suppression. Additional strategies that may limit the need for long-term high steroid doses include thymectomy early in the course of the disease, as well as azathioprine during the period of steroid dose reduction. The differential diagnosis of ocular MG includes oculopharyngeal dystrophy, mitochondrial disorders, congenital MG and other NMJ disorders, oculomotor neuropathies, and brainstem lesions. In autoimmune ocular MG, the usual laboratory findings that support a diagnosis of MG may be absent. SeFrom the Department of Neurology, University of California, Davis. CONTROVERSIES IN NEUROLOGY

New drugs: which should be included in the formulary? Epilepsy: all new drugs should be included.

B Y THE THIRD quarter of the 20th century, 5 major antiepileptic drugs (AED) had been recognized and compared in clinical trials for their efficacy in partial and secondarily generalized seizures and adverse-effect profile: phenytoin, phenobarbital, carbamazepine, primidone, and valproate sodium. These firstgeneration drugs leave about 20% of patients with uncontrolled seizures and cause adverse effects such as drowsiness, dizziness, diplopia, gingival hyperplasia, hirsutism, memory impairment, tremor, and excessive weight gain. Phenytoin, owing to its saturation kinetics, requires careful blood level monitoring. Carbamazepine occasionally causes neutropenia and hyponatremia, and requires frequent dosing. Valproate causes thrombocytopenia and alopecia at high doses. All of these drugs except valproate induce liver enzymes and may potentiate drug interactions; this latter feature is enhanced by the high affinity for serum protein of phenytoin, carbamazepine, and valproate. Although all these drugs are associated with some risks of fetal malformations, carbamazepine and valproate are specifically recognized for additional risks of fetal neural tube defect. Because of the number of patients with refractory partial seizures and the adverse effects of available drugs, 2 things have happened in the last quarter of the century: the number of epilepsy surgery centers has increased dramatically, and, through a concerted effort by both government and the pharmaceutical industry, new AEDs have been developed at a frantic pace. These new developments have brought more choice in the management of epilepsy, but at considerable financial costs. Felbamate, gabapentin, lamotrigine, topiramate, and tiagabine hydrochloride were all marketed in the United States during the last decade as adjunct therapy for partial and secondarily generalized seizures. Lamotrigine was recently approved for monotherapy. As a group, these second-generation drugs seem to have novel mechanisms of action, fewer drug interactions, and perhaps better adverseeffect profiles, although they have not been adequately compared with each other or with previous drugs. They are also substantially more expensive than the first-generation AEDs. The most common adverse effects include dizziness, drowsiness, skin rash, and mental slowing. The need for drug level monitoring and the potential for teratogenicity of the new AEDs have not been established. Felbamate was found to be useful in children with symptomatic generalized epilepsies of the Lennox-Gastaut type, while lamotrigine seems to work in the idiopathic generalized epilepsies. The use of felbamate, however, was substantially reduced owing to a high incidence of aplastic anemia. In addition, several old AEDs have been reformulated. Rectal diazepam is used in the home environment for clusters of seizures, thus preventing a visit to the emergency department. Fosphenytoin is a precursor of phenytoin that can be mixed with dextrose, administered intramuscularly, and given faster than phenytoin, properties that are cherished by emergency department staff. Two extended-release carbamazepine formulations now allow twice daily dosing of that drug and therefore better compliance. An intravenous valproate can replace the oral form when needed, thus preventing interruption of treatment. As expected, these new formulations are generally more expensive than their predecessors. In sum, the second-generation AEDs grew out of a systematic drug development program that recognized a need for new drugs because the first-generation drugs failed to control seizures in many patients or caused clinically significant adverse effects. These new drugs may play a role in some of the refractory generalized epileptic syndromes of childhood and may be easier to administer. They also tend to have more specific sites of action, based on our evolving understanding of the pathophysiology of the epilepsies. However, since they have not been adequately compared with older AEDs, it seems appropriate to start treatment with selected first-generation drugs and move to the more expensive secondgeneration drugs only when indicated. The new formulations of established AEDs were created to respond to specific needs of patients and specific clinical situations, and should be used accordingly. Thus, there is room for the old drugs, the new drugs, and the new formulations of old drugs in hospital formularies. The cost of these new AEDs is certainly of concern. However, denying their use to hospitals and health care providers may be to the The Department of Neurological Sciences, Cook County Hospital/Rush Medical College, Chicago, Ill. CONTROVERSIES IN NEUROLOGY

Is cholesterol a risk factor for stroke?: Yes.

A THEROSCLEROSIS is the most common cause of coronary artery disease (CAD), peripheral vascular disease, and stroke worldwide. Atherogenesis is a multifactorial process involving cholesterol internalization, vascular smooth muscle cell proliferation, inflammation, “foam cell” formation, and connective tissue production. Experimental and epidemiological studies of CAD, peripheral vascular disease, and stroke have identified powerful risk factors that directly affect these multifactorial processes and include hypertension, diabetes, smoking, and aging. The relevance of cholesterol, however, has only been definitively associated with CAD and peripheral vascular disease, and has a seemingly tentative and controversial role with strokes. For example, in the Framingham Study no correlation was found between cholesterol and vascular disease of the brain. The Honolulu Heart Study of Japanese American men showed no significant association with cerebral infarction but an inverse relationship with intracerebral hemorrhage. However, in the large Multiple Risk Factor Intervention Trial of more than 350 000 men, death from nonhemorrhagic strokes correlated with elevated cholesterol, suggesting but not proving an association with atherothrombotic brain infarction (ABI). The Eastern Stroke and Coronary Heart Disease Collaborative Research Group study of 69 767 participants revealed a trend toward a reduction in the risk of nonhemorrhagic stroke with decreasing cholesterol concentrations. How can this apparent paradox be explained and resolved when it is recognized that the arterial tree throughout the body is continuous, and the expectation is that risk factors for atherosclerosis for one area, such as the coronary circulation, might be the same as another, such as the cerebral circulation? A possible explanation may be that the cerebral vasculature has inherent biological processes that differ from other vascular beds with respect to endothelial cell function and does not experience the same degree of mechanical trauma exerted on the heart or other peripheral vessels that augment shear and stress forces that provoke and aggravate atherogenesis. In addition, previous studies have technical limitations in their analyses of cholesterol fractionation and of stroke subtypes, particularly distinguishing strokes due to atherosclerosis from other causes. However, while these inaccuracies may help to clarify the presumed paradox, the multifactorial process of atherogenesis cannot be reduced to these factors alone. For example, genetic, racial, environmental, and other as yet to be proven factors, such as hyperhomocysteinemia, are recognized to play a role. Nonetheless, laboratory evidence supports the major role of cholesterol trafficking in the molecular biology of atherothrombotic brain infarction (ABI). For example, patients with ABI have demonstrated abnormal dynamic synthesis and turnover for highdensity lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C) compared with healthy individuals and longitudinal follow-up results of subjects with carotid stenoses show plasma LDL-C levels to strongly predict stenosis progression. Despite these mounting evidences implicating an association of cholesterol in ABIs, they have eluded appreciation. A methodological problem with stroke diagnosis is the fact that “stroke” is not a diagnosis of a single pathological entity but rather a generic term for a variety of cerebrovascular disorders. These include subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction. And the last may be due to ABI, or a variety of other arterial diseases, emboli from heart or aorta, and prothrombotic states. Only definitive cases of ABI should be correlated with cholesterol levels, but, unfortunately, other stroke subtypes have often been included in analyses of cholesterol in “strokes.” Thus, the inclusion of patients with cardioembolic stroke due to atrial fibrillation or lacunar stroke due to hypertension or diabetes dilutes the stroke group with stroke due to atherosclerosis. Of course, the only reliable way to differentiate these stroke subtypes is by precise neuroimaging and/or autopsy information, which were less commonly performed or available when most studies had been done during the 1960s and 1970s. Unfortunately, death certificate information, without autopsy study, is often used, yet both are particularly unreliable, especially between counFrom the Departments of Neurology, University of Texas–Houston Medical School, Houston (Drs Demchuk and Yatsu), Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Ga (Dr Hess), and Yale University School of Medicine, and Veterans Affairs Medical Center, New Haven, Conn (Dr Brass). CONTROVERSIES IN NEUROLOGY

Is there still a role for intravenous heparin in acute stroke? Yes.

I NTRAVENOUS (IV) heparin was frequently considered a treatment option in acute ischemic stroke. However, only limitation of thrombus growth and facilitation of spontaneous endogenous thrombolysis are reasons to believe in its value in treating the index stroke. Most clinicians nowadays agree that the use of heparin, either IV or subcutaneously (SC), prevents deep venous thrombosis and pulmonary embolism. However, the question remains whether heparin does prevent recurrent stroke. In view of the potential hemorrhagic complications and heparin-induced thrombocytopenia, early treatment with IV heparin has always been a matter of controversy. In 1994, the Stroke Council of the American Heart Association did not recommend heparin because data about safety and efficacy were insufficient and conflicting. Nevertheless, in the absence of other acute treatment options and with proved primary and secondary preventive effects of oral anticoagulation in cardioembolic stroke, IV heparin was frequently applied in several parts of the world. Although such treatment was used for decades, the first placebocontrolled, randomized trial addressing full-dose unfractioned heparin treatment in acute stroke was the one performed by the Cerebral Embolism Study Group. The study was terminated early because of excess mortality in the placebo arm. Later, statisticians and others claimed that the termination of the trial was premature and that there could be a type II error explaining the difference in early mortality. In another study, Duke and coworkers found no significant difference between IV heparin and placebo in a small number of patients with presumably noncardioembolic stroke. From 1995 on, important studies on anticoagulation early after stroke have been published. In the Hong Kong Study, therapy with SC nadroparin calcium was safe and beneficial at 6 months (primary outcome variable) but not at 3 months or 10 days after stroke. The larger follow-up Fraxiparine in Ischaemic Stroke Study, however, failed to replicate the positive aspects of the Hong Kong Study. In the Trial of ORG 10172 in Acute Stroke Treatment study, an intravenously administered heparinoid (danaparoid sodium) showed a positive response to treatment at 7 days, but not at 3 months (primary outcome variable). In this trial, the risk of recurrent stroke within 1 week was very low (1.2%) and was similar in different stroke subtypes. In post hoc analyses, patients with stroke from large-artery atherosclerosis (n = 230) had a benefit from treatment with danaparoid. In the Trial of ORG 10172 in Acute Stroke Treatment, the factor Xa–adjusted use of the heparinoid was associated with an increased risk of extracranial and intracranial hemorrhage, especially in patients with large stroke. Particularly since the International Stroke Trial, treatment with heparin has increasingly come under fire. The International Stroke Trial used a high dose of twice-daily SC heparin, which in some patients probably led to systemic anticoagulation. However, there was no systematic assessment of the activated partial thromboplastin time to monitor anticoagulant effects. Certainly, the results of twice-daily SC heparin cannot be used as proof against full-dose IV heparin with proper monitoring of activated partial thromboplastin time, mandatory computed tomographic scanning before therapy, and formal exclusion criteria for anticoagulant treatment, such as severe cerebral microangiopathy, large cerebral infarcts, and uncontrolled severe hypertension. Because of the factorial design of the International Stroke Trial, many patients receiving either dose of heparin also received aspirin, which makes the assignment of complications to one part of the treatment probably more difficult than assumed. In the absence of blinding, there may be a bias toward assigning bleeding complications to the presumably more dangerous drug. All data reviewed so far stem from randomized trials. The inclusion of patients into such trials is based on detailed inclusion and exclusion criteria. Once patients are entered, the prescribed treatment follows, mostly with strict dosaging and treatment times. Clinical practice is different: treatment may be halted, reinstituted, or, most importantly, prematurely terminated if the supposed cause of stroke for which anticoagulation was chosen is not confirmed. There are few data about the safety of anticoagulation in a routine clinical setting. In the European Cooperative Acute Stroke Study I, the European trial of tissue plasminogen activator, it was up to the local investigators to use heparin 24 hours after stroke IV, SC, or From the Neurology Department, University of Heidelberg, Heidelberg, Germany. CONTROVERSIES IN NEUROLOGY