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VOL. 26 • NO. 2 • APRIL 2011 World Neurology

THE OFFICIAL NEWSLETTER OF THE WORLD FEDERATION OF NEUROLOGY South Africa Battles HIV-Related Disease INSIDE United Kingdom London’s National BY AHMED I. BHIGJEE, M.D. ture, and a lack of commitment to Hospital for Neurology addressing the crisis. As a result, outh Africa is made up of nine most patients who were depen- and Neurosurgery marks provinces, one of which is KwaZulu- dent on the state for care were 150 years of excellence in SNatal (KZN). As of July 2010, Statistics ARV naive. In turn, many patients clinical care, research, South Africa has put the estimated popula- presented with advanced disease. and training.

tion of the country at 49.9 million, of which At IALCH, as with other inter- HIGJEE PAGE 2

10.6 million reside in KZN. The 30-bed neu- nal medicine units in South I. B rology unit at the Inkosi Albert Luthuli Africa’s public sector, 50%-60% of Afghanistan/Pakistan Central Hospital (IALCH) in Mayville, KZN, the neurological inpatient work- HMED . A

R Physicians from

and a smaller 12-bed unit at Grey’s Hospital load in the state hospitals is HIV D in Pietermaritzburg, about 90 km away, are related. The range of neurological Afghanistan will train in the only neurological facilities in the public manifestation of HIV-related dis- neurology at neighboring OURTESY

sector serving KZN and the northern part ease at IALCH is similar to that in C Pakistan’s Aga Khan of the Eastern Cape, a neighboring province the rest of the country. The fol- Dr. Ahmed I. Bhigjee says HIV accounts for about 55% University under a to the south of KZN with a population of lowing is a discussion of some of of neurological workload in South African hospitals. program initiated by the 6.7 million people. Only about 20% of the the more common or serious neu- 2 American Academy of population can afford private health insur- rological complications seen at our hospital. culous lymphadenopathy is more common in Neurology. ance, which means that most patients have HIV-positive patients, who also suffer com- to be managed in public sector facilities. Neurotuberculosis plications such as strokes and hydrocephalus. PAGE 8 Against the above scenario, one should also The HIV epidemic has made the tubercu- However, HIV-positive patients requiring ven- note that South Africa probably has the high- losis (TB) problem catastrophic. In 2007, triculoperitoneal shunting have poorer out- Child Neurology est infection rate of the human immunode- there were about 315,000 cases of new or comes. No patient with Medical Research The International Child ficiency virus (HIV) in the world. About 5.7 recurrent TB in South Africa.3 There has Council grade 3 or 4 has survived shunting.4 Neurology Association million individuals of the total population been a corresponding increase in extrapul- The common difficulty of confirming a di- says global cooperation is 1 (11.4%) are infected. Until recently, the man- monary tuberculosis (EPTB). agnosis of TBM in the HIV-negative setting crucial in its efforts to agement of this epidemic was bedeviled by Ǡ Tuberculous meningitis (TBM) is the is compounded when there is HIV coinfec- train more pediatric the inadequate roll-out of antiretroviral drugs most serious of the EPTB conditions. In tion. Cerebrospinal fluid (CSF) smears (about (ARVs). Some of the reasons for the tardy re- HIV-positive patients, it presents in a manner 0% positive) and cultures (about 20% positive) neurologists in sponse by the state included the prevailing de- similar to that in HIV-negative patients – have low sensitivity in Southern Africa,5,6 developing countries. nialist attitudes about HIV/AIDS, the lack of fever, headaches, and a change in mental PAGE 11 funding, inadequate staffing, poor infrastruc- state are common but not invariable. Tuber- See South Africa • page 12 Premortem Transferrin Level May Flag Creutzfeldt-Jakob

BY MATTHEW STENGER formance of diagnostic testing curs in patients in the absence of the observation that brain iron CJD-positive vs. CJD-negative Elsevier Global Medical News was improved when measure- any known risk factors. It is the dyshomeostasis is accompanied cases than was T-tau. T-tau ment of total transferrin (T-TF) most common of the three by increased TF in sCJD cases, showed a significant correlation ow CSF total transferrin lev- was combined with measure- types of CJD, the others being they measured levels of T-TF and with duration of sampling prior Lel is a reliable premortem ment of the established sporadic hereditary and acquired. TF isoforms (TF-1 and TF-beta- to death in CJD-positive but not marker for sporadic Creutzfeldt- Creutzfeldt-Jakob disease (sCJD) In the current study, the re- 2) in CSF from the two groups. CJD-negative cases, whereas no Jakob disease, according to a biomarker, total-tau (T-tau). searchers obtained human pre- Compared with CJD-negative correlations were observed for study by researchers at Case Sporadic Creutzfeldt-Jakob mortem CSF autopsy-confirmed cases, CJD-positive cases had the TF markers in either group. Western Reserve University in disease (sCJD) is a rare, fatal samples from 99 sCJD-positive lower median CSF T-TF and This indicates that “T-tau Cleveland, Ohio, USA. prion disorder that typically cases and 75 sCJD-negative cases higher median T-tau values. T- changes as sCJD progresses, Dr. Ajay Singh and her col- goes undetected until biopsy or collected about 10 days to 36 TF and both TF isoforms were leagues also reported that per- autopsy. This form of CJD oc- months before death. Following more sensitive differentiators of See Creutzfeldt-Jakob • page 4

WCN 2011: Meeting of Minds in Marrakesh Interested in participating in the Tournament of the Minds at this year’s Congress? Find out what you have to do to join in on the fun and test your neurological prowess. See Page 2 01_7_12wfn11_4.qxp 4/1/2011 10:33 AM Page 2

2 • WORLD NEUROLOGY WWW.WFNEUROLOGY.ORG • APRIL 2011

EDITOR IN CHIEF’S COLUMN WCN 2011 The Future of Books Team Up for Marrakesh

his issue of WORLD NEUROLOGY features learn by reviewing cases and to acquire knowl- ducation and entertainment tions on a range of neurological three book reviews, two on practical mat- edge about how to use modern methods such Ewill again share a platform at topics based on clinical cases Tters of peripheral neuropathies and one as MRI. John D. Stewart’s Focal Peripheral Neu- this year’s World Congress of from around the world. The on neurological history. Do books matter these ropathies can be read cover to cover, but it will Neurology in Marrakesh, Mo- questions will focus on visual ma- days? Does anyone still read them? Should have a long shelf life as a source for quickly rocco, when participants “exer- terial, videos, and stills, with a anyone read them? There is plenty of materi- checking up on those critical, but easily for- cise their brains” in the Tourna- minimum of text. The winning al available in journals, there are lots gotten details. Justin A. Zivin and ment of the Minds. team will receive a prize. of review articles, and the Internet is John Galbraith Simmons’ tPA for The popular Tournament of All of the teams will participate overflowing with information. There Stroke: The Story of a Controversial the Minds offers a unique in a qualifying round. are really two issues here; one is the Drug is a modern history of the opportunity for com- The eight teams that intellectual content of the book, and new therapy, detailing its devel- peting national teams achieve the highest the other is the format. opment. It is at once educational to interact with their scores will advance to As to the content, books have sig- and entertaining. These are all colleagues from other a semifinal round and nificant value for different types of valuable as books. countries and test compete in two readers. The value comes from the fact But what about the format? their clinical prowess groups of four teams, that they can harbor an extended Some readers must hold the print- and intellectual with the winners of overview of a field as a single entity. ed book in hand; easy to read af- tenacity. This is the each group advancing It is difficult to get an easily accessible BY MARK HALLETT, M.D. ter many years of use, and easy to fourth time the to the final. overview by looking at a series of ar- navigate, it allows the reader to World Federation In general, there ticles, even review articles. A book can be a valu- shift rapidly from one part of the book to an- of Neurology will be one able source for someone learning about a new other. Others, mainly younger readers, are hap- has held the team per area because the information often is organized py with electronic media such as the Kindle and tourna- coun- for ease of learning – start with the basics in the iPad. Once a reader is used to these reading de- ment at one of its congresses. try, but for countries where there front of the book and gradually build up to the vices, they are easy to use, and in addition, they “I am thrilled that the Tourna- are a limited number of neurol- more complex details toward the end. This is the can store many books in a single package about ment of the Minds will be in- ogists, a team may consist of na- textbook. Books can also be useful for more ad- the size of a book. Why do you need a shelf if cluded in WCN 2011,” said Prof. tionals from more than one vanced readers who want a systematic approach you have an iPad? Books can also be available El Mostafa El Alaoui Faris, pres- country. Congress organizers to a complex topic, perhaps to present a review online, which blurs the distinction between the ident of WCN 2011, which will hope that the tournament will at- or organize information into a coherent frame- “book” and the multiplicity of smaller, gener- take place Nov. 12-17. “Based on tract competitors from all of the work. In addition, books can be helpful just to ally disconnected items that can be found by previous tournaments, we know participating countries. have on the shelf as a reference. There are many searching Google and PubMed. In fact, many that this dynamic and enjoyable Those who are interested in details one needs to remember in medicine, and books now come with a parallel online version activity enriches the congress for participating in the tournament once you are familiar with a book, you can find – buy the book and you get to access the same all participants – both profes- should contact the president of what you need quickly. content online. To some extent, this may signal sionally and socially.” the local member society who is Let’s consider the three books that are re- a transition to the future for many books, some WFN member societies are in- responsible for coordinating the viewed on page 16 as examples. Companion to of which will be e-only. This may not be bad. vited to enter a team of four neu- national teams. Peripheral Neuropathy: Illustrated Cases and New I already think that the printed journal will rologists in the tournament. The For more details about the Developments, by Dr. Peter James Dyck and his be gone soon. The important thing is to have teams will face each other in a tournament and WCN 2011, vis- coauthors, would be helpful to the generalist the connected intellectual content. The format knockout competition, during it the WCN Web site at www. or neuromuscular specialist who wants to has to go with the flow. ■ which they will be asked ques- wcn-neurology.com. ■

GLOBAL MEDICAL RESEARCH WORLD Publisher Peter F. Bakker, ELSEVIER GLOBAL MEDICAL NEWS A Division of International Medical News Group NEUROLOGY President IMNG Alan J. Imhoff WORLD FEDERATION OF NEUROLOGY WORLD NEUROLOGY, an official publication of the World Federation Editor in Chief Mary Jo M. Dales Editor in Chief Dr. Mark Hallett (USA) of Neurology, provides reports from the leadership of the WFN, its Executive Editors Denise Fulton, Kathy Scarbeck Managing Editor Renée Matthews EDITORIAL ADVISORY BOARD member societies, neurologists around the globe, and news from Clinical News Editor Jeff Evans Dr. Pierre Bill (South Africa); Dr. William M. Carroll (Australia); the cutting edge of clinical neurology. Content for WORLD NEUROLOGY Dr. Jagjit S. Chopra (India); Dr. Michael Finkel (USA); is provided by the World Federation of Neurology and Elsevier Global Audience Development Manager Barbara Cavallaro Executive Director, Operations Jim Chicca Dr. Osvaldo Fustinoni (Argentina); Dr. Francesc Graus (Spain); Medical News. Dr. Alla Guekht (Russia); Dr. Steven Ringel (USA); Director, Production and Manufacturing Yvonne Evans Struss Dr. Daniel Truong (USA); Dr. Alexandros Tselis (USA) Disclaimer: The ideas and opinions expressed in WORLD NEUROLOGY Production Manager Judi Sheffer do not necessarily reflect those of the World Federation of Neurol- Creative Director Louise A. Koenig WFN OFFICERS ogy or the publisher. The World Federation of Neurology and Else- President: Dr. Vladimir Hachinski (Canada) EDITORIAL OFFICE 5635 Fishers Lane, Suite 6000 First Vice-President: Prof. Werner Hacke (Germany) vier Inc., will not assume responsibility for damages, loss, or claims Rockville, MD 20852 Secretary-Treasurer General: Dr. Raad Shakir (United Kingdom) of any kind arising from or related to the information contained in +1-240-221-4500 Fax: +1-240-221-2541 this publication, including any claims related to the products, drugs, ELECTED TRUSTEES US ADVERTISING Dr. Wolfgang Grisold (Austria); Dr. Ryuji Kaji (Japan); Dr. Gustavo or services mentioned herein. Aaron Wattenberg Roman (USA) Editorial Correspondence: Send editorial correspondence to 60 Columbia Rd., Building B CO-OPTED TRUSTEES WORLD NEUROLOGY, 5635 Fishers Lane, Suite 6000, Morristown, NJ 07960 Donna Bergen (USA); Stephen Sergay (USA) Rockville, MD 20852, U.S.A.; [email protected]; +1-973-290-8212 Fax: +1-73-290-8250 REGIONAL DIRECTORS Phone +1-800-798-1822 [email protected] Dr. Ahmed Khalifa (Pan Arab); Dr. Robert Griggs (North America); Classified Sales Manager, IMNG Prof. Richard Hughes (Europe); Dr. Alfred K. Njamnshi (Pan Address Change: Fax change of address to +1-973-290-8245 Robert Zwick Africa); Dr. Ana Mercedes Robles de Hernandez (Latin America); +1-973-290-8250 Fax: +1-973-290-8250 POSTMASTER: Send change of address (with old mailing label) [email protected] Dr. Ching-Piao Tsai (Asia-Oceania) nd to WORLD NEUROLOGY, Circulation, 60 B, Columbia Rd., 2 Fl., Classified Sales Representative XECUTIVE IRECTOR E D Morristown, NJ USA 07960 Andrea LaMonica Keith Newton 800-381-0569, Fax: 914-381-0573 World Federation of Neurology WORLD NEUROLOGY, ISSN: 0899-9465, is published bimonthly by [email protected] Hill House, Heron Square Elsevier Inc., 60 B, Columbia Rd., 2nd Fl., Morristown NJ 07960. Richmond, Surrey, TW9 1EP, UK INTERNATIONAL ADVERTISING Phone +1-973-290-8200; Fax: +1-973-290-8250. Chris Woods Tel: +44 (0) 208 439 9556/9557 Fax: +44 (0) 208 439 9499 32 Jamestown Road [email protected] ©Copyright 2011, by the World Federation of Neurology Camden London NW1 7BY EDITOR OF THE JOURNAL OF THE NEUROLOGICAL SCIENCES +44 207424 4454 Dr. Robert Lisak (USA) [email protected] 01_7_12wfn11_4.qxp 4/1/2011 10:34 AM Page 3

APRIL 2011 • WWW.WFNEUROLOGY.ORG WORLD NEUROLOGY • 3

PRESIDENT’S COLUMN Brain Health Must Be Part of a World Agenda he new ad- A connection we value especially high- Our Annual General Meeting of the importance of seeking partners and ministration ly is with the American Academy of Neu- Council of Delegates in Geneva in Sep- fundraising to support these initiatives Tis a year old, rology, the largest of our member soci- tember, during the 14th Congress of the wherever possible. and it is time to eties. During the AAN’s annual meeting in European Federation of Neurological So- Dr. Robert Lisak has done an out- take stock. When Toronto last April, a number of WFN Del- cieties (EFNS), was memorable because it standing job as Editor of the Journal of we began our egates and Committee Chairs, together illustrated the extent to which the Feder- the Neurological Sciences. During his tenure, we were with the Chairs of the Initiatives and Task ation serves as a platform of unity for the unprecedented three-term tenure, the BY VLADIMIR mindful of strik- Forces, were able to convene with the Fed- global neurological community. China Journal’s impact factor has increased HACHINSKI, M.D. ing a balance be- eration’s Trustees and each other. It is was absent, but gave its proxy to Taiwan, steadily, its quality has improved, and its tween continuity thanks to the Academy’s generous and on- and the Delegate from Israel moved the profitability has grown. He has agreed to and change, on the premise that conti- going support in the form of donations of acceptance of the Palestinian Neurologi- continue in the post until a successor has nuity without questioning presented a copies of their Continuum journal that we cal Society’s application for WFN mem- been appointed (see p. 14). risk for obsolescence and that the best are able to run our extremely successful bership. Neurological societies from This year has brought new challenges time to plan for change was during a time CME program in developing countries. Yemen and Ivory Coast became new and opportunities. In September, the Unit- of stability. The change I referred to at the outset members of the Federation, which now ed Nations will hold its first-ever Summit One word has guided our thinking of this column was much in evidence af- comprises 113 member societies repre- on Non-Communicable Diseases, where- throughout the year: synergy. Working ter the Strategic Planning and Priority senting most of the world’s neurologists in most neurological disorders fall, in with others, be they individuals or orga- Setting Retreat in London last June, – and through them, the hundreds of New York. Last month, the WFN con- nizations. That will continue. The World when the WFN leaders got to know millions of current and future neurolog- vened a meeting in Geneva of leaders of Federation of Neurology (WFN) already each other and learn about their respec- ical patients. Dr. Donna Bergen and Dr. international organizations: European has excellent relationships with major in- tive priorities. We began that meeting by Stephen Sergay,both of the United States, Brain Council, IBRO, International Child stitutions such as the European Federa- exploring what makes the WFN unique: were appointed as Co-opted Trustees to Neurology Association (see p. 11), World tion of Neurological Societies, the In- namely, that we are the voice of neurol- serve with the three Elected Trustees. Federation of Neurosurgical Societies, ternational Brain Research Organization ogy worldwide. We agreed on a refor- Dr. Shakir presented the financial re- World Federation NeuroRehabilitation, (IBRO), and the World Health Organi- mulation of the WFN’s mission: “To port for 2010. The Federation’s operating and the World Psychiatric Association. A zation. The Secretary-Treasurer Gener- foster quality neurology and brain costs are modest and last year’s World representative from the World Heart Fed- al, Dr. Raad Shakir, for example, chairs health worldwide.” We addressed many Congress in Bangkok fared exceptional- eration will also be attending. We will all the WHO’s Topic Advisory Group for other topics during the 3-day gathering, ly well financially. Nevertheless, we shall meet with representatives of the WHO. Neurology, which is advising on the re- from regional initiatives to membership be facing increasing costs in our planned The WFN is doing everything possible to vision of the International Classification dues, and from the Federation’s voting investment in the Web site upgrade and ensure that the brain becomes part of a of Diseases in our specialty. system to upgrading its Web site. our numerous projects. It underlines the world agenda. ■

SECRETARY-TREASURER GENERAL’S ANNUAL It’s Time to Pay REPORT FOR 2010 Those Dues friendly reminder that the World Federa- Fiscal Success, Sound Investments Ation of Neurology’s 2011 annual fees for your member society are now due. Pave the Way for Future Growth The subscription is unchanged at £3.00 ster- ling per member. here can projects while remaining mindful of cisions regarding the support the Fed- It is very important the WFN maintains an Tbe no ar- the need to safeguard the Federation's eration provides to various projects up-to-date list of all our members. If there are gument about future financial health. As President worldwide. any changes to your officers or members, please ad- the World Vladimir Hachinski has made plain in It was with the long-term interests vise us as soon as possible. If you didn’t send a Federation of his columns, it is vital that we focus of the WFN in mind, however, that list of members last year, please do so now, in- BY RAAD SHAKIR, M.D. Neurology's firmly on “modest investment, high- I invited our independent financial cluding e-mail addresses and full mailing ad- financial high- yield activities.” We must look for adviser, Mr. Nick Millar of Ashburn dresses for the mailing of WORLD NEUROLOGY. light of 2010. During October, we fi- added value at low cost and routine Wealth Management Ltd., Darling- For further information, please contact nally received our share of the pro- post hoc evaluation of funded activi- ton, England, to address the Trustees Keith Newton or Laura Druce at the WFN of- ceeds from the 19th World Congress ties will inform us on their impact. and the Finance Committee at their fice in London at [email protected]. ■ of Neurology on Bangkok in 2009. The WFN cannot assume the role of meetings during the European Fed- Various estimates had been made an ad hoc funding agency: There are eration of Neurological Societies about the amount we might receive, more worthy projects than we could congress in Geneva last September. some of which we scarcely dared possibly afford to support. Neverthe- He gave invaluable guidance and re- A Call for Papers hope might be possible. In the end, less, the Federation is doing well fi- minded the Trustees of their fiscal the sum of £600,206.59 was deposit- nancially with assets of more than duties and responsibilities under he Journal of Nervous and Mental Disease, ed into the WFN account, exceeding £2.6m and this healthy financial status charitable law. With his expert guid- T America’s oldest continuously published in- all expectations. will allow us to seek partners for ance, the Trustees have decided to dependent monthly journal in the field, will May I record in this column the sin- some of our new initiatives, raise commit £1,000,000 to a portfolio of celebrate its 200th volume in 2012. cere congratulations of all WFN Of- funds for other initiatives, and invest investment funds, comprising John A. Talbott, M.D., the Editor in Chief, ficers, Trustees, and members for the properly in key activities such as our £600,000 in medium-term invest- has announced that the anniversary issue will excellent way in which the Neuro- Web site, which is our face to the ments (4-10 years) and £400,000 in be dedicated to the History of Psychiatry and logical Society of Thailand, aided by world. We are continually examining long-term investments (more than Neurology and has asked that submissions of the organizing team from Congrex, the roles of our committees and ad- 10 years). If, as expected, the next papers of a historical nature (especially on achieved such a wonderful and mem- dressing their needs because it is cru- two World Congresses - this year in subjects from 1974 to present) be submitted orable event that was not only a huge cial that they receive our support. In Marrakesh and Vienna in 2013 - are online by going to www.editorialmanager. scientific and social success, but a addition, the WFN is expanding and the all-around successes that previ- com/jnmd. highly profitable one as well. diversifying; keeping up with the ous congresses have been, the Fed- These review articles should be between We are now embarking on a peri- rapid change is challenging, and all of eration could go from strength to 4,400 and 8,800 words. The deadline for sub- od of planned expenditure on certain the Trustees are involved in major de- strength. ■ mission is Dec. 1, 2011. ■ 01_7_12wfn11_4.qxp 4/1/2011 10:35 AM Page 4

4 • WORLD NEUROLOGY WWW.WFNEUROLOGY.ORG • APRIL 2011 ‘The National’ Reflects on Its 150-Year Legacy

BY CHARLES CLARKE, MB, BCH, AND also maintains a worldwide SIMON SHORVON, MB, BCHIR, M.D. teaching role, offering courses to visiting fellows ew medical institutions today can show an unbroken and postgraduate students EUROLOGY AND record of development and achievement over more from around the world. N Fthan a century and a half, as is the case with Lon- There has been the fore- don’s National Hospital for Neurology and Neurosurgery. sight to develop into areas

The National, as it is known worldwide today, began in of neurology that were less OSPITAL FOR a small house in 24 Queen Square, in 1860, when it was fashionable in the past, such H called the National Hospital for the Relief and Cure of as neurorehabilitation, ATIONAL

the Paralysed and Epileptic. It was funded through the stroke, headaches, and dis- N hard work, generosity, and broad charitable intent of orders of movement. At a many people, but especially a London family, sisters Jo- scientific level, experimen- hanna and Louisa Chandler and their brother Edward. tal work in neurophysiolo- The siblings were orphans who lived with their gy, neurochemistry, and EUROSURGERY HOTOS COURTESY

grandmother. When she was paralyzed by a stroke, her molecular genetics has blos- P N grandchildren were struck by the lack of amenities for somed, and more recently, Joanna Chandler, left, and her sister Louisa, sold bead ornaments to raise funds caring for her. After she died, the granddaughters be- in imaging prion diseases for a hospital that could care for patients who had been paralyzed by stroke. gan raising funds by making and selling bead and pearl and mechanisms of neu- ornaments. They raised £200 over 2 years before seek- rodegeneration. Above all, the two institutions have rological and neurosurgical highlights of its history. A his- ing input from the Lord Mayor of London, David Wire, maintained an emphasis on the needs of patients and on tory of the hospital is to be recorded in a new scholarly himself partially paralyzed from a stroke. focusing on what they do best. book, The National Hospital, Queen Square 1860-2010, to be The doors of that original building opened in 1860, Many illustrious neurologists have served on the staff published in limited edition this year. It will complement while the present hospital, with the façade preserved to during its 150 years, including, during the first 100 years, the textbook in neurology by members of the hospital this day, was completed in 1890. Since then, it has de- Charles-Édouard Brown-Séquard, John Hughlings Jack- consultant staff (Neurology: A Queen Square Textbook, edit- livered continuous service both to clinical neurology son, William Richard Gowers, Victor Horsley, David ed by Charles Clarke, Robin Howard R, Simon Shorvon, and, with the neighboring Institute of Neurology Ferrier, Gordon Morgan Holmes, Samuel Alexander and Martin Rossor. Oxford: Wiley-Blackwell, 2009, 991 pp.) founded in 1950, to the experimental neurosciences. Kinnear Wilson, Francis Walshe, Charles Putnam Former students, staff and visitors at Queen Square are The secret of the National’s achievements is essential- Symonds, and Derek Denny-Brown. invited to join the Queen Square Alumnus Association. ly rooted in its commitment to assisting patients with neu- In November 2010, the hospital held a study day as part Membership offers many attractive benefits. Please con- rological disease and the quality of its staff. The hospital of its 150th anniversary celebrations, reflecting the neu- tact [email protected] for further information or to register for membership. Ǡ For information about the courses for vis- iting fellows and postgraduate students, write to: Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom; or e- mail [email protected]. Ǡ To order a copy of the limited edition book of the hospital’s history at a prepublication of- fer (£45 plus postage), write to: National Hos- pital Development Foundation, Box 123, Na- tional Hospital, Queen Square, London WC1N 3BG, UK; e-mail NHDFFundraising@ uclh.nhs.uk; or call +44-0-207-829-8724. ■

DR. CLARKE is honorary consultant neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, London. DR. The National Hospital for Neurology and Neurosurgery has remained steadfastly committed to assisting patients with SHORVON is professor of clinical neurology at the neurological disease and ensuring the quality of its staff, as well as offering training courses and pursuing research. Institute of Neurology, also at Queen Square.

CJD-positive cases with a specificity of because TF is relatively resistant to lim- Promise for Other Prion Diseases 87.5%, positive likelihood ratio of 6.8, neg- ited degradation by proteinase-K. Creutzfeldt-Jakob • from page 1 ative likelihood ratio of 0.2, positive pre- Ǡ Levels of CSF TF are in the mcg/mL dictive value of 91.0%, negative predictive range, compared with the pg/mL range while the new biomarkers remain fairly forms than with T-tau. Accuracy was im- value of 80.0%, and accuracy of 86.2%. of T-tau and 14-3-3, which allows for ac- stable in CJD-positive and CJD-negative proved over that with T-TF by using T-TF The researchers noted that the study curate detection from a small sample vol- cases,” the authors wrote (PLoS ONE and T-tau together. The ROC AUC was shows that CSF T-TF and the TF iso- ume without requiring pre-absorption of 2011;6:e16804[doi:10.1371/journal. pone. 0.90 for T-TF and 0.93 for T-TF combined forms are superior to T-tau alone in albumin and immunoglobulins. 0016804]). None of the markers showed with T-tau. Values for the Akaike’s Infor- identifying sCJD and suggests that the Ǡ And CSF T-TF is quantifiable. any correlation with age of the cases. mation Criterion, which is used to com- combination of T-TF and T-tau is supe- The authors concluded that their stud- Diagnostic accuracy of T-TF, the TF iso- pare different logistic regression models rior to the currently used combination of ies “provide confidence that CSF TF holds forms, and T-tau was assessed using non- for different biomarkers alone or in com- T-tau and the biomarker 14-3-3. promise as a biomarker of sCJD. Evalua- parametric tests, logistic regression, and re- bination and for which a lower value is su- There are additional advantages of tion of additional CSF samples from sCJD ceiver operating characteristic (ROC) area perior, were 0.81 with T-TF and 0.70 for CSF T-TF alone or in combination with and other forms of prion disorders and under the curve (AUC) analysis. Although T-TF combined with T-tau. T-tau as a potential diagnostic test for comparison with cases of rapid-onset de- T-TF was measured by both Western blot With cut-offs defined to achieve a sen- sCJD, which include: mentia will validate these observations and enzyme-linked immunosorbent assay sitivity of about 85% (based on the litera- Ǡ It is likely to be more specific for sCJD, further and probably lead to the opti- (ELISA), the Western blot results are ture for biomarker comparisons in because it reflects prion disease–associ- mization of current automated proce- deemed more accurate, because the ELISA Alzheimer’s disease), T-TF identified CJD- ated brain iron imbalance. dures for quantifying serum TF to CSF test is optimized for measuring serum TF positive cases with a specificity of 71.6%, Ǡ There is an opportunity for early di- TF [ultimately providing] a quick and that lacks TF-beta-2 and is thus less accu- positive likelihood ratio of 3.0, negative agnosis of sCJD, because there is a sig- sensitive premortem diagnostic test for rate in measuring brain levels of T-TF. likelihood ratio of 0.2, positive predictive nificant decrease in CSF T-TF at more sCJD and other prion disorders.” Overall diagnostic accuracy was better value of 81.7%, negative predictive value than 12 months before end-stage disease. The authors had no conflicts of interests. with T-TF than with the individual TF of 77.4%, and accuracy of 80.1%. The Ǡ Consistent results can be achieved The study was supported by funds from isoforms, and better with each of the iso- combination of T-TF and T-tau identified even in poorly preserved CSF samples, the National Institutes of Health. ■ 01_7_12wfn11_4.qxp 4/1/2011 10:37 AM Page 5

APRIL 2011 • WWW.WFNEUROLOGY.ORG WORLD NEUROLOGY • 5

NEUROLOGICAL HISTORY An American in Paris (and Other European Cities) etween 1870 and 1914, many Faculty and its far-famed all- American students and postgradu- gemeines Krankenhaus [gen- Bates visited European cities to com- eral hospital], was the mec- plete their medical training. William ca of all American students. Osler, the distinguished Canadian clini- The hospital and teaching arrangements BY PETER J. KOEHLER, were such that M.D., PH.D one could easily get special courses Dr. Koehler is a neurologist in and special labo- the department of neurology at ratory opportuni- the Atrium Medical Centre, ties in any Heerlen, the Netherlands. Visit subject. While his Web site at www.neurohis- cerebral anatomy

tory.nl. and neuropsychi- OEHLER

atry were my es- J. K cian and medical educator, stated that pecial aims and took up most German universities became the second of my time … ETER . P R

home of all who loved science, scholar- But my chief purpose was D ship, and truth. to learn brain anatomy un- Indeed, thousands of American, Russ- der Meynert – the great and ian, and Japanese physicians went to Vi- most original brain enna – which the American pathologist anatomist. Great as a scien- HOTOS COURTESY

William Welch called the “convention- tific investigator; but as a P al Mecca of American practitioners” teacher, far from great. … Bernard Sachs received his medical degree Theodor Meynert, “great as a scientific (American Doctors in German Universities, Meynert and Westphal were in Strasbourg during his European travels. investigator; but as a teacher, far from great.” TN Bonner. Lincoln: Nebraska Univer- great psychiatrists because sity Press, 1963, pp. 1-21) – and Berlin to they were also great neurologists. It would mental torticollis presented by L. Pierce skill in presentation of the average French in- be fortunate if the young Clarke in 1914, Sachs said, “if this indi- structor [Autobiography, p. 57]. psychiatrists of the pre- cated the future trend for our present- sent day were trained in day neurology, then the less we heard of In the spring of 1883, Sachs stayed the same way, and not it, the better.” with Hughlings Jackson in London and given certificates in psy- Sachs compared Meynert with Char- made a comparison between his Vien- chiatry without the fun- cot and Hughlings Jackson, both of nese and London teachers: damental knowledge of whom he visited after his stay in Vienna. organic neurology. … It became very evident, after a few days, that In the laboratory, I I spent a number of months with Jean- like Meynert, Jackson was not an easy man found myself in good Martin Charcot at La Salpêtrière in 1883. It to follow. … I determined to get at Jackson’s company. Allen Starr was was a great experience, after the dry and mat- medical thinking, and … followed closely a hard and patient work- ter-of-fact teaching methods of German sci- Jackson’s publications, especially on epilepsy er. … Both of us were am- entists, to revel in the more or less dramatic and aphasia… for many years, Jackson’s bitious and were equally presentation and discussion of clinical phe- views influenced me more than did those of devoted to the advance of nomena by this great French master of sci- any other teacher with the possible exception neurology and psychiatry ence. All Frenchmen, even to the lesser Pro- of Kussmaul [Autobiography, pp. 58-9]. Jean-Martin Charcot, a “great French master of science.” in America fessors, seem to be possessed by a dramatic [Sachs, B. Autobiogra- fervor. Every lecture at La Salpêtrière or at the Sachs returned to New York in 1884, pursue popular courses in neurology phy. New York, privately owned, 1949, p. Hotel Dieu [sic] was as enjoyable as the av- where he entered general practice and that were often held in English. 56]. erage dramatic performance. I wish we devoted himself to neurology and psy- After Vienna and Berlin, Paris and British and American teachers of medicine chiatry, starting the translation of Meyn- London were also important centers for Here, Sachs met several other stu- had half the elegance of diction and half the ert’s Psychiatrie. ■ those wishing to train in neurology. dents, some of whom became Among these students was the Ameri- famous. can neurologist Bernard Sachs (1858- 1944), who made a long European pere- Starr, [Gabriel] Anton, and I sat grination between 1878 and 1884. He alongside of one another and studied under the German physicians close to Sigmund Freud, now by Adolf Kussmaul, Friedrich von Reck- all odds the best known of the linghausen, and Friedrich Goltz in group. None of us suspected Strasbourg, where he received his med- Freud’s future fame. He pegged ical degree in 1882. He continued to away at anatomy, as we all did, Berlin, where he studied under Karl and although his doctrines took Westphal and where he likely also met him far afield, in his last letter to Carl Wernicke; to Theodor Hermann me, written only a few months Meynert in Vienna; Jean-Martin Char- before his death, he acknowl- cot in Paris; and John Hughlings Jack- edged he had never severed his re- son in London. lations with organic neurology In his autobiography, Sachs recounted [Autobiography, pp. 56-7]. his experiences during his postgraduate studies with Meynert: Indeed, Sachs was not very pleased with the psychoanalyt- I began my postgraduate studies in Vienna ic movement, especially with in October of that year [1882] under Meyn- respect to dystonic afflictions. ert. At that time, Vienna, with its famous In reaction to an explanation of 01_7_12wfn11_4.qxp 4/1/2011 10:37 AM Page 6

6 • WORLD NEUROLOGY WWW.WFNEUROLOGY.ORG • APRIL 2011

FROM THE JOURNAL OF THE NEUROLOGICAL SCIENCES Study Highlights Dengue Role in Viral Meningitis, Encephalitis

BY ALEX TSELIS, M.D., PH.D. to very extensive epidemics that can have cephalitis in the Midwest; Eastern equine causes a subacute subcortical dementia, a serious public health impact. encephalitis in Massachusetts; Japanese herpes encephalitis can change a pa- iral encephalitis and meningitis are The recent epidemic of West Nile en- encephalitis in the Far East; and en- tient’s basic personality and cause an uncommon but important diseases cephalitis in North America is a promi- cephalitis lethargica from 1917 to the late amnestic state, and encephalitis lethar- Vfor two reasons: Encephalitis is of- nent example, but it was preceded by 1920s in Europe and North America. gica can result in a parkinsonian state. ten followed by very significant cognitive other epidemics in North America and The effects of these diseases can tell us It is important to understand the epi- and motor deficits, which can be quite elsewhere: the pandemic of HIV en- much about the basic biology of the demiology of these diseases, because it disabling; and both diseases can give rise cephalitis in St. Louis, Missouri; en- nervous system. Thus, HIV encephalitis provides considerable information about the public health importance of the dis- ease as well as its basic biology. Thus, patterns of disease incidence and its spread can help identify ages of suscep- tibility and modes of dissemination. Most epidemiologic studies have been done in temperate regions, where the countries tend to have the necessary ex- pertise and infrastructure to manage these outbreaks. Thus, there is much data on the epidemiology of herpes en- cephalitis, HIV encephalitis, Eastern equine encephalitis, St. Louis en- cephalitis, and West Nile encephalitis in North America; but not for the less de- veloped regions of the world. The epidemiology of viral encephali- tis and meningitis in South America has fallen under the latter scenario, but is now the subject of a paper by Brazil- based researchers led by Cristiane N. Editor Soares (J. Neurol. Sci. 2011;303:75-9). The researchers prospectively collected data on patients who had been diag- nosed with viral encephalitis and menin- 7KH-RXUQDORIWKH1HXURORJLFDO6FLHQFHVWKHRI¿FLDOMRXUQDORI gitis between March 2006 and March 2008 in a dengue-endemic area. the World Federation of Neurology, published by Elsevier B.V. They recruited 81 patients; 37 met the diagnostic criteria for viral meningitis LV D SHHUUHYLHZHG PXOWLGLVFLSOLQDU\ MRXUQDO ZKLFK SXEOLVKHV (20) and encephalitis (17). The re- research articles of high quality in all areas of the neurological searchers were able to determine the eti- ology of 85% of the meningitis and 76% sciences. of the encephalitis cases. These figures are impressive, since most previous stud- ies were not able to diagnose any more We are looking for a new editor to take over from Dr Robert than 50% or 60% of encephalitis cases. This has implications for the patho- /LVDNWRGULYHIRUZDUGWKLVVXFFHVVIXOMRXUQDO7KHSRVLWLRQZLOO genesis of the infection. It is probably due begin in January 2012 with a prior run-in period. to the high endemicity of dengue in the area, which is the most common cause of encephalitis. Thus, dengue can cause en- cephalitis if the virus is common enough. The successful candidate will be a highly motivated, neurological Another example of the contribution of clinician-scientist with a broad knowledge of the clinical epidemiology to the understanding of the biology of viral infections arises from neurosciences and a strong academic record. the meningitis series. The authors found that herpes simplex virus 1 (HSV-1) is a common cause of aseptic meningitis, sec- ond only to the expected enteroviruses. Please contact The association between HSV-1 and viral meningitis may reflect the site of latency in the lumbosacral roots, because HSV-1 Professor Christopher Kennard, is becoming an increasingly common cause of genital herpes, and therefore, the Chairman, WFN Publications Committee at location of viral latency. [email protected] Further epidemiologic studies such as this are needed to give us information about the public health burden of these diseases, and to tell us about the basic char- acteristics of viral disease in humans. ■

Submission deadline May 15, 2011 DR. TSELIS is associate professor of neurology at Wayne State University in Detroit, USA, and book review editor for the Journal of the Neurological Sciences. 01_7_12wfn11_4.qxp 4/4/2011 11:03 AM Page 7 Worldsleep2011 New Horizons of Sleep Research for Our Planet

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8 • WORLD NEUROLOGY WWW.WFNEUROLOGY.ORG • APRIL 2011 WFN JUNIOR TRAVELLING FELLOWSHIP REPORT Calendar of A Rich Line-Up of Presentations International At Neuroscience 2010 Events attended Neuroscience 2010, the summarized how dendrites form which blind students in India are be- 2011 annual meeting of the Society for and organize among themselves, ing treated and provided health care INeuroscience, in San Diego, and how dendritic ion channels are and education. Among the other 9th Congress of European Paediatric Calif., USA, last November as a regulated by synaptic activities and issues discussed in this category Neurology Society World Federation of Neurology in turn modulate neuronal activity were child poverty and human cap- May 11-14 Travelling Fellow. and synaptic plasticity; then they ital and conferring legal rights to Cavtat/Dubrovnik, Croatia More than 35,000 neuroscientists led a discussion on the implications animals in research. www.epns2011.com attended the meeting, making it one of neurological diseases and mental At a very practical level, staff of the world’s largest forums for disorders to etiology. from the US National Institutes of 20th European Stroke Conference neuroscientists to debut their re- In another presentation, Dr. Ma- Health ran workshops and discus- May 24-27 search findings and network with hendra Bishnoi, a postdoctoral fel- sions on writing research data and Hamburg, Germany their international col- preparing manuscripts in accor- www.eurostroke.eu/ leagues. The attendees BY ANURAG KUHAD, M.D. dance with the requirements of included researchers; high-quality journals. I found an- European Neurological Society 21st academics; undergradu- Dr. Kuhad is in the other session on the mentor- Meeting ate, doctorate, and post- Pharmacology Research mentee relationship very informa- May 28-31 doctorate students; and Laboratory, University tive, especially on how to be an Lisbon, Portugal industry representatives. Institute of Pharmaceuti- effective mentor. www.congrex.ch/ens2011 Several neuroscien- cal Sciences, at Panjab Several companies demonstrated tists reported their latest University, Chandigarh, their newer technologies for the neu- research findings on India. roscience lab, for example, the auto- 15th International Congress of Parkinson’s neurodegenerative dis- mated software-operated instrument Disease and Movement Disorders orders such as Alzheimer’s disease, low from Southern Illinois Universi- for injecting drugs into different re- June 5-9 parkinsonism and movement disor- ty School of Medicine, Springfield, gions of the animal brain, a high-res- Toronto, Canada ders, multiple sclerosis, pain, and USA, reported findings from a study olution confocal microscope for www.movementdisorders.org/congress/ depression in oral and poster pre- on the effect of systemic and in- studying the different biomarkers of congress11/ sentation sessions. trathecal administration of resinifer- neurodegenerative disease patholo- A number of the lectures were atoxin on nociceptive behavior in gies, and electrophysiological equip- European Neuro-Ophthalmology Society particularly interesting. Prof. Yas- rats. The findings were encouraging ment for tracking changes in ionic Meeting min L. Hurd of Mount Sinai School because the role of different tran- current alteration in neurodegener- June 18-21 of Medicine, New York, spoke sient receptor potential vanilloid re- ative disorders. Barcelona, Spain about the feasibility of studying dis- ceptors in nociception in rats was be- I made many new contacts at the www.eunos2011barcelona.com/ crete gene and protein expression in ing studied. conference and learned much about the brains of drug abusers to illu- Apart from the scientific and my field, which I feel helped bridge 15th Congress of the International minate specific neurobiological fea- technological presentations, there the gaps in my knowledge and al- Headache Society tures underlying addiction disor- were a number that also addressed lowed me to return to India with June 23- 26 ders. Dr. Yuh Nung Jan and Dr. Lily social and ethical issues. One such novel ideas and valuable informa- Berlin, Germany Jan from the University of Califor- impressive talk was by Dr. Pawan tion that my colleagues and I can ap- www2.kenes.com/ihc2011/pages/home.aspx nia, San Francisco, delivered an in- Sinha of the Massachusetts Institute ply to our research. I was highly mo- formative lecture titled “Dendrites, of Technology, Boston, USA, who tivated after discussing my research 8th International Brain Research From Form to Function.” They spoke about Project Prakash, under findings on nociception in rats. ■ Organisation World Congress of Neuroscience July 14-18 Florence, Italy Afghan Physicians to Train in Pakistan www.ibro2011.org/site/home.asp

BY MOHAMMAD WASAY, M.D., rological disorders are seen by family physicians, pedi- AND PARVEZ NAYANI, M.P.H. atricians, and internists, who not only have limited 4th Congress of the Pan-Asian Committee training in neurology but also lack the necessary equip- for Treatment and Research in Multiple ga Khan University in Karachi, Pakistan, and the ment for neurological examination and diagnosis. Sclerosis AAmerican Academy of Neurology have signed a mem- The AAN has started an Afghan Neurology Training Aug. 25-27 orandum of understanding for two candidates from Fund and has approved US$40,000 to fund the program, Kyoto, Japan Afghanistan to train in neurology at AKU. The candidates which is due to start May 1, 2011. Over the course of the www.pactrims.org will be internists or family physicians and after receiving 2-year program, trainees will learn about the diagnosis 2 years of intensive neurology training, they will and treatment of common adult and pediatric neuro- 29th International Epilepsy Congress be able to practice as trained neurologists. logical disorders as well as go through neuroradiology, Aug. 28-Sept. 1 Afghanistan has been devastated by recurring wars psychiatry, and neurophysiology rotations. Rome, Italy over many decades, and the effects of this protracted In the second year, they will also learn how to set up http://www.epilepsyrome2011.org/ turmoil are reflected in some of its key health indica- and run a neurology training program. When the tors – an infant mortality of 129 per 1,000 live births, trainees have completed the program, they will return World Congress on Huntington’s Disease total life expectancy of 46 years at birth, two physicians to Afghanistan, where they will be expected to establish Sept. 11-14 per 10,000 population (out of a total population of 25 neurology training programs at their home institu- Melbourne, Australia million). tions. The AAN and the World Federation of Neurolo- www.worldcongress-hd2011.org/ Although there are 11 medical colleges and about gy will continue as advisers to the trainees on their re- 1,700 specialist doctors in Afghanistan, none of those in- turn to Afghanistan. ■ stitutions have neurology departments, neurology train- 20th World Congress of Neurology Nov. 12-17 ing programs, or trained neurologists on their staff or DR. WASAY is professor in the department of neurology at Marrakesh, Morocco faculty. As such, large number of patients with neuro- Aga Khan University, Karachi, Pakistan, and MR. NAYANI logical disorders travel to Pakistan, Iran, and India for is the director of the French Medical Institute for Children www2.kenes.com/wcn/Pages/Home.aspx diagnosis and treatment. Currently, all patients with neu- in Kabul, Afghanistan. 08_11wfn11_4.qxp 4/1/2011 10:46 AM Page 9

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10 • WORLD NEUROLOGY WWW.WFNEUROLOGY.ORG • APRIL 2011 Genetic Insights May Guide Pediatric Stroke Therapies

BY JEFF EVANS clusive disease most often results from the loss of vascular smooth- muscle cells, and physical trauma to the head or neck, ab- Elsevier Global Medical News overgrowth of smooth-muscle cells caused hyaline degeneration in arterial media. normal inflammatory response, or ox- by the lack of elastin; aneurysmal disease Other features of CARASIL such as idative injury. A range of phenotypes rimary and secondary prevention has not been reported. alopecia can begin in adolescence. Mu- has been associated with mutations in measures for children at risk for idio- ACTA2, the gene for a member of the tations in genes for TGF-beta receptors, the gene that encodes the alpha-1 chain Ppathic arterial ischemic stroke need to highly conserved actin proteins, actin alpha TGFBR1 and TGFBR2, cause Loeys-Di- of type IV collagen, COL4A1. It re- target disease mechanisms unique to 2, codes for a main contractile protein in etz syndrome, which is characterized by duces the stability of vascular basement nonatherosclerotic arteriopathies, accord- vascular smooth-muscle cells. Mutations arterial tortuosity and large-vessel, non- membranes and can lead to idiopathic ing to pediatric stroke researchers. affecting it result in dysfunctional smooth- cerebrovascular aneurysmal disease. In small-vessel disease in children, includ- Risk factors, signs, and symptoms differ muscle cell contraction and the proliferation arterial tortuosity syndrome, the loss of ing occlusive and aneurysmal cerebral for arterial ischemic stroke (AIS) in adults of smooth-muscle cells that occlude small- arteriopathies associated with ischemic and children. Early recognition of factors er arteries but seem to make larger arteries and hemorrhagic stroke phenotypes. unique to at-risk children can prompt initi- vulnerable to aneurysmal disease. A diverse THE EARLY RECOGNITION OF Cerebral hemorrhage in individuals ation of prophylactic treatment with an- number of vascular beds can be involved, FACTORS UNIQUE TO AT-RISK with COL4A1 mutations might be as- tiplatelet drugs, anti-inflammatory drugs, which is most noticeable in the fact that all sociated with trauma, based on a study and anticoagulants when thrombosis and in- mutation carriers have livedo reticularis. CHILDREN CAN LEAD TO THE that identified trauma to the head or flammation play important roles in the PROMPT INITIATION OF neck in the preceding 2 weeks as a risk pathogenesis, Dr. Pinki Munot of Great Or- Homeostasis and Remodeling factor in previously healthy children. mond Street Hospital for Children NHS The Notch signaling pathway is essential in PROPHYLACTIC TREATMENT. A mutated form of SAMHD1 is one Trust, London, and coauthors wrote in a re- determining the differentiation of smooth- of five genes that have been associated view (Lancet Neurol. 2011;10:264-74). muscle cells and their response to vascular with the encephalopathic syndrome Many of these arteriopathies appear to injury. Mutations in NOTCH3 and JAG1 function of a facilitative glucose trans- called Aicardi-Goutières. Children with be caused by single-gene mutations that af- genes affect this pathway. porter encoded by SLC2A10 (or this mutation had cerebral arteriopathy fect various parts of an artery’s structure NOTCH3 mutations lead to arterial wall GLUT10) leads to defective collagen, with either occlusive or aneurysmal at different points in its development, thickening and stenosis in mostly small ves- elastin, or both, and activates TGF-beta features, peripheral vascular disease, homeostasis, or response to environmen- sels in the condition called CADASIL (cere- as a secondary response to a defective ex- which shows that “as with ACTA2-re- tal stress, offering a range of different tar- bral autosomal dominant arteriopathy with tracellular matrix. lated disease, the skin can indicate the gets for research. subcortical infarcts and leukoencephalopa- Abnormal vascular homeostasis in presence of cerebrovascular disease.” To detect the underlying genetic disorder, thy). Most reports of cerebral infarction pseudoxanthoma elasticum, caused by a Excessive smooth-muscle cell prolif- Dr. Munot and colleagues advised asking have been reported in adults but might be mutated ABCC6 gene, leads to a calcifi- eration and vascular occlusion occur in about clinical history of stroke, migraine, underrecognized in childhood. cation of elastic fibers and might be seen individuals with neurofibromatosis type porencephaly, learning difficulties, and sta- The jagged-1 surface protein encoded by with cutaneous signs in childhood, 1 (NF1), which is caused by mutations tic motor disorders, and to look for disease JAG1 is mutated in nearly 90% of individu- though it is most often diagnosed in teens in the NF1 tumor-suppressor gene. NF1 in vascular beds outside the brain. They rec- als with Alagille syndrome. Individuals with and young adults when AIS and periph- normally inhibits activity of the Ras ommended pursuing genetic investigations this syndrome appear to harbor abnormal- eral vascular disease become prominent. signaling pathway, but its disinhibition only in patients with cerebrovascular and ly thin-walled vessels with myointimal hy- Persons with mutations in the peri- results in intimal proliferation, smooth- noncerebrovascular features that are sug- perplasia of the vascular wall. Occlusive centrin gene PCNT that cause the au- muscle nodules, and fibrosis of the vas- gestive of a genetic cause. and aneurysmal arterial disease observed in tosomal recessive disorder micro- cular media and adventitia. About 6% of The authors described how single-gene the syndrome are associated with ischemic cephalic osteodysplastic primordial children with NF1 have diffuse cerebral mutations contribute to known pheno- and hemorrhagic strokes. dwarfism type II (MOPD II) have an arteriopathy with features of occlusive types described in various pediatric cere- Dysregulation of transforming growth emergent and progressive cerebrovas- and aneurysmal disease. Evidence sug- bral arteriopathies (not including inherit- factor beta (TGF-beta) signaling caused by cular disease in childhood such as moy- gests that chronic inflammation is an ed metabolic disorders). mutations in the gene coding for HtrA ser- amoya syndrome and, less often, important factor in NF1 arteriopathy, ine peptidase-1, HTRA1, is known to result aneurysmal disease that support a role but the trigger for this is unclear. Vascular Development in the condition called CARASIL (cerebral of the centrosomal protein pericentrin Mutations in ATP7A, in X-linked re- The deletion of a region of chromosome 7 autosomal recessive arteriopathy with sub- in vascular homeostasis. The mutations cessive Menkes disease, affect copper that contains the gene for elastin (ELN) cortical infarcts and leukoencephalopathy). also cause vascular disease in many ar- transport. These present with varying causes Williams-Beuren syndrome. Arteri- The disease causes a dysfunction in vascu- eas outside of the cerebral circulation phenotypes and degrees of severity. The opathy in most cases of the syndrome (70%) lar homeostasis, resulting in diseased cere- in individuals with MOPD II, which is disorder mainly causes connective-tissue results in supravalvular aortic stenosis but bral small arteries, which usually arises in characterized by microcephaly, pre- and abnormalities but can cause a progres- can involve other vascular beds, and causes adulthood. They show arteriosclerosis with postnatal growth failure, skeletal dys- sive neurodegenerative disorder that re- an overgrowth of smooth-muscle cells. Oc- intimal thickening and dense collagen fibers, plasia, and dysmorphism. sults in death in infancy. Ischemic and The rare, nonatheromatous arteri- hemorrhagic stroke, structural abnor- opathy called moyamoya usually caus- malities in cerebral arteries, oxidative in- es bilateral occlusive disease of the ter- jury, and energy failure have been re- Child Stroke Scale Validated minal internal carotid arteries and is ported with the vascular phenotype. considered one of the most severe or the first time, a pediatric stroke subset of 25 patients who underwent si- childhood cerebral arteriopathies. The Abnormal Metabolites Fseverity scale has been validated in a multaneous examinations by two pedi- overproliferation of smooth-muscle The X-linked lysosomal storage disorder prospective clinical trial. atric neurologists. Characteristics of the cells in the syndrome, with colocaliza- called Fabry’s disease is caused by a de- The study in 15 North American med- subgroup were similar to those of the en- tion of inflammatory cells such as ficiency of alpha-galactosidase that aris- ical centers showed excellent interrater tire cohort. The simultaneous raters’ macrophages and T cells, is “probably es from mutations in the GLA gene that reliability when neurologists used the Pe- scores were identical in 60% of ratings genetically mediated,” said the authors. encodes the enzyme. The metabolite diatric NIH Stroke Scale (PedNIHSS), a and were within a 1-point difference in But genotype-phenotype correlations globotriaosylceramide builds up in vas- pediatric version of the National Insti- 84% of ratings (Stroke 2011;42:613-7). have been difficult because of varying cular endothelium, causing injury and tutes of Health Stroke Scale for adults, –Sherry Boschert degrees of precision used to describe progressive arteriopathy in large and to examine 113 patients aged 2-18 years moyamoya in the literature. “Identifi- small vessels. About 40% of hemizygous with acute arterial ischemic stroke, Dr. A video interview with Dr. Ichord about cation of single-gene disorders associ- men develop stroke with vessel ectasia. Rebecca N. Ichord, director of the pedi- the scale can be viewed using the QR code ated with moyamoya might lead to a The autosomal recessive disorder ho- atric stroke program at the Children’s (see p. 14), or go to better understanding of childhood mocystinuria leads to a deficiency in cys- Hospital of Philadelphia, reported at the www.clinical cerebral arteriopathy,” because the dis- tathione-beta synthase and an increased International Stroke Conference in Los neurologynews.com, order “often represents one aspect of a risk of stroke and abnormal blood clots. Angeles. click on the video more diffuse arteriopathy.” These effects of hyperhomocysteinemia The patients were examined daily icon, and search for are suspected to occur through a dys- from admission to discharge, or day 7 of “Pediatric Stroke Response to Injury function of the vascular endothelium hospitalization. Severity Scale Stroke phenotypes in some single-gene and procoagulation effects. The authors Interrater reliability was tested in a Validated.” disorders have been associated with had no financial conflicts to report. ■ 08_11wfn11_4.qxp 4/1/2011 10:47 AM Page 11

APRIL 2011 • WWW.WFNEUROLOGY.ORG WORLD NEUROLOGY • 11 Child Neurology Association’s Global Education Plan rogress in pediatric neurosciences rious effects on a child’s development. gies have been adopted to promote ed- ical disorders that affect millions of chil- is proceeding rapidly, and we are There is an urgent need to identify re- ucation in emerging countries. Among dren worldwide. ICNA has a unique role Pentering an era in which technolo- gional centers and reference labs to im- these was for the ICNA executive board in improving international cooperation gies will allow for a greater knowledge prove diagnosis of neurological disease to hold its annual meeting in conjunction and promoting clinical and scientific re- and understanding of normal and ab- in children in developing countries. In with local or regional child neurology or- search by providing a medium through normal brain development. Because of Central Asia, the number of qualified ganizations in different countries or re- which physicians can exchange opinions our improved diagnostic abilities, it is child neurologists has increased in recent gions, and for the association to provide at an international level for the advance- now possible to identify even subtle brain years, but they are not equally distributed speakers and scientific support to local ment of pediatric neurosciences. abnormalities early on, thus allowing between urban and rural areas, with conferences. In doing these things, ICNA The Internet is the key to coordinating for early intervention. However, in cer- about 95% of them concentrated global education in pediatric neurology. tain areas of the world, many children do in the countries’ capital cities. BY PAOLO CURATOLO, M.D. ICNA supports a Web site, www.icnape- not benefit from this progress because of The situation is worse in Africa, dia.org, that provides access to pertinent the shortage of child neurologists and where many countries have no Dr. Curatolo is professor papers, clinical guidelines, consensus adequately equipped medical centers. child neurologists at all. of pediatric neurology at statements, and management protocols. In recent years, this progress in diag- Education is one of the prima- Tor Vergata University, The association is deeply committed to nostic and therapeutic capabilities and ry goals and purposes of the In- Rome, and a former providing innovative educational and the growing necessity for advanced tech- ternational Child Neurology As- president of the Interna- training programs for all professionals in- nology to diagnose CNS disorders have sociation (ICNA). The ICNA tional Child Neurology As- volved in the care of children with neu- greatly increased the divide between de- Education Committee has orga- sociation. rological disorders. Its International Ed- veloped and developing countries. In ad- nized numerous programs for ucation Committee plans to develop a dition, child neurologists from develop- improving participants’ knowledge of has had a significant impact on the de- distance learning course in pediatric neu- ing countries are hampered by the lack pediatric neurological disorders at the velopment of regional child neurology rology for those who are not able to of professional networks that could pro- primary care level and for promoting associations in Asia, Africa, Eastern Eu- travel to attend courses and conferences vide continuous education and updates clinical research interest in child neurol- rope, the Middle East, and South Amer- in person. on new developments in the specialty. ogy. In the past decade, these clinically ica. ICNA is uniquely qualified and well About 70% of children with disabilities oriented events have focused on com- In 2002, my administration established positioned to remedy this deficit by re- live in resource-poor countries, and most prehensive aspects of child neurology research as the top prerogative of our so- ducing the gap and increasing the level of them have neurological diseases. Pro- and have been organized in several coun- ciety. Not surprisingly, ICNA’s primary of child neurology care all around the tein-energy malnutrition, dietary mi- tries, including Egypt, Estonia, research priority is to document and de- world. To accomplish this ambitious cronutrient deficiencies, environmental Guatemala, India, Kazakhstan, Kenya, fine the causes of neurological handicaps goal, ICNA should work with the World toxins, and a lack of early sensory stimu- Peru, Ukraine, and Uruguay. The main in children in various geographic regions Federation of Neurology and World lation may contribute to the high preva- goals of these events were to improve the so that approaches to prevention and Health Organization. This international lence of neurodevelopmental disabilities use of relevant diagnostic measures and treatment can be tailored to a region’s cooperation is more important than ever in these countries. Access to up-to-date management in pediatric neurological specific needs. to promote brain health globally. ■ imaging and genetic and biochemical test- care, and enrich the teaching and acade- We urgently need to build this research ing is limited in some regions, which is mic skills of local trainers. capacity in emerging countries through Part of this article is adapted from a paper particularly problematic because delaying Under the ICNA educational pro- international cooperation so that we are by Dr. Curatolo that appeared in the Journal diagnosis and treatment can have delete- grammes, a number of different strate- united against the devastating neurolog- of Child Neurology (2010;25:1444-9). Cultural Differences Could Inform Migraine Therapy

BY MATTHEW STENGER 41.3% of Brazilian patients and 34.0% of Spanish pa- convulsants (28.5% vs. 2.8%), antidepressants (24.5% vs. Elsevier Global Medical News tients, with visual aura being the most frequent aura type 10.6%), beta-blockers (20.5% vs. 5.7%), and calcium (80.7% of all cases), followed by sensory aura. The most channel blockers (19.2% vs. 8.5%). n appreciation of sociocultural differences in knowl- common symptoms of migraine overall were photo- Aedge of migraine triggers and symptoms and mi- phobia (83.2%), phonophobia (82.2%), and nausea Brazilians ‘Undertreated’ graine treatment may result in improved management (78.4%). Significantly more Brazilian patients reported The findings show that “Brazilian migraineurs are of migraine, according to findings from a study con- nausea (90.8% vs. 66.9%) and vomiting (68.8% vs. more often undertreated for migraine, [with] under- ducted in Spain and Brazil. 22.6%), whereas photophobia (84.4% vs. 82.1%) phono- utilization of triptans and preventatives [being] ob- Researchers led by Francisco Carod-Artal, from the phobia (86.5% vs. 78.2%), and headache aggravation dur- served,” the authors wrote (J. Neurol. Sci. 2011 neurology departments at Virgen de la Luz Hospital, ing physical activity (75.2% vs. 68.2%) were reported by [doi:10.1016/j.jns.2011.02.027]. “The differences found Cuenca, Gregorio Marañón University General Hos- similar proportions of Brazilian and Spanish patients. in symptom frequency (such as nausea and vomiting, pital, Madrid, and University Hospital, Valladolid, Spain, Significantly more Brazilian patients identified mi- often related to pain intensity) and susceptibility to trig- showed substantial differences in reported triggers of graine triggers (79.4% vs. 66.2%, P = .01). Overall, sleep gers may be partially explained by a lesser use of trip- migraine and frequency and types of treatment be- disturbance and stress were the most commonly report- tans in treating acute attacks in our Brazilian series and tween migraineurs in Spain and those in Brazil. ed triggers. Brazilian patients reported food (30.5% vs. a significant difference in the use of preventatives.” Recent data indicate a 1-year gender- and age-adjusted 12.6%, P = .0002), sleep disturbance (56.7% vs. 28.5%, P Triptan use was greater in Spanish patients even prevalence of migraine of 15.2% in Brazil and a 1-year less than .0001), smells/odors (52.5% vs. 9.3%, P less than though they had a significantly lower mean number of prevalence of 11.0% in Spain (15.9% in women, 5.9% in .0001), stress (73.1% vs. 46.4%, P less than .0001), and, acute attacks, with this latter fact likely related to the men). In the current study, 292 patients were consecu- among women, menstruation (55.6% vs. 38.1%, P = .02) greater use of preventive medication by Spanish mi- tively recruited over a 4-month period from one Brazil- as triggers with significantly greater frequency. graineurs. The greater recognition of migraine triggers ian and two Spanish neurology outpatient clinics (141 and among Brazilian patients may be related to the in- 151 patients, respectively). All of the patients were from Differences in Treatments, Preventive Medications creased frequency of acute attacks associated with the urban environments and were of middle socioeconom- For treatment of acute migraine attacks, analgesics (as- reduced use of preventive treatments. ic class. They had to have primary headache and a neu- pirin, acetaminophen) and anti-inflammatory drugs were Other data from an urban headache center in Brazil rologist’s diagnosis of migraine to be included. Mean ages used by 98.2% of Brazilian patients and 87.5% of Span- indicate a wide use of vitamins/herbal therapies (24%) were 33.1 years for Brazilian migraineurs and 35.9 years ish patients (P not significant). Ergotamine was used by and nonmedicinal therapies (32%) for migraine in for Spanish migraineurs, and 81.6% and 78.1%, respec- 4.6% and 7.1% (P not significant), respectively, but sig- Brazil, perhaps accounting for the underuse of effica- tively, were female. The age at first migraine was 17.5 nificantly more Spanish patients used triptans (16.3% vs. cious preventive drugs observed in the current study. years in Brazilian patients and 19.8 years in Spanish pa- 47.0%, P less than .0001). Differences in medication use between the populations tients. Family history of migraine was more common in There were also major differences between popula- may be explained by additional sociocultural differences the Brazilian patients (79.4% vs. 64.3%, P = .004). tions in terms of use of preventive medication: 52.9% or differences in access to particular medications; such Brazilian patients had a greater mean number of mi- of Spanish patients used preventative medicine, com- factors were not investigated in the current study. graine attacks during the preceding month (7.3 vs. 3.8, pared with 21.9% of Brazilian patients (P less than The authors reported that they had no conflicts of in- P less than .001). Migraine with aura was reported by .0001); significantly more Spanish patients used anti- terest and no source of financial support. ■ 01_7_12wfn11_4.qxp 4/1/2011 10:38 AM Page 12

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However, a peculiar large vessel extracra- Delay in Antiretroviral Delivery nial vasculopathy has been responsible for South Africa • from page 1 cerebral or limb ischemia in HIV-positive patients. Aneurysms and stenoses occur which contrasts with the high yields of volvement.10 These latter presentations (Figure 2) and, in addition, there is an iso- 69% smear and 87.9% culture positivity were seldom seen in the pre-HIV era. lated intracranial aneurysmal vasculopathy rates in a Vietnam study.7 Molecular stud- (Figure 3) that presents either as ischemia ies improve the yield of a positive diagno- Cryptococcal Meningitis or subarachnoid hemorrhage. However, OSPITAL

sis, but there is an unacceptable false-neg- Cryptococcal meningitis continues to extensive investigations have failed to re- H ative result rate.4 Findings from a recent be a major problem in HIV-positive pa- veal a secondary cause, suggesting HIV local study examining an interferon-gam- tients, with mortality in those admitted may be the etiologic factor. ENTRAL ma T cell ELISPOT assay, hold promise for in a disturbed state of consciousness ap- C the rapid immunodiagnosis of TBM.8 proaching 100%. Visual loss is a major Parainfectious Disorders UTHULI

An added burden has been the emer- problem despite aggressive attempts to Ǡ Acute disseminated encephalo- L gence of multidrug and extensively drug- lower intracranial pressure. myelitis is poorly documented in the lit-

13 LBERT

resistant (MDR and XDR, respectively) An added problem is the limited avail- erature, but is not a rare diagnosis (and A TB, and now total drug-resistant ( TDR) ability of amphotericin B in the rural ar- unpublished data). Patients present with NKOSI

eas. In these instances, we recommend major neurological deficits, but with ad- ,I high-dose fluconazole – for example, 800 equate support and no specific therapy mg daily – for 6-10 weeks, depending on apart from steroids in some of the cases,

the response, then followed by mainte- most of them show significant improve- EPARTMENT nance therapy. Some studies have safely ment. The usual investigations to find D used daily doses as high as 1,200-1,400 mg. other triggers for acute disseminated en-

cephalomyelitis have been uniformly un- ADIOLOGY Intracranial Mass Lesions rewarding. The better prognosis contrasts R The causes of intracranial mass lesions with that seen in the viral exanthems, (IMLs) in HIV-positive patients are similar where the fatality rate may vary from 5% to those reported in developed countries, (varicella) to 25% (measles).

Ǡ MAGES COURTESY except that the intracranial tuberculoma- Chronic inflammatory demyelinating I ta are more common.11 Another peculiar neuropathy is seen in two to three HIV- Figure 1. Sagittal MRI scan of the observation is that intracranial abscesses positive patients each year. The clinical and spinal cord with an epidural tend to be multiple and more than one or- investigative profiles are identical to those tuberculous abscess (arrows). Note ganism may be isolated from a single ab- of HIV-negative patients, except that there there is no bony disease. scess cavity. A primary source of infection is also a mild lymphocytic CSF pleocyto- Figure 2. A carotid angiogram showing is usually not identified, and the progno- sis. Sural nerve biopsies show inflamma- lion individuals are estimated to be on an aneurysm on the left (white arrow) sis of these patients is uniformly poor. The tory infiltrates and varying degrees of de- antiretroviral drugs – the highest num- and an occlusion (right, black arrow). standard treatment for toxoplasmosis is myelination and axonal degeneration. ber in the world. Although commend- sulfadiazine and pyrimethamine; howev- Patients show a good response to steroids. able, this is only about 40% of the pa- er, sulfadiazine is not available locally. My It could be argued, however, that in some tients who are eligible for therapy. The colleagues and I undertook a prospective cases, HIV status may be incidental given potential pool of patients who require study using a high dose of cotrimoxazole the infection’s high prevalence. ARVs has been further increased by new as sole therapy with excellent results.12 guidelines stipulating that anyone with Miscellaneous Disorders a CD4 count of less than 350 should be Spectrum of Myelopathies Ǡ Immune reconstitution syndrome is offered therapy. The spectrum of myelopathies is wide the exacerbation of the clinical or radio- The ARV roll-out will bring prob- and includes the usual causes, such as tu- logical features of a pathogenic antigen not lems of its own such as side effects and berculosis, syphilis, herpes simplex, her- due to relapse or recurrence. Much is the possible emergence of resistant pes zoster, and unexplained myelitis.10 made of neurological IRIS, but the condi- HIV strains because of poor compli- KwaZulu-Natal, a province in South tion is not common. Furthermore, in the ance. But health care providers hope Africa, is a human T-lymphotropic virus pre-HIV era, one saw similar paradoxical the roll-out will lead to a better quali- Type I (HTLV-I) endemic area. A num- reactions when initiating specific therapy. ty of life for HIV-positive patients and Figure 3. An MR angiogram of the ber of patients therefore present with Ǡ Progressive multifocal leukoen- a decrease in mortality and in oppor- intracranial vessels showing fusiform dual HIV and HTLV-I infections. cephalopathy (PML) has a global preva- tunistic infections. ■ aneurysmal dilatation (arrows). The cause of the myelopathy in the du- lence of 4%-7%, but for reasons that are ally infected patients is thought to be from not clear, it is less prevalent in South Africa. DR. BHIGJEE is in the department of TB. South Africa has the fourth-highest the HTLV-I rather than HIV, because most There are no good population-based data neurology at the Nelson R. Mandela School number of MDR TB cases in the world.3 patients do not have features of sympto- of the frequency of the virus in South of Medicine and Inkosi Albert Luthuli A knock-on effect has been the develop- matic HIV infection, such as weight loss, Africa. Findings in one study14 found that Central Hospital in Mayville, South Africa. ment of MDR and XDR TBM with dev- candidiasis, or multiple organ disease. Du- 60% of HIV-positive individuals without astating results.9 Conventional confirma- ally infected patients present with myelopa- PML have JC virus DNA in the peripher- References tion by culture and sensitivity of MDR or thy at an earlier age compared with those al blood. (The virus causes PML.) My col- 1. AIDS Epidemic Update 2009, facsheet XDR TBM is hopelessly prolonged and pa- infected with HTLV-I alone. There is some leagues and I have not been able to con- for Sub-Saharan Africa (UNAIDS) tients have usually died by the time their evidence that coinfection accelerates the firm this in patients in an ongoing study. 2. J. Neurovirol. 2005;11(Suppl. 1):17-21 drug-resistant disease has been confirmed. progression of each virus to clinical disease. Ǡ Painful distal sensory neuropathy 3. Global Tuberculosis Control 2009, Molecular techniques that include drug re- Patients with syphilitic myelopathy (DSP) was seen intermittently in state WHO Report 2009, http://whqlib- sistance in their assays have been shown have shown an excellent response to in- hospitals before the ARV rollout, but the doc.who.int/publications/ to be useful in sputum samples. A study travenous penicillin. Zoster myelitis may disorder markedly increased after the 2009/9789241563802_eng.pdf. is currently underway in our unit to eval- occur coincident with the cutaneous le- rollout because stavudine was part of the Accessed 08/29/2010 uate the role of these tests in the CSF. sion or several weeks later. When my col- initiating regimen. Patients with drug-in- 4. Neurosurgery 2000;47:644-50 Ǡ Intracranial tuberculomas are com- leagues and I originally did a study of duced DSP are otherwise well, but pre- 5. Int. J. Infect. Dis. 2007;11:348-54 mon in HIV-positive patients and behave myelopathies in HIV-positive patients,10 sent with a disabling neuropathy with 6. Infection 2001;29:213-17 like any other intracranial mass, though we rarely saw vacuolar myelopathy. With dysesthesia and hyperpathia. As of 2010, 7. PLoS ONE 2008;3:e1772 unlike with other masses, they are seen the advent of ARVs, patients are surviv- stavudine, which was also responsible for 8. Am. J. Respir. Crit. Care Med. 2010; in patients with higher CD4 counts. ing longer and cases of vacuolar myelopa- deaths from lactic acidosis, has been re- 182:569-577. Ǡ Myelopathy may occur as spinal tu- thy, which emerges in the late stages of placed with tenofovir. 9. Clin. Infect. Dis. 2004;38:851-6 berculosis – or Pott’s disease – or cran- HIV infection, are seen more frequently. 10. Neurology 2001;57:348-5 iospinal meningitis. Other presentations Conclusion 11. S. Afr. Med. J. 1999;89:1284-8 include multiple intramedullary tuber- Cerebrovascular Disease There has been a renewed initiative by 12. S. Afr. Med. J. 2004;94:51-3 culomata and epidural tuberculous ab- Strokes related to tuberculosis and syphilis the government of South Africa to make 13. S. Afr. Med. J. 1999;89:283-4 scesses (see Figure 1) without bony in- because of endarteritis are easily explained. ARVs widely available. More than 1 mil- 14. Ann. Neurol. 1992;31:454-62 13_16wfn11_4.qxp 4/1/2011 2:39 PM Page 13 Where great minds come together

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BOOK REVIEWS A Comprehensive Work on Focal Neuropathies Focal Peripheral Neuropathies (4th ed.) ropathies was originally that of Thompson and Kopell of the pattern of sensory loss in a patient with mononeu- By John D. Stewart (Peripheral Entrapment Neuropathies [1st ed.]; Walter A. L. ritis multiplex from Churg-Strauss syndrome taken from West Vancouver: JBJ Publishing, 2010, 700 pp. Thompson and Harvey P. Kopell; Baltimore: Williams Richard Rosenbaum and José Ochoa’s book, Carpal Tun- & Wilkins, 1963), but it was long out of date, which was nel Syndrome and Other Disorders of the Median Nerve BY MARK HALLETT, M.D. what motivated Dawson, Millender, and me to write the (Boston: Butterworth-Heinemann, 2002). Editor in Chief, WORLD NEUROLOGY first edition of Entrapment Neuropathies (Boston: Little, Stewart also discusses laboratory evaluation, includ- Brown, 1983). The first edition of Stewart’s Focal Pe- ing electrodiagnosis, but this is not the place for the elec- had to review this book. It has a tribute to Asa Wilbourn, ripheral Neuropathies came out in 1987. The general no- tromyographer to learn the details of technique. Ther- Inow deceased, who was an expert in electromyography tion of focal peripheral neuropathies is broader than en- apy is discussed, again on the background of a and peripheral neuropathies and who reportedly said he trapment neuropathies, but entrapment is likely the comprehensive literature review, but it is also not the preferred an earlier edition of this book to his own book. most frequent etiology. Thus, books formally on either place for learning about the details of surgical proce- By that I presume he meant the third edition of Entrap- topic have largely overlapping material. dures that are undertaken for some entrapments. ment Neuropathies, which he coedited with me and David Focal Peripheral Neuropathies has the obligatory chapters The field is full of controversial topics such as the tho- Dawson after we invited him to fill in for the late Lewis on anatomy and pathology, but the meat is in the chap- racic outlet syndrome, resistant tennis elbow, and the Millender, who had worked with us for the first two edi- ters on the individual nerves, individual roots, and the piriformis syndrome, all of which are approached tions. Never having read any of the earlier editions of Fo- brachial and lumbosacral plexes. (Who doesn’t need a thoughtfully and sensibly and summarized with per- cal Peripheral Neuropathies, I thought it was time. handy reference on the brachial plexus?) Each chapter be- sonal opinions. I agreed with them all. Every neurologist should have a book on focal pe- gins with a description of the anatomy and then discusses There are occasional typographical errors and very rare ripheral neuropathies. Thomas Willis, the 17th century the pathologies. The individual pathologies are discussed factual errors, such as, in different places, ascribing the ori- English doctor who coined the term neurology, meant in detail and accompanied by a comprehensive review of gin of the accessory deep peroneal nerve to the deep and it to be the study of the peripheral nerves, so from a his- the literature on each. There are many illustrations of pa- superficial peroneal nerves; the latter is correct (though torical point of view neurologists should be experts in this tients showing the distribution of sensory loss and mus- the peroneal nerve is now preferentially called the fibular field. But neurology training often emphasizes central cle wasting. Some figures are rather artistic, such as one nerve). This is a particularly good and comprehensive nervous system disorders, and some of the neuropathies of a right-sided suprascapular neuropathy in a patient book. Its emphasis differs somewhat from that of En- are uncommon and forgettable. It is comforting and valu- with a large tattoo on the upper back. Most of the fig- trapment Neuropathies, and it is certainly much more up to able to have a source of this information at hand. ures are original; some are borrowed, including from En- date. And, while I cannot go as far as my coeditor, Asa, I The idea of writing a book on entrapment neu- trapment Neuropathies; and there is a beautiful illustration am happy to have a copy. ■ Case-Based Examples, Expert Treating Mild Stroke Could Reviews Inform and Advise Save Patients, Cut Costs he use of clot-busting drugs in pare clinical outcomes over time. Companion to Peripheral The section on diagnostic case reports in- Tpatients with mild stroke could However, she said, based on two ex- Neuropathy: Illustrated Cases cludes a large series of very different cases. save thousands of them from long- tant studies, about 30% of mild and New Developments In each, the clinical presentation suggests a term disability, and about US$200 stroke patients experience deficits By Peter James Dyck, Kimberly specific diagnosis. Certain particularities, million a year in stroke-related costs. that affect their lives. Amrani, Christopher J. Klein, however, give the clinician cause to consid- In deciding whether to administer She extrapolated her findings to P. James B. Dyck, Phillip A. er other diseases in the differential diagno- tissue plasminogen activator (tPA) to the entire U.S. population in 2010, es- Low, JaNean Engelstad, and sis, leading to relevant changes in the pa- patients with mild stroke, one must timating that mild strokes would have Robert J. Spinner tients’ specific diagnosis and therapy. The balance the possible benefits with the occurred in 27,203 patients without Philadelphia: Saunders Elsevier, 2010, cases chosen by the different authors are in- risk of further bleeding, Dr. Pooja baseline disability. If all had received 432 pp. variably instructive and well documented, Khatri said at a press briefing at the In- an effective treatment, up to 13% and the discussions clearly portray the ternational Stroke Conference in Los (3,761) could be saved from disability. his fine book opens with a fascinating fore- strategies used in each scenario to approach Angeles. But her epidemiologic study The U.S. National Institutes of Tword by Arthur K. Asbury, M.D., emeri- and reach the diagnosis. It is extremely in- of 150 mild strokes – of which 4 were Health sponsored the study. None of tus professor of neurology at the University formative to read these cases carefully and treated with tPA – suggests the drug the reseachers had any disclosures. of Pennsylvania, Philadelphia, USA, in which to understand the thinking behind each could prevent the disability that affects –Michele G. Sullivan he details how Guillain-Barré syndrome came one. This same recommendation applies to up to one-third of these patients. to be associated with the autonomic Of 441 patients treated for is- View a video of Dr. Khatri by using autoimmunity and ex- BY ISABEL ILLA, M.D disorders section, chemic stroke during 2005, 56% the QR code, or go to www. clinical plores the role of the which affords (247) had mild strokes. Of those, neurologynews. GBS animal model, Prof. Illa is chief of the practical, stimu- 62% (150) were considered eligible com, click on experimental allergic neuromuscular diseases lating, and re- for tPA treatment, but only 1% (4) the video icon, neuritis. unit in the department warding reading. received the drug. and search for The book is laid of neurology at Hospital The final sec- Dr. Khatri, of the University of “Treating Mild out in four sections: Santa Creu i Sant Pau, tion on scientific Cincinnati Academic Health Center, Strokes Could MRI-targeted fascicu- Universitat Autònoma reports is a did not follow the patients to com- Yield Benefits.” lar nerve biopsy, di- de Barcelona, Spain. must-read, be- agnostic case reports, cause each of INTRODUCING QR CODES… autonomic disorders, and scientific reports, the invited authors has succeeded in the I QR C … each of which is highly informative and difficult task of summarizing their many n this and upcoming issues of WORLD NEUROLOGY, you will find bar- worthwhile reading. years of knowledge on each of the sub- Icodes at the bottom of some stories that will link you to video inter- In the first section, neurologists and neu- jects chosen. (In addition to Dr. Dyck views with experts in the field. You can link with the videos by: rosurgeons will see what a tremendously and his coauthors, all from the Mayo Ǡ Downloading a mobile barcode reader from your smartphone’s app valuable technique MRI can be for diag- Clinic in Rochester, Minn., USA, there is store, then swiping your phone over the barcode to go directly to the nosing diseases involving the peripheral an impressive list of 146 distinguished videos; or nervous system. The authors provide many contributors.) Ǡ If you do not have a smartphone, you can go to www.clinicalneu- excellent cased-based examples consisting of The book is available online and contains rologynews.com, click on the video icon, and type in the video label pro- illustrated computed tomography images valuable references to current literature in vided at the end of the story. and the corresponding nerve pathology. the field. ■ 13_16wfn11_4.qxp 4/1/2011 10:50 AM Page 15

APRIL 2011 • WWW.WFNEUROLOGY.ORG WORLD NEUROLOGY • 15

BOOK REVIEW Lessons and Reflections on the tPA Debate tPA for Stroke: ure in the development and implemen- of stroke onset time; the other half tributing to its success) and for constant The Story of a Controversial Drug tation of tPA for stroke. Although the within 180 minutes); the dose-finding communication between the investiga- By Justin A. Zivin and drug would eventually have been test- preliminary study; the careful selection tors and their hospital emergency de- John Galbraith Simmons ed and proven effective for stroke with- of investigators; the protocol develop- partment and emergency medical ser- Oxford University Press USA, out him, there is no question that he ment entirely by investigators without vice partners. Any interruption 2010, 208 pp. had the intelligence and combination of influence from marketing and pharma- between part 1 and part 2 would have clinical and scientific knowledge led to the decay of these carefully de- his book presents a review of the to appreciate the potential of BY JAMES C. GROTTA, M.D. veloped networks, and there was no discovery, development, testing, tPA at a time when few knew guarantee that they could be re-estab- Tand implementation of recombi- about it, and those who did, Dr. Grotta is professor and lished. The “seamless” progression nant tissue plasminogen activator for thought it would never be a safe chair of the department of from part 1 to part 2 saved time and re- treating stroke patients. As the subtitle or effective treatment for stroke. neurology and director of sources. implies, it is intended to be a factual He had the perseverance to ob- the vascular neurology pro- Furthermore, contrary to Dr. Zivin’s account of that history and also an tain the drug from its discover- gram at the University of assertion, I think it would have been exposé. ers and Genentech, and to ob- Texas Medical School at highly unlikely that the U.S. Food and The “controversy” is the failure of the tain funding from the NIH and Houston. Drug Administration would have ap- medical community, including stroke NINDS to carry out the initial proved tPA for stroke on the basis of specialists, neurologists, emergency animal studies that demonstrated its ceutical company interests; and the part 1, which was not designed as a piv- physicians, government regulators, and effectiveness and safety; and then he careful statistical and administrative otal efficacy study, had fewer than 300 Genentech (the company that developed had the forcefulness to lobby strongly oversight by Dr. Barbara C. Tilley, Dr. patients, and was not positive for its pri- the drug in the United States) to appro- for its clinical testing and, eventually, its K. Michael Welch, and Dr. John Marler. mary end point. priately accept, promote, and use what use. All of these points are accurately iden- Finally, the oversight of the studies by the authors forcefully and convincingly There are probably only a few other tified and emphasized in the book. the independent data board and NINDS argue was a groundbreaking and effec- individuals who could provide as au- leaders in my opinion was key to the tive new treatment for the most com- thoritative perspective or who played as Releasing vs. Withholding Findings success of the studies by keeping them mon neurological disease and cause of important a role in the development of So it is somewhat surprising that Dr. on track. adult disability. tPA for stroke. Zivin takes strong issue with the con- When the DSMB saw that part 1 was Of particular relevance to the WORLD Unfortunately, some of those other duct of the NINDS studies, in particu- not positive on its prespecified 24-hour NEUROLOGY readership was (and still is) people and their opinions are not ade- lar the failure to release the part 1 re- primary outcome measure, but was pos- the failure of the neurological commu- sults when that portion of the study was itive on most other prespecified sec- nity in this regard, which should be completed. ondary measures, including the most enough to make most conscientious THE BOOK IS A WAKE-UP CALL Dr. Zivin obviously felt and still feels critical for proving efficacy – 3-month neurologists squirm when reading those FOR PEOPLE TO UNDERSTAND very strongly about this point, enough outcome – they encouraged the investi- portions of the book. The authors save to generate a personal postscript ex- gators to immediately begin a pivotal their most pointed criticisms for those THE IMPORTANCE OF BEING plaining his position. This is perhaps the second trial to prove the effect at 3 leaders of the emergency medicine spe- FULLY INFORMED ABOUT most interesting part of the book for months. NINDS leadership facilitated cialty who used misinformation and the stroke specialists who were involved the continuation of funding to enable non–peer-reviewed opinion pieces to at- EFFECTIVE STROKE CARE. in the NINDS studies or for readers this to happen. tempt to discredit studies by researchers who are interested in the details of at the National Institute of Neurologi- their conduct. Importance of Being Educated cal Disorders and Stroke (NINDS), an af- quately represented in the book. In Dr. Zivin argues forcefully that with- Imagine if the same neurologists who filiate of the U.S. National Institutes of particular, there is very little mention of holding the results of part 1 until the inappropriately attacked the results of Health (NIH). others, some of whom Dr. Zivin prob- completion of part 2 was one reason for the NINDS studies after their eventual The book is easy to read, is carefully ably considered competitors, who were the failure of the medical community publication had been on the study sec- referenced and indexed, and was re- pivotal in the early testing of throm- to accept the final results of the trial, tion that would have had to review a searched by conducting personal inter- bolytics for stroke. These would in- and he criticizes NINDS leadership and part 2 protocol after the results of part views (portions of which are reproduced clude Dr. Hermann Zeumer of Ger- the studies’ data and safety monitoring 1 were published! as direct quotations) with most – but not many, who did the first thrombolytic board (DSMB) for providing too much I do agree with Dr. Zivin that instead all – of the key players involved with tPA procedures using an endovascular ap- “top-down” direction, rather than using of combining the results in a single and stroke. Although the book is written proach; Dr. Gregory Del Zoppo of the the traditional investigator-driven ap- brief article in the New England Jour- at a technical level that the lay audience United States, who followed the early proach that would have required inter- nal of Medicine, it would have been bet- can easily understand, it contains suffi- work of Dr. Zeumer and eventually ruption of the study after part 1, pub- ter to release the part 1 data earlier, af- cient detail and facts to be of interest to helped lead studies that paralleled the lication of its results, and reapplication ter part 2 was underway. That would any clinician or scientist interested in NINDS studies; and Dr. Etsuro Mori, and peer review of part 2. have made it more evident that the this topic. who carried out a clinical evaluation of NINDS studies were in fact two tPA in Japan essentially at the same A Different View separate studies and perhaps made the Patient Stories Convey the Message time the NINDS studies were starting. My own view is the opposite, and Dr. final results appear more convincingly There are actual patient stories that There is also insufficient recognition Zivin does not consider any alternate confirmatory. bring home the human message of why that the first European study of intra- view in his postscript. In fact, the in- In summary, despite the quibbles I the appropriate use (and unfortunately, venously administered tPA (ECASS-1) vestigators did not want their research have just listed, tPA for Stroke serves as frequent nonuse) of tPA is so critically began at the same time as the NINDS interrupted between the two parts if it a loud and effective wake-up call to the important; and the facts contained in studies and in fact was completed first; appeared that they were headed in the public to understand why they are still the book, with a few relatively minor and although the findings were not pos- right direction, which the DSMB rec- not likely to get effective stroke care un- exceptions, are accurate. Specifically, I itive, they certainly trended in the ognized was the case after its review of less they are fully informed. If they found the chapter on how the drug direction of success and imbued the en- the part 1 data. read this book, they will be informed was discovered and initially developed, tire stroke research community with It was labor intensive to develop and consumers and will know the impor- and another on the economic issues optimism. maintain the clinical infrastructure at tance of recognizing stroke symptoms, that affect its use, particularly well What set the NINDS studies apart, each site to allow recruitment of pa- acting immediately, and getting the done. and what led to their success, was how tients within 90 minutes of symptom stroke patient to an appropriate stroke My main criticism of the book is also they differed from these other studies in onset, and required funding both for ex- center. in some respects one of its strengths, certain important aspects, including tra nursing personnel (another unique It is indeed a sad commentary on that is, the review is very “Zivin-cen- their short time window (half of the pa- aspect of the NINDS study which is not our health care system that such a tric.” Dr. Zivin was and still is a key fig- tients were enrolled within 90 minutes widely enough recognized as con- book is needed. ■ 13_16wfn11_4.qxp 4/1/2011 2:39 PM Page 16