Clinical review

Recent developments in neurology

Samuel Wiebe, associate professor in neurology, Michael W Nicolle, associate professor in neurology. 

Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada

Correspondence to: S Wiebe, London Health Sciences Centre, University Campus, 339 Windermere Road, London, ON, Canada N6A 5A5 swiebe{at}uwo.ca

Neurology has evolved from a rich, descriptive discipline to one with many diagnostic and therapeutic options supported by an increasingly robust evidence base. This review looks at new evidence on the management of temporal lobe epilepsy, which shows that surgery can now prevent years of ineffective drug treatment and unnecessary disability. In stroke, simple clinical scales can accurately identify patients who will benefit most from evidence based treatments, although interventions of proved efficacy and safety continue to be underused. In dementia, while the promise of early preventive measures looms on the horizon, the clinical importance of available antidementia drugs continues to be investigated. Finally, the usefulness of the clinical neurological examination is being systematically analysed in specific conditions, such as migraine and carpal tunnel syndrome.

	Methods

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We identified important neurological advances by canvassing subspecialty neurologists, performing hierarchical literature searches with SUMSearch (SUMSearch.UTHSCSA.edu/searchform4.htm), and reviewing medical collections such as bmj.com (www.bmj.com/collections/), Lancet Neurology Network (www.lancetneuronet.com/journal), Bandolier (www.jr2.ox.ac.uk/bandolier/), Health Technology Assessment (www.hta.nhsweb.nhs.uk/), Best Evidence 5, and the Cochrane Library. We chose topics that we judged to be of general interest and appraised the corresponding literature.

	Epilepsy

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Surgery and drugs for epilepsy
Epilepsy affects one in 1000 people. Although seizures are easily controlled with anticonvulsants in some patients, others are refractory to drugs. Until now, it has been difficult to identify patients who will become refractory to drugs, which is important for counselling and for seeking alternative non-pharmacological treatments. A recent study found that early response to anticonvulsants is a good indicator of future control of seizures.¹ Patients whose seizures are uncontrolled with the first anticonvulsant have a very low probability of being free from seizures with subsequent drugsonly 13% became free from seizures with the second drug and 4% with the third drug.

The optimum treatment for temporal lobe epilepsy, one of the most common forms of drug resistant epilepsy, is no longer controversial. In the first randomised controlled trial comparing surgery with medical treatment, surgery was greatly superior to antiepileptic drugs. At one year, 58% of surgically treated patients and 8% of medically treated patients were free from seizures, with a number needed to treat of 2 (fig 1). Patients treated surgically also had fewer seizures and better quality of life.² Surgery for other types of epilepsy has not been assessed in randomised controlled trials.

View larger version (18K): [in this window] [in a new window]   Fig 1.   Cumulative percentage of patients with temporal lobe epilepsy remaining free from disabling seizures and from any seizures at one year with surgery and with medical treatment. The number needed to treat with surgery was 2 (95% confidence interval 1 to 3) for disabling seizures and 3 (2 to 5) for any seizures

Risk of death in epilepsy
Clinicians and patients may misjudge the risk of death in epilepsy. Recent evidence about mortality and risk factors allows clinicians to provide better counselling to patients with epilepsy. In one study of epilepsy in children, the risk of death during the first five years after diagnosis was 7 (95% confidence interval 2.4 to 11.5) times higher than expected, and all the deaths occurred in children with neurological abnormalities (risk increased 22.9 (7.9 to 37.9) times). No deaths were attributed directly to seizures, and sudden unexplained death in epilepsy did not occur.³ In a study of patients of all ages, the age adjusted risk of death was 3.2 (2.9 to 3.5) times higher than expected.⁴ In another study, mortality was higher in the first few years after diagnosis and in patients with a neurological cause for their epilepsyfor example, congenital neurological abnormalities, in which the risk increased 11-12 times.⁵ Epilepsy was not common as a direct cause of death in these patients. In contrast, in patients with chronic, medically refractory epilepsy the cause of death was more often directly related to epilepsy. In a cohort of 393 patients undergoing surgery for epilepsy, the fivefold increase in risk of death was abolished if they became free from seizures after surgery. This underlines the importance of striving for complete freedom from seizures.⁶

	Cerebrovascular disease

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Atrial fibrillation and stroke
Atrial fibrillation affects 2-5% of the general population over the age of 60, is more common in elderly people, and is associated with a stroke rate of 4-6% a year. Meta-analyses of randomised controlled trials of warfarin in non-rheumatic atrial fibrillation have shown a relative risk reduction for stroke of 60-65%, with a target international normalised ratio of 2.0-3.0, compared with an approximately 20% relative risk reduction with aspirin.⁷ These benefits persist despite potential haemorrhagic complications. Other risk factors significantly increase the rate of stroke with atrial fibrillation. A recent study assessed a simple six point scheme (CHADS₂) for classifying stroke risk on the basis of the presence of risk factors (fig 2).⁸ In patients aged 65 to 95 with atrial fibrillation, the rate of stroke was 4.4 per 100 patient years. The risk adjusted rate ranged from 1.9 with 0 points to 18.2 with 6 points (fig 2). Thus aspirin alone is probably sufficient in patients with atrial fibrillation and a CHADS₂ score of 0, whereas in the presence of one or more risk factors warfarin is the better choice. However, warfarin continues to be underused, especially in elderly patients, in whom atrial fibrillation and other risk factors are more common; appropriate anticoagulation was used in only 30-60% in one survey.⁹

View larger version (21K): [in this window] [in a new window]   Fig 2.   The CHADS2 scoring system for stroke in patients with atrial fibrillation, showing points assigned to risk factors (top) and the risk of stroke (with 95% confidence interval) corresponding to the number of points (bottom)

Carotid endarterectomy for symptomatic carotid stenosis in elderly patients
The efficacy of carotid endarterectomy for symptomatic carotid stenosis of greater than 70% is well established.¹⁰ Although the risks of carotid endarterectomy may be higher in elderly patients, the benefits are even greater.¹¹ In patients aged over 75 who were studied in the NASCET trial, the absolute risk reduction for ipsilateral ischaemic stroke after carotid endarterectomy was 28.9% (12.9% to 44.9%), compared with 15.1% for patients aged 65-74 and 9.7% for those aged under 65.¹¹ Surprisingly, perioperative risks of stroke and death were no higher in elderly patients.¹¹ However, these carefully selected elderly patients might be healthier than those in the general population.

Thrombolysis
A meta-analysis of thrombolysis in stroke showed that patients receiving thrombolysis within six hours of the onset of symptoms were less likely to die or become dependent than were controls (odds ratio 0.83, 0.73 to 0.94), despite an increase in complications.¹² Treatment within three hours of onset of symptoms produced even better results (odds ratio 0.58 for death or dependency).¹² Reassuringly, administration of tissue plasminogen activator in the community had similar effectiveness, provided the recommended protocol was followed. ^{12 13} Complications from tissue plasminogen activator are more likely with large strokes or late treatment. ^{12 13} A scoring system using computed tomography, in which the amount of the middle cerebral artery territory involved was quantified, showed a good correlation between larger stroke, poorer clinical outcome, and increased risk of symptomatic intracerebral haemorrhage.¹⁴ Pending validation, this system could be used to identify patients who should not receive tissue plasminogen activator.

Alcohol and risk of stroke
Two recent studies showed a protective effect of light to moderate intake of alcohol on the risk of stroke. In the first study, consumption of up to two drinks a day had a protective effect for stroke (odds ratio 0.51, 0.39 to 0.67), even after adjustment for other risk factors.¹⁵ However, the risk of stroke increased with consumption of more than seven drinks a day. A second study showed that intake of more than one drink a week reduced the risk of stroke.¹⁶ The protective effect decreased with consumption of more than one drink a day.

	Dementia

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Antidementia drugs
Few therapeutic alternatives exist for people with Alzheimer's disease. A systematic review assessed the efficacy of donepezil (1980 patients), rivastigmine (1990 patients), and galantamine (1614 patients). The studies were of good quality but short duration (<3-6 months). Donepezil and rivastigmine improved global and cognitive assessments, and galantamine at higher dosages also improved functional outcomes. Side effects were generally mild. The clinical relevance of the small but statistically significant improvements remains uncertain.¹⁷

Statins
Patients prescribed hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) have a reduced chance of having dementia. In a cross sectional study of patients aged 60 or over, the prevalence of dementia was 60-70% lower (P<0.001) in those prescribed statins.¹⁸ Similarly, in a case-control study of patients aged 50 or over, the risk of dementia in patients prescribed statins was one third that of those not prescribed statins (P=0.002). The benefit was independent of non-statin lipid lowering agents, cerebrovascular risk factors, and use of cardiovascular drugs.¹⁹ Could these findings signal the advent of drugs for preventing dementia? Possibly, but the current evidence cannot substantiate a direct drug effect. A randomised controlled trial currently is under way in Scotland, Ireland, and the Netherlands.²⁰ It is investigating whether 40 mg/day of pravastatin prevents cognitive decline in 5840 people aged 70-82 years. Cognitive function is being measured annually for three years, and results are expected in 2002.

Vaccines
Although still at an early, experimental stage, immune therapy in Alzheimer's disease is uniquely promising. In animal models, vaccination with amyloid  prevented memory loss²¹ and reversed the putative brain abnormalities (amyloid deposits) of Alzheimer's disease²² without apparent toxicity. No clinical trials have yet been conducted.

	Multiple sclerosis

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Interferon for multiple sclerosis
Although interferon decreases the frequency of relapses in multiple sclerosis, a more important question is whether it averts progression of disability. Of three randomised controlled trials, only the earliest found a benefit. At two years, disability occurred in 38.9% of patients treated with interferon and 49.7% of patients given placebo.²³ Two subsequent trials involving 1499 patients failed to show any benefit on accumulating disability at two or three years. ^{24 25} Interferon does not seem to prevent disability in multiple sclerosis.

About 50% of patients with a first demyelinating episode develop multiple sclerosis; interferon decreases this risk. In two randomised controlled trials, fewer patients developed clinically definitive multiple sclerosis in the interferon group than in the placebo group at two and three years. The number needed to treat to prevent clinically definite multiple sclerosis in one patient was 6 (4 to 44) at two years. ^{26 27}

	Neuromuscular conditions

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Bell's palsy
Although the prognosis for untreated Bell's palsy is good, 16% of patients are left with significant dysfunction of the facial nerve. An evidence based review assessed nine prospective studies of early treatment with corticosteroids in Bell's palsy.²⁸ The methodologically strongest studies showed no benefit from corticosteroids, whereas poorer studies suggested a 1.2-fold increase in the likelihood of a good recovery and a 1.7-fold increase in complete recovery. The relative rate of improvement was 1.16 (1.05 to 1.29) after combination of class I and class II studies (see additional educational resources). Another meta-analysis found similar results.²⁹ The evidence is hardly an overwhelming demonstration of efficacy, but as the treatment is inexpensive and brief and has a low rate of adverse effects, the early use of corticosteroids (<7 days from onset) in Bell's palsy is probably justified. The routine use of aciclovir or surgical decompression in Bell's palsy was not supported.²⁸

Carpal tunnel syndrome
Carpal tunnel syndrome affects about 5% of the population. A systematic review looked at the usefulness of elements of the history and physical examination for the diagnosis of electrophysiologically proved carpal tunnel syndrome.³⁰ Useful diagnostic findings included decreased sensation in the median nerve territory (likelihood ratio 3.1, 2.0 to 5.1), drawing of symptoms within the appropriate distribution by patients (2.4, 1.6 to 3.5), and weakness of thumb abduction (1.8, 1.4 to 2.3). Other traditional signs, including Phalen's and Tinel's signs, had little or no diagnostic value.³⁰ There is little evidence to guide treatment of carpal tunnel syndrome. Notably, a recent prospective study that monitored the hands of 196 patients (274 hands) with untreated carpal tunnel syndrome showed spontaneous improvement rates of 27% for neurophysiological studies and 34% for symptoms.³¹

	Migraine

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Many patients with severe headaches carry a diagnosis of migraine, reached by themselves or by their doctors. But how is migraine diagnosed? A comprehensive review established likelihood ratios for possible diagnostic features in migraine.³² The presence of nausea was the most useful feature, while photophobia, phonophobia, exacerbation by physical activity, unilateral headache, and throbbing headache were moderately useful (table). Both precipitation of headaches by chocolate, cheese, or any food and a positive family history of migraine were specific but not sensitive diagnostic features. Features not useful for diagnosing migraine included duration of headache, precipitation by stress, missed meals, lack of sleep, changes in weather, menses, or alcohol.

	Acknowledgments

We are grateful for helpful comments from Kelly Zarnke, Keith Ferguson, and Sarah Cairncross on an earlier version of this manuscript.

	Footnotes

Competing interests: None declared.

	References

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1.	Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314-319[Abstract/Free Full Text].
2.	Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001; 345: 311-318[Abstract/Free Full Text].
3.	Callenbach PM, Westendorp RG, Geerts AT, Arts WF, Peeters EA, van Donselaar CA, et al. Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood. Pediatrics 2001; 107: 1259-1263[Abstract/Free Full Text].
4.	Shackleton DP, Westendorp RG, Trenite DG, Vandenbroucke JP. Mortality in patients with epilepsy: 40 years of follow up in a Dutch cohort study. J Neurol Neurosurg Psychiatry 1999; 66: 636-640[Abstract/Free Full Text].
5.	Lhatoo SD, Johnson AL, Goodridge DM, MacDonald BK, Sander JW, Shorvon SD. Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort. Ann Neurol 2001; 49: 336-344[CrossRef][ISI][Medline].
6.	Sperling MR, Feldman H, Kinman J, Liporace JD, O'Connor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999; 46: 45-50[CrossRef][ISI][Medline].
7.	Koudstaal PJ. Anticoagulants for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attacks. Cochrane Database Syst Rev 2000;(2):CD000185.
8.	Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864-2870[Abstract/Free Full Text].
9.	Gage BF, Boechler M, Doggette AL, Fortune G, Flaker GC, Rich MW, et al. Adverse outcomes and predictors of underuse of antithrombotic therapy in Medicare beneficiaries with chronic atrial fibrillation. Stroke 2000; 31: 822-827[Abstract/Free Full Text].
10.	Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339: 1415-1425[Abstract/Free Full Text].
11.	Alamowitch S, Eliasziw M, Algra A, Meldrum H, Barnett HJ. Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic internal-carotid-artery stenosis. Lancet 2001; 357: 1154-1160[CrossRef][ISI][Medline].
12.	Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2000;(2):CD000213.
13.	Buchan AM, Barber PA, Newcommon N, Karbalai HG, Demchuk AM, Hoyte KM, et al. Effectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness. Neurology 2000; 54: 679-684[Abstract/Free Full Text].
14.	Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Alberta stroke programme early CT score. Lancet 2000; 355: 1670-1674[CrossRef][ISI][Medline].
15.	Sacco RL, Elkind M, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60[Abstract/Free Full Text].
16.	Berger K, Ajani UA, Kase CS, Gaziano JM, Buring JE, Glynn RJ, et al. Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians. N Engl J Med 1999; 341: 1557-1564[Abstract/Free Full Text].
17.	Bryant J, Clegg A, Nicholson T, McIntyre L, De Broe S, Gerard K, et al. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease: a rapid and systematic review. Health Technol Assess 2001; 5: 1-137[Medline].
18.	Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000; 57: 1439-1443[Abstract/Free Full Text].
19.	Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000; 356: 1627-1631[CrossRef][ISI][Medline].
20.	Shepherd J, Blauw GJ, Murphy MB, Cobbe SM, Bollen EL, Buckley BM, et al. The design of a prospective study of pravastatin in the elderly at risk (PROSPER). Am J Cardiol 1999; 84: 1192-1197[CrossRef][ISI][Medline].
21.	Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 2000; 408: 982-985[CrossRef][Medline].
22.	Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, et al. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 2001; 7: 369-372[CrossRef][ISI][Medline].
23.	European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491-1497[CrossRef][ISI][Medline].
24.	Secondary Progression Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001; 56: 1496-1504[Abstract/Free Full Text].
25.	Goodkin DE. Interferon beta-1b in secondary progressive MS: clinical and MRI results of a 3-year randomized controlled trial. Neurology 2000; 54: 2352.
26.	Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343: 898-904[Abstract/Free Full Text].
27.	Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357: 1576-1582[CrossRef][ISI][Medline].
28.	Grogan PM, Gronseth GS. Practice parameter: steroids, acyclovir, and surgery for Bell's palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56: 830-836[Abstract/Free Full Text].
29.	Ramsey MJ, DerSimonian R, Holtel MR, Burgess LP. Corticosteroid treatment for idiopathic facial nerve paralysis: a meta-analysis. Laryngoscope 2000; 110: 335-341[CrossRef][ISI][Medline].
30.	D'Arcy CA, McGee S. Does this patient have carpal tunnel syndrome? JAMA 2000; 283: 3110-3117[Abstract/Free Full Text].
31.	Padua L, Padua R, Aprile I, Pasqualetti P, Tonali P. Multiperspective follow-up of untreated carpal tunnel syndrome: a multicenter study. Neurology 2001; 56: 1459-1466[Abstract/Free Full Text].
32.	Smetana GW. The diagnostic value of historical features in primary headache syndromes: a comprehensive review. Arch Intern Med 2000; 160: 2729-2737[Abstract/Free Full Text].