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									               Volume 91   No. 7   July 2008

Lyme Disease
                                                           Medicine                                    Health
UNDER THE JOINT                                                                                                                                            VOLUME 91 NO. 7 July 2008
The Warren Alpert Medical School of
  Brown University
  Edward J. Wing, MD, Dean of Medicine
  & Biological Science
                                         RHODE ISLAND                                             PUBLICATION OF THE RHODE ISLAND MEDICAL SOCIETY
Rhode Island Department of Health
  David R. Gifford, MD, MPH, Director
Quality Partners of Rhode Island
  Richard W. Besdine, MD, Chief
  Medical Officer
Rhode Island Medical Society
  Nick Tsiongas, MD, MPH, President      206          When Is a Somatic Disorder Psychiatric?
                                                          Joseph H. Friedman, MD
Joseph H. Friedman, MD
                                         207          The Awkward Birth Pangs of Bolero
   Editor-in-Chief                                        Stanley M. Aronson, MD
Joan M. Retsinas, PhD
   Managing Editor                       CONTRIBUTIONS
Stanley M. Aronson, MD, MPH              SPECIAL ISSUE: Lyme Disease
   Editor Emeritus                       Guest Editors: Jerome Larkin, MD, and Jennifer Mitty, MD, MPH
EDITORIAL BOARD                          208          Introduction: Lyme Disease
Stanley M. Aronson, MD, MPH                                Jerome Larkin, MD, and Jennifer Mitty, MD, MPH
Jay S. Buechner, PhD
John J. Cronan, MD                       209          Ticks and Tick-Related Illness
James P. Crowley, MD                                       Jerome M. Larkin, MD
Edward R. Feller, MD
                                         212          Lyme Disease In Children and Pregnant Women
John P. Fulton, PhD
Peter A. Hollmann, MD                                      Jerome M. Larkin, MD
Sharon L. Marable, MD, MPH               213          Musculoskeletal Manifestations of Lyme Disease
Anthony E. Mega, MD                                        Imad Bitar, MD, and Edward V. Lally, MD
Marguerite A. Neill, MD
Frank J. Schaberg, Jr., MD               216          Neurological Complications of Lyme Disease
Lawrence W. Vernaglia, JD, MPH                             Syed Rizvi, MD, and Amanda Diamond, MD
Newell E. Warde, PhD                     219          Updates and Controversy In the Treatment of Lyme Disease
OFFICERS                                                   Jennifer Mitty, MD, MPH, and David Margolius
Nick Tsiongas, MD, MPH
  President                              COLUMNS
Diane R. Siedlecki, MD                   224          GERIATRICS FOR THE PRACTICING P HYSICIAN – Dementia Screening: Should
  President-Elect                                          We Screen Asymptomatic Older Adults?
Vera A. DePalo, MD                                         Ana Tuya Fulton, MD
  Vice President
Margaret A. Sun, MD                      226          THE CREATIVE CLINICIAN – Rituximab In Treating Refractory Thrombotic
  Secretary                                                Thrombocytopenic Purpura: Three Case Reports
Mark S. Ridlen, MD                                         Samir Dalia, MD, Brendan McNulty, MD, and Gerald A. Colvin, DO
  Treasurer                              229          HEALTH BY NUMBERS – Estimating the Incidence of New Onset Lyme
Barry Wall, MD                                             Disease in Rhode Island
  Immediate Past President
                                                           John P. Fulton, PhD
DISTRICT & COUNTY PRESIDENTS             232          PUBLIC HEALTH BRIEFING – The RI Board of Medical Licensure and
Geoffrey R. Hamilton, MD                                   Discipline, 2007 Year Summary
  Bristol County Medical Society                           Robert Crausman, MD, Mary E. Salerno, MA, Linda Julian, Lauren Dixon,
Herbert J. Brennan, DO
                                                           and Bruce McIntyre, JD
  Kent County Medical Society
Rafael E. Padilla, MD                    235          PHYSICIAN ’S LEXICON – The Eight Little Wrist Bones
  Pawtucket Medical Association                            Stanley M. Aronson, MD
Patrick J. Sweeney, MD, MPH, PhD
  Providence Medical Association         235          Vital Statistics
Nitin S. Damle, MD                       236          July Heritage
  Washington County Medical Society
Jacques L. Bonnet-Eymard, MD
  Woonsocket District Medical Society

Cover: “What Makes Lyme Disease
Tick?” oil. The artist is an itinerant
New England physician.
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                                                                                                                                              VOLUME 91                   NO. 7           JULY 2008

      When Is a Somatic Disorder Psychiatric?

      This issue is devoted to Lyme disease,         column in the last few decades. Undoubt-      confront him, the father then falling
      an important illness in our state, which       edly many more will. Restless legs syn-       helplessly to the ground because of cata-
      boasts, on Prudence Island, the highest        drome was described about 30 years ago        plexy.
      seropositive region in the world. It is a      but didn’t “catch on” until recently, get-         In the 1800s the term “neurosis”
      disease with interesting clinical phenom-      ting a big boost from drug companies          described neurological syndromes that
      ena, similar to, but less devastating than     that market drugs that treat the disorder.    had no known pathological basis. Char-
      its spirochete cousin, syphilis. Like syphi-   Most doctors, who didn’t suffer from          cot, the great French neurologist, who
      lis, it may cause a chronic illness, quite     RLS, considered it a non-entity. After all,   renamed “Paralysis agitans” Parkinson’s
      different than the acute illness. Unlike       everyone gets restless sometime. But then     disease (PD), classified that disease as a
      syphilis, which may have been the final        as polysomnography became popular, it         neurosis. The term was then hijacked by
      common answer for sporadic dementias           turned out that 60% of people who re-         Freud and colleagues, although it should
      and behavioral disorders 100 years ago,        ported RLS had a peculiar kicking move-       be pointed out that Freud studied with
      Lyme is being used to explain a large num-     ment during sleep, obviously something        Charcot. Affixing the term neurosis did
      ber of fairly nebulous symptoms that oc-       that was organic and not emotionally          not imply that a pathology wouldn’t be
      cur in the general American population.        based. This year two genes have been          found, just that it wasn’t known. Inter-
      It may be the only illness in which an of-     found to explain RLS, and more are likely     estingly however, some psychoanalysts in
      ficial medical group has been sued by a        to be found.                                  the mid-20th century published papers
      state government (Connecticut) for issu-            Writer’s cramp had been considered       blaming childhood conflicts for the
      ing evidenced-based guidelines that con-       a psychiatric syndrome until recently. It     tremors, and rigid personalities for
      tradict non-scientific beliefs embraced by     is very clear how one might divine an         muscle rigidity, in PD, misunderstand-
      a politically influential voting block.        unconscious urge to twist one’s hand,         ing, perhaps, the difference between
      Medicine by democracy, as it were.             when it occurred only when writing, but       Charcot’s neurosis and Freud’s.
            There are two fascinating aspects to     not doing anything else, an explanation            In this issue the authors grapple with
      this issue. One is the problem that clini-     that makes a lot more intuitive sense than    the battle between the infectious disease
      cal physicians (in contrast to test-based      an organic physiological one. There is no     experts who base recommendations on
      physicians         like      radiologists,     more evidence today that these are or-        evidence-based medicine, and self pro-
      interventionalists and pathologists) face      ganic than there was before, but we’ve        claimed Lyme experts who base opinions
      ever yday, of discriminating the “psy-         developed a greater reliance on psychi-       on their common experience, without
      chogenic” from the organic, a topic I          atric experience to exclude a psychody-       addressing the pathophysiology of “post
      never tire of. The other is political.         namic formulation rather than found an        treatment Lyme disease”. Post treatment
            There is no doubt that political be-     objective measure of organicity. This is an   Lyme disease is an entity, perhaps based
      liefs influence medicine. It is hard to        unusual form of nosology. We often do         on an organic etiology, probably, like
      imagine that cultural change rather than       tests to exclude certain diagnoses, and,      neurasthenia, a disorder that is so diffuse
      scientific evidence alone altered the psy-     like Sherlock Holmes, conclude that           that it includes a large overlap between
      chiatric classification of homosexuality.      when all the various possibilities one can    the organic and the psychological, mak-
      How did “neurasthenia” develop into            think of have been eliminated, what is left   ing it a daunting challenge to figure out.
      chronic fatigue syndrome? Why is               must be the truth. Yet one can never be       The fact is that long term antibiotic treat-
      Chronic Fatigue Syndrome not in DSM            “sure” in excluding psychiatric etiologies.   ment hasn’t worked and causes compli-
      IV, but classified by the Centers for Dis-          Another organic disorder that pro-       cations. Yet a lay organization has sued
      ease Control and Prevention? Why is            vided fuel for psychoanalysis is cataplexy,   an organization of bone fida experts to
      fibromyalgia or Irritable Bowel Syn-           the sudden loss of body tone, causing         claim that double blind placebo con-
      drome not in DSM? Where does mul-              people with narcolepsy to fall to the         trolled trials have been inadequate, not
      tiple chemical sensitivity syndrome be-        ground when experiencing a sudden             because of study design but because their
      long? When is a physiologically inexpli-       emotion. I will never forget, in the early    results fly in the face of the organization’s
      cable syndrome a somatoform disorder,          days of sleep medicine, hearing a lecture     common experience.
      or a conversion disorder rather than a         from a sleep doctor pioneer, who de-               If blood letting didn’t work, why
      specific organ system disorder?                scribed a teenage boy who would delib-        would we use it, asked our predecessors
            Many disorders have moved from           erately provoke his father to the point of    two hundred years ago, or steroids a mere
      the psychological column to the organic        getting him to jump out of his chair to       20 years ago? I think there is a rationale
for a democratic process for disease clas-      Disclosure of Financial Interests                 Ingelheim, Sepracor, Glaxo; Speakers’ Bureau:
sification, limiting voting to experts, but         Joseph Friedman, MD, Consultant: Acarta       AstraZeneca,Teva,Novartis,Boehringer-Ingelheim,
surely not for disease treatment.               Pharmacy, Ovation, Transoral; Grant Research      GlaxoAcadia, Sepracor, Glaxo Smith Kline
                                                Support: Cephalon, T Novartis, Boehringer-
              – JOSEPH H. FRIEDMAN, MD

                              The Awkward Birth Pangs of Bolero

Creative genius in the arts, as portrayed in our current mythology,      leagues noted then subtle changes in Ravel’s behavior and personal-
is allegedly born in travail, matures in unyielding poverty and ulti-    ity. He exhibited a gradual loss of empathy, showing an increasing
mately enriches the world despite rampant tuberculosis. Survival         indifference to the illnesses and travails of others. His remarks be-
is typically brief – Keats is given only 26 years, Mozart 35 years       come increasingly inappropriate, tactless, annoyingly repetitive, even
and Schubert a mere 31 years. And disease is always there, an            embarrassing, with evidence of a loss of inhibitions. Even his eating
insistent impediment to be overcome in some unheated attic.              became both repetitive and indiscriminately excessive.
       When assembling the biography of many an artist, the word,              In the next year Ravel withdrew from the public eye, be-
despite, seems to be an essential element of this bohemian scenario.     came apathetic, increasingly incommunicative and only belat-
[For example, we read: “The artist managed to write three slim           edly, losing his sense of memory, orientation and capacity to
books of immortal poetry despite his lung disease.”] It therefore        compose – or even understand - music. A diagnosis of fronto-
becomes an act of shear perversity, outright blasphemy, to suggest       temporal dementia [Pick’s disease] was offered. In 1937 an ill-
that some great work of art might never have been created were it        considered neurosurgical intervention was attempted, but
not for the accompanying burden of some disease. Yet, as the cre-        Ravel died without regaining consciousness.
ative forces underlying art are evaluated, three possibilities emerge.         Frontotemporal dementia is not as common as Alzheimer’s
The disease and the concerto are causally unrelated; or the vir-         disease. It differs not only in frequency but in its manifestations of
tuoso writes an immortal concerto despite the weight of his illness;     behavioral and judgmental deterioration long before there is loss
or this same virtuoso writes an immortal concerto because of the         of orientation or memory. The mean duration of frontotemporal
weight of his illness, with the inescapable implication that this con-   dementia tends to be somewhat longer and the disease tends to be
certo might never have been born were it not for the malign ill-         hereditary in about 40% of cases. Patients frequently exhibit re-
ness. The third possibility, however, seems implausible. Yet the life    petitive, compulsive behavior associated with outbursts of chagrin
of Joseph-Maurice Ravel, one of France’s greatest musical geniuses,      and decay of social graces, a loss of cognitive skills in planning and
might say otherwise.                                                     organizing - yet with relative preservation of memory.
       Ravel, of Swiss-Basque heritage, was born in the French vil-            Ravel’s works have been characterized by musicologists as
lage of Ciboure near Biarritz, on March 7, 1875. The family moved        graceful, intricately nuanced, impressionistic, subtle, highly inven-
to Paris when Ravel was seven. He began piano lessons then and           tive, discriminating, ingeniously contrived and delicate. But then
within a few years was enrolled in Conservatoire de Paris. His co-       there is Bolero, admittedly Ravel’s most famous, most financially
hort of students described him as slight and delicate of build, re-      successful venture [and the title for at least two motion pictures,
mote in behavior, a perfectionist in his musical efforts, suspicious     the first, starring George Raft and Carole Lombard in 1934, and
of others, a fractious personality easily given to argument and per-     the second, starring Bo Derek in 1984.]
haps slightly paranoid toward his colleagues and teachers. He was              Bolero, one of Ravel’s last compositions, differs appreciably from
not known to enter into any intimate relationships with either men       his other works and does not seem to be the culmination of his
or women; and rumors of a labile sexuality followed him through-         genius. Instead of intricate orchestration, it is a somewhat primitive,
out his life.                                                            iterative and erotic enterprise that emphasizes insistence and crude
       The legendary impresario, Sergei Diaghilev, was impressed with    rhythmicity rather than subtle tonalities or musical development.
Ravel’s musical genius; and in 1920 the two collaborated in staging      And so, some neurologists have quietly speculated that this late or-
Ravel’s “Daphnis et Chloe,” danced by the immortal Valsav Nijinsky.      chestral effort, thought banal by many, is more a consequence of
By 1925 Ravel and Diaghilev were no longer on speaking terms;            Ravel’s organic dementia than his innate musical genius. They ex-
only the intervention of mutual friends prevented a mortal duel.         press these tentative speculations in whispers, knowing that Bolero is
       Ravel was invited to the United States in 1928 where his con-     one of the world’s most played, most popular pieces of music.
certs were uniformly successful. He met George Gershwin in one
of his California performances and the two shared their musical                                              – STANLEY M. ARONSON, MD
thoughts on jazz, altered tonality and Afro-Caribbean folk music.
For the remainder of Ravel’s life, less than a decade, he felt that      Disclosure of Financial Interests
only America understood and appreciated his music.                            Stanley M. Aronson, MD, has no financial interests to disclose.
       In a motor accident in 1932, Ravel sustained a mild head in-
jury. His behavior from this point on visibly deteriorated although      CORRESPONDENCE
many colleagues dated his neurological deficits back to 1928. Col-       e-mail:

                                                                                                           VOLUME 91       NO. 7     JULY 2008
                                             Introduction: Lyme Disease
                                               Jerome Larkin, MD, and Jennifer Mitty, MD, MPH

      Lyme disease is named for a small town on the southeast                   and should not be used to rule out acute infection but may be help-
      coast of Connecticut. In 1977, Steere et al described a cluster-          ful if positive or if seroconversion can be demonstrated with later
      ing of 51 patients (39 children and 12 adults) in three contigu-          testing. Most if not all illness, when diagnosed acutely and even for
      ous towns with recurrent attacks of arthritis of the large joints.        weeks to months after the initial manifestations, responds promptly
      Approximately 25% of patients had developed a preceding                   to oral antibiotics. Central nervous system involvement, however,
      erythemetous annular rash. Arthritic attacks typically lasted one         should be treated parenterally. Later manifestations of illness, in
      week. Although originally thought to be juvenile rheumatoid               particular heart block, arthritis and neurologic symptoms may war-
      arthritis, diagnostic testing did not support this hypothesis; and        rant judicious use of antibiotics but should be limited to patients
      seasonal and geographic clustering suggested transmission by an           with serologic evidence of infection and rarely if ever should be ex-
      arthropod vector.1 Over the next few years effective antibiotic           tended beyond a month of treatment. There is no scientific evi-
      regimens were developed, and in 1982 Willy Burgdorfer cul-                dence that long term (months to years) of antimicrobial therapy is
      tured a spirochete (subsequently named Borrelia burgdorferi and           ever indicated.6
      demonstrated to be the cause of Lyme disease) from the mid-gut                  In October, 2006 the Infectious Diseases Society of
      of ixodes (hard-bodied) ticks.2 Ixodes damini (formerly scapularis)       America published guidelines for the assessment, treatment and
      was eventually shown to be the vector for Lyme disease (borreliosis)      prevention of Lyme disease. The Centers for Disease Control
      as well as for babesiosis and erhlichiosis (anaplasmosis). It is also     and Prevention (CDC) have endorsed those guidelines. Like
      now apparent that human disease attributable to B. burgdorferi            other such tools, it is a concensus document based on the best
      has been described in the medical literature, particularly in Eu-         available scientific evidence and meant to assist physicians in in-
      rope, since at least 1909 and likely as early as 1883.3 Since 1977,       dividualizing patient care in a scientifically and medically appro-
      other aspects of the disease have also been described, in particu-        priate manner. In November, 2006, Connecticut Attorney
      lar the involvement of the central nervous and cardiovascular             General Richard Blumenthal launched an investigation into
      systems in addition to the more typical skin and musculoskeletal          possible violation of antitrust laws on the part of the IDSA in
      manifestations of illness.                                                formulating the guidelines, stating they “may severely constrict
            A unique aspect of Lyme disease and its history since 1977 is       choices and legitimate diagnosis and treatment options for pa-
      advocacy. The original investigation of the outbreak was in part          tients.”7 The absurdity of his proposition almost does not war-
      spurred by two parents who contacted the Connecticut State Health         rant comment. How will the story end? It certainly will not be
      Department and physicians at Yale University School of Medicine,          with Mr. Blumenthal’s investigation and perhaps not with the
      questioning the seemingly too frequent incidence of JRA in their          latest iteration of the IDSA guidelines. In an agreement an-
      community. This has, in a sense, set the tone for the public medical      nounced in April 2008, Mr. Blumenthal agreed to end the in-
      and political debate over Lyme disease. As with many previously           vestigation. In exchange, the IDSA will convene a special review
      unrecognized illnesses, the period following its original description     panel to “conduct a comprehensive and up-to-date evaluation
      was characterized by an expanding body of knowledge regarding             of the scientific literature, in order to determine whether the
      pathophysiology, diagnosis and treatment. However, concurrent             2006 guidelines should be revised or updated. As part of the
      with this progress came a growing tendency on the part of some            review process, interested individuals will be invited to submit
      clinicians and patients to attribute a wide variety of often subjective   relevant information, and a public hearing will be held. The
      and nonspecific symptoms, persisting at times for decades, to Lyme        review panel will consider all the evidence and make recommen-
      disease. Unfortunately, the debate has reached a level such that          dations regarding whether the Lyme disease guidelines should
      clinicians are intimidated and threatened for withholding antibiot-       be revised. If the panel recommends revisions, they will be car-
      ics despite the scientific validity of this position, and patients are    ried out in accordance with our normal procedures overseen by
      therefore exposed to the toxicity of long courses of antimicrobial        the IDSA Standards and Practice Guidelines Committee.”8 The
      agents of no proven benefit.4 Misinformation abounds on the               agreement by the IDSA was explicitly to avoid the considerable
      internet and even such lay publications as Yankee Magazine, usually       costs of litigation, and to protect the volunteer authors of the
      confining itself to serious topics such as country inns and flower        guidelines, with every expectation that the guidelines will stand
      arrangements, have joined in the fray.5 It is a free for all.             as written after the review. That the Society would have been
            The diagnosis of Lyme disease relies on three principal find-       vindicated if the matter had gone to court was never in question.
      ings: epidemiologic exposure, appropriate clinical manifestations and           Research continues and our knowledge and experience
      serology. All residents of the mid-Atlantic states and coastal New        increase. Ultimately these are matters of biology and medicine
      England are at risk of infections regardless of occupation or habits.     and we have every confidence that science will prevail. To-
      Typical symptoms include headache, myalgias, arthralgias and fa-          ward that end, this edition of Medicine & Health/ Rhode Island
      tigue. Frank meningitis may be present as part of the acute illness.      is intended to provide insight into the diagnosis and treatment
      Physical findings include erythema migrans, arthritis and Bell’s Palsy.   of Lyme disease and other tick-related illnesses and assist the
      Other cranial nerves may be involved and transverse myelitis is a         clinician in negotiating the thicket of controversy and misin-
      rare but reported manifestation. Serology may be negative initially       formation while attempting to help afflicted patients.
 REFERENCES                                                                         Disclosure of Financial Interests
1. Steere AC, et al. Lyme arthritis. Arthritis Rheum 1977; 20:7                         The authors have no financial interests to disclose.
2. Burgdorfer W, et al. Lyme Disease. Science 1982; 216:1317.
3. Sternbach G, Dibble CL. Willy Burgdorfer. J Emerg Med 1996; 14:631.
4. Grann D. Stalking Dr. Steer over Lyme disease. NYTimes Magazine June 17, 2001.   CORRESPONDENCE:
5. Clark E. Lyme Disease. Yankee Magazine July/August 2007.                         Jerome M. Larkin, MD
6. Wormser GP, Dattwyler RJ, Shapiro ED. The clinical assessment, treatment         Rhode Island Hospital
   and prevention of lyme disease, human granulocytic anaplasmosis, and babe-
                                                                                    593 Eddy St.
   siosis. Clin Infect Dis 2006; 43: 1089.
7. Hamilton E. Lyme Disease Guidelines Focus of Antitrust Probe. Hartford           Providence, RI 02903
   Courant, November 17, 2006.                                                      Phone: (401 444-8130
8. Electronic communication to the membership of The Infectious Diseases So-        e-mail:
   ciety of America, May 1, 2008.

                                                                                    Jennifer A. Mitty, MD, MPH
     Jerome M. Larkin, MD, is Assistant Professor of Medicine,
                                                                                    The Miriam Hospital
Division of Infectious Diseases, The Warren Alpert Medical School
                                                                                    164 Summit Avenue
of Brown University.
                                                                                    Providence, RI 02906
     Jennifer Mitty, MD, MPH, is Assisstant Professor of Medi-
                                                                                    phone: (401) 793-4851
cine, The Warren Alpert Medical School of Brown University and
the Director of the Lyme Clinic at Rhode Island Hospital.

                                         Ticks and Tick-Related Illness
                                                                   Jerome M. Larkin, MD

There are over 800 described species of                 a febrile illness in the spring, summer or       throughout most of the rest of the year.
ticks all of which share the characteristic of          fall months, and physicians in endemic           Disease activity drops off after the first hard
requiring blood meals during their life cycle.          areas should be familiar with their presen-      frost in the fall or early winter. However
They are often adapted to specific seasons              tation, diagnosis and treatment. 2               ticks may still be active in areas which expe-
and environments and feed on a specific                                                                  rience less severe cold weather, such as
animal or group of animals. Their bites tend            ERHLICHIOSIS                                     coastal areas, or in years of relatively little
to be painless and feeding lasts for hours to                 Ehrlichiosis is caused by three distinct   freezing weather. 2963 cases of HGA have
days. Affinity for humans is variable. Ix-              species: Ehrlichia chaffeensis, Ehrlichia        been reported since 1994 with over 700
odes damini, the vector of Lyme disease,                ewingii and Anaplasma phagocytophilum.           in 2005 alone. Although a reportable dis-
belongs to the group of hard-bodied or                  The three species have the capacity to in-       ease, most surveillance is passive and so the
damini ticks. I. damini has three distinct              fect a number of mammals other than              true incidence of infection and or disease is
life cycles, larva, nymph and adult, and                humans including deer, dogs, coyotes,            likely underreported. The highest preva-
must take a blood meal once during each                 mice and other rodents.                     A.   lence is reported in Minnesota, Connecti-
cycle. A single nest may harbor as many as              phagocytophilum can also infect I.               cut and Rhode Island, the last with 36.5
10,000 insects. The tick must itself be in-             damini. Accordingly it is typically the          cases/million. Infection and disease are
fected with the bacterial pathogen in or-               pathogen of ehrlichiosis in the northeast-       more likely to occur in males and in those
der to transmit infection to humans. In-                ern United States while E. chaffeensis is        over the age of 50. As with infection with
fection in the tick persists across the stages          more common in the southern United               Borrelia burgdorferi, the majority of pa-
of its life cycle and can be transmitted to             States. Human granulocytic anaplasmo-            tients do not recall a tick bite. A lack of
offspring.                                              sis and human granulocytic erhlichiosis are      outdoor exposure does not reliably exclude
      Two infections other than Lyme dis-               synonymous terms. All three pathogens            the diagnosis. In one study approximately
ease, ehrlichiosis and babesiosis, are of con-          are small, gram negative intracellular bac-      1% of Connecticut residents were serop-
cern in Lyme-endemic areas. The patho-                  teria. They exhibit a trophism for white         ositive with no current or past history of
gens of both diseases can be transmitted                blood cells; A. phagocytophilum for the          disease. Other studies have reported
by the tick Ixodes scapularis and ticks and             granulocyte. As a result, infection may be       seroprevalence rates as high as 36%.
people can be dually or triply infected.1               evident by the observation of clusters of              Incubation is two to three weeks al-
Infection can be asymptomatic for both                  bacteria in cytoplasmic vacuoles known as        though shorter periods have been de-
microorganisms. Presentation, as with                   a morula. This is, however, a relatively rare    scribed. The typical patient with
Lyme disease, can be non-specific with fe-              finding.3                                        ehrlichiosis caused by any of the three
ver, malaise and an otherwise flu-like syn-                   Human granulocytic anaplasmosis            pathogens is likely to present with fever
drome. Similarly, patients often do not                 (HGA) follows a seasonal pattern reflect-        and malaise. The fever is often persistent
recall a tick bite at presentation. Accord-             ing the activity of the I. damini tick. Peaks    and out of proportion to the typical viral
ingly, ehrlichiosis and babesiosis are in the           of clinical illness occur in July and Novem-     illness and usually striking for its presenta-
differential for any patient presenting with            ber with a low level of endemic activity         tion during the summer months. Head-
                                                                                                                   VOLUME 91      NO. 7     JULY 2008
      ache is very common, myalgias and gas-             patients intolerant of or allergic to doxy-         Babesia microti is the more typical
      trointestinal symptoms frequent. Other             cycline. Children should be treated with      pathogen in the United States and many
      reported symptoms include rash, cough              doxycycline at 3-4 mg/kg/day divided bid.     infections are clinically silent. An epide-
      and confusion. No single symptom is spe-           Successful treatment of children with         miologic study in blood donors in Con-
      cific for ehrlichiosis. Physical exam is simi-     rifampin has been reported but should be      necticut found a seroprevalence rate of
      larly nonfocal. The classic laboratory find-       reserved for those under the age of eight     1.4%.8 Fifty-three percent of seroposi-
      ing is leukopenia with thrombocytopenia.           years and who are judged to be only mildly    tive patients were parasitemic. Other
      Transaminitis is relatively common. Mild           ill. Beta-lactams, cephalosporins,            studies in highly endemic areas indicate
      anemia may also be present.                        macrolides, quinolones and chloram-           a relatively high incidence of asymptom-
            More fulminant disease is possible           phenicol are all ineffective therapy.         atic infection. The parasite can also in-
      and appears to be relatively more common                                                          fect white-footed mice and white-tailed
      from infections with E. chaffeensis and in                                                        deer which serve as a reservoir of infec-
      the immunosuppressed, the latter includ-                The majority of                           tion in the environment. Infection of
      ing those with HIV infection and solid                  patients do not                           ticks is endemic in southern New En-
      organ transplant recipients . Manifesta-                                                          gland and its coastal islands and New
      tions of more severe disease include men-              recall a tick bite.                        York. Cases have also been described in
      ingoencephalitis, adult respiratory distress                                                      the mid-Atlantic states, the midwest and
      syndrome, acute renal insufficiency and                 A recent report describes treatment      on the west coast. Several transfusion re-
      sepsis. Opportunistic infections with fun-         of nine woman diagnosed with HGA dur-         lated cases have been reported in Rhode
      gal and viral pathogens are possible. Pe-          ing pregnancy from 1997 to 2006. Ges-         Island. Distinct species, designated MO-
      ripheral neuropathies including an isolated        tational age at time of diagnosis ranged      1 and WA-1 have been described as caus-
      facial palsy are also possible.                    from 10 to 39 weeks. Four women re-           ing disease in Missouri and Washington
            Diagnosis relies on clinical suspicion in    ceived therapy with doxycycline and five      respiectively. Asymptomatic parasitemia
      an appropriate epidemiologic setting be-           received therapy with rifampin. One           can persist for months. Treatment of as-
      cause no single symptom, physical finding          woman was not treated. None of the            ymptomatic but parasitemic patients re-
      or laboratory value is specific. The spec-         woman presented with fulminant disease        sults in more rapid clearance and is indi-
      trum of fever, a nonfocal exam and find-           and all those treated responded promptly      cated if the patient remains parasitemic
      ings of leukpenia and thrombocytopenia             to antimicrobial therapy. One perinatal       for more than three months. Treatment
      during the summer in an endemic area               infection occurred. All pregnancies went      of a seropositive but not parasitemic, as-
      warrant therapy. More difficult is the pa-         to term and no adverse outcomes were          ymptomatic patient is not indicated.
      tient with fever alone. Cautious observa-          observed in the children at 21 months of            Babesia species infect the red blood
      tion for 48 to 72 hours is reasonable. Treat-      follow-up. 4                                  cell of humans and other species where
      ment should be initiated in the face of any             Overall prognosis is generally good      they undergo asexual reproduction. This
      worsening or if the fever persists and no          with the exceptions described above.          results in the classic tetramer or “maltese
      other diagnosis, such as enterovirus, is ap-       There is no known chronic syndrome as-        cross” inclusion seen on examination of the
      parent. Approximately 25% of patients              sociated with ehrlichiosis. Reinfections      peripheral blood smear. The diagnosis of
      have positive serologic evidence of infection      have been reported.5,6,7                      malaria should be considered in a patient
      at the time of presentation; 95-100% of                                                          with anemia, red blood cell inclusions and
      patients are positive within two weeks of the      BABESIOSIS                                    an appropriate epidemiologic risk profile.
      onset of symptoms. Polymerase chain reac-                Babesiosis is a parasitic infection     Eventually hemolysis occurs with subse-
      tion is highly specific but has a sensitivity of   caused by one of many different species       quent infection of uninfected cells. Pa-
      only 60 to 85%. The presence of morula             of Babesia. The genus is names for            tients typically present with non-specific,
      on peripheral smear is variable, reported as       Viktor Babes who first described disease      “flu-like” symptoms: fever, headache, mal-
      approximately 7% in infections with E.             in cattle in 1888. The first case of hu-      aise, anorexia. Rash is distinctly unusual.
      chaffeensis and 20-80% in infections with          man disease was described in an asplenic      The typical finding on laboratory testing
      A. phagocytophylum. Culture is difficult and       farmer from Yugoslavia in 1957 and the        is anemia and thrombocytopenia. It is not
      currently used only in research.                   first case in the United States in a resi-    unusual for the diagnosis to be made when
            All forms of ehrlichiosis respond to         dent of Nantucket in 1969. There are          and automated blood counter mandates
      treatment with tetracycline. Doxycycline           more than 100 known species of Babe-          review of a smear as a result of thromb-
      at a dose of 100 mg twice daily for seven          sia infecting many different vertebrates.     ocytopenia. Red blood cell inclusions are
      to ten days is the therapeutic regimen of          The two most common species to infect         then noted by the laboratory technician
      choice. The use of doxycycline has the             humans are Babesia microti and Babe-          as consistent with either babesiosis or ma-
      advantage of potent activity against B.            sia divergens. Babesia divergens is pri-      laria. In suspected cases in which initial
      burgdorferi and so is effective treatment          marily seen in Europe, usually results in     smears are negative repeating the smear
      for dually infected patients. Treatment,           symptomatic disease, often in asplenic        several times over the course of days or
      however, should be extended to 21 days             individuals, and typically presents as a      PCR testing may be helpful.5, 9
      in this instance. Rifampin is an alterna-          more fulminant disease with a high                  Patients       with       significant
      tive agent at 300 mg bid for 7-10 days for         mortality.                                    immunocompromise such as HIV infec-
tion, asplenia, chronic steroid dependence         CONCLUSION                                       REFERENCES
and solid organ transplantation are at risk              Ticks are ubiquitous arthropods            1. Nadelman RB, Horowitz HW, et al. Simulta-
                                                                                                        neous human granulocytic ehrlichiosis and Lyme
for more fulminant disease. This can present       which are highly adapted to specific envi-
                                                                                                        borreliosis. NEJM 1997; 337:27.
as rapidly progressive sepsis with multisys-       ronments and seasons. They are the vec-          2. Parola P, Raoult D. Ticks and tickborne bacterial
tem organ failure, particularly acute renal        tors of a multitude of human diseases. Ix-           disease in humans. Clin Infect Dis 2201; 32:897.
failure and pulmonary edema with respi-            odes damini is endemic to the coastal north-     3. Bakken JS, Krueth J, et al. Clinical and laboratory
                                                                                                        characteristics of human granulocytic ehrlichiosis.
ratory failure. Review of the peripheral           eastern United States, including Rhode Is-           JAMA 1996; 275:199.
smear is critical to diagnosis in this instance.   land. It requires a single blood meal dur-       4. Dhand A, Nadelman R, et al. Human granulo-
Increased age also appears to be a risk fac-       ing each of its three life stages. During            cytic anaplasmosis during pregnancy. Clin Infect
tor for more fulminant disease. 9,10               feeding it can transmit infection with Bor-          Dis 2007 45:589.
                                                                                                    5. Gakken JS, Dumler JS. Human granulocytic
      Treatment is with one of two differ-         relia        burgdorferi,       Anaplasma            ehrlichiosis. Clin Infect Dis 2000; 31:554.
ent antibiotic combinations. Effective             phagocytophilum and Babesia microti. Pa-                          ,
                                                                                                    6. Wormser GP Dattwyler RJ, Shapiro ED, The clini-
therapy was first achieved with                    tients with dual and even triple infection           cal assessment, treatment and prevention of lyme
clindamycin 600 mg three times daily and           have been described. Ehrlichiosis (ana-              disease, human granulocytic anaplasmosis, and
                                                                                                        babesiosis. Clin Infect Dis 2006; 43:
quinine 650 mg both three times daily for          plasmosis) and babesiosis typically present      7. Dumler JS, Madigan JE, et al. Ehrlichioses in
7 to 10 days. More recently, a combina-            with non-specific, “flu-like” symptoms               humans. Clin Infect Dis 2007; 45:S45.
tion of atovaquone 750 mg twice daily and          during the spring, summer and fall. The          8. Krause PJ, Telford SR, et al. Babesiosis. Pediatrics
azithromycin 500 mg on day one and                 majority of patients do not recall a tick bite       1992; 89:1045.
                                                                                                    9. Krause PJ. Babesiosis. Med Clin North Am 2002;
then either 250 mg or 500 mg thereafter,           and all residents of endemic areas are at            86:361.
both for 7 to 10 days have been shown to           some degree of risk of infection regardless      10. Sun T, et al. Morphologic and clinical observa-
be equally effective. The combination of           of lifestyle and habits. Diagnosis rests on          tions in human infection with Babesia microti. J
                                                                                                        Infect Dis 1983; 148:239.
atovaquone and azithromycin is better tol-         clinical suspicion and the finding of ab-
                                                                                                    11. Krause PJ, Lepore T, et al. Atovaquone and
erated with fewer side effects than                normalities on blood count and smear.                azithromycin for the treatment of babesiosis.
clindamycin and quinine. Quinine has               Ehrlichiosis is suggested by leukopenia and          NEJM 2000; 343:1454.
the advantage of offering treatment for            thrombocytopenia, babesiosis by anemia,          12. Bonoan JT, Johnson DH, Cunha BA. Life-threat-
                                                                                                        ening babesiosis in an asplenic patient treated with
malaria in instances where this diagnosis          thrombocytopenia and intraerythrocytic
                                                                                                        exchange transfusion, azithromycin and
may be of concern. Additionally, quinine           parasites on peripheral smear. Ehrlichiosis          atovaquone. Heart Lung 1998; 27: 424.
appears to result in a more rapid drop in          is effectively treated by doxycycline and
parasite burden.11                                 so is covered when treating with typical              Jerome M. Larkin, MD, is Assistant
      Patients presenting with fulminant           regimens of this drug for Lyme disease. Ba-      Professor of Medicine, Division of Infec-
disease should be treated in an intensive          besia infection while quite common is as-        tious Diseases, The Warren Alpert Medical
care unit (ICU). Parasite burden can be            ymptomatic in more than 95% of cases in          School of Brown University.
as high as 85%. Exchange transfusion is            otherwise healthy individuals. Symptom-
indicated for high levels of parasitemia           atic disease is effectively treated in most      Disclosure of Financial Interests
(>10%), severe hemolysis or evidence of            cases by a combination of clindamycin and              The author has no financial inter-
liver, kidney or pulmonary involvement.            quinine or atovaquone and azithromycin.          ests to disclose.
In such patient, antimicrobial therapy             Fulminant disease in the immune-com-
should continue at least until the parasite        promised requires hospitalization, often         CORRESPONDENCE:
level is less than .04% or for 10 days, which-     admission to the ICU and potentially ex-         Jerome M. Larkin, MD
ever is longer. Repeat exchange transfu-           change transfusion.                              Rhode Island Hospital
sion should be considered for patients with                                                         593 Eddy St.
a parasitemia persisting over 5% after an                                                           Providence, RI 02903
initial exchange. Patients who are immune                                                           Phone: (401) 444-8130
compromised and/or present with fulmi-                                                              e-mail:
nant illness should be rechecked for para-
sites both by smear and PCR at one and
three months. Retreatment is indicated
for positive results.12

                                                                                                               VOLUME 91          NO. 7       JULY 2008
                 Lyme Disease In Children and Pregnant Women
                                                              Jerome M. Larkin, MD

      Two populations, pregnant women and             daily. Azithromycin 500 mg daily and            REFERENCES
      children under the age of eight, warrant        clarithromycin 500 mg twice daily also          1. Committee on Infectious Diseases American
                                                                                                         Academy of Pediatrics, Red Book: 2006 Report
      special mention as therapy with the drug        have activity but are inferior to amoxicillin      of the Committee on Infectious Diseases, The
      of choice for Lyme disease, doxycycline,        and cefuroxime. Doxycycline may be                 American Academy of Pediatrics, 2006:428.
      is contraindicated for both.                    used safely in children over the age of                         ,
                                                                                                      2. Wormser GP Dattwyler RJ, Shapiro ED. The clini-
                                                      eight. Patients should be advised regard-          cal assessment, treatment and prevention of lyme
      CHILDREN                                        ing simultaneous calcium consumption               disease, human granulocytic anaplasmosis, and
                                                                                                         babesiosis. Clin Infect Dis 2006; 43.
            The epidemiology, presentation and        and photosensitivity when taking doxy-          3. Schlesinger PA, Duray PH, , et al. Maternal-fetal
      clinical course of Lyme disease in children     cycline. Central nervous system involve-           transmission of the Lyme disease spirochete. Ann
      is similar to that in adults. Children be-      ment and third degree heart block should           Intern Med 1985; 103:67.
                                                                                                      4. Strobino BA, Williams CL, et al. Lyme disease
      tween the ages of five and nine years com-      be treated with ceftriaxone 75-100 mg/             and pregnancy outcome. Am J Obstet Gynecol
      prise one of the peaks of incidence in re-      day daily up to 2 grams total dose for 21-         1993; 169:367.
      gard to age. An intriguing notion is the        28 days. Isolated cranial nerve palsies and     5. Williams CL, Strobino B, et al. Maternal Lyme
      possibility that children under the age of      lower degrees of heart block are treated           disease and congenital malformations. Paediatric
                                                                                                         Perinatal Epidemiol 1995; 9:320.
      five may have less incidence of disease de-     as for early disseminated disease although      6. Gerber MA, Zalneratis EL. Childhood neuro-
      spite exposure because children in this age     for longer periods of time i.e. 28 days.           logic disorders and Lyme disease during pregnancy.
      group are often treated with courses of         Frank arthritis (warmth, redness, swell-           Peaditric Neurol 1994; 11:41.
      amoxicillin and second and third genera-        ing, pain, and as opposed to arthralgia)
      tion cephalosporins for presumed otitis         should likewise be treated with a 28 day             Jerome M. Larkin, MD, is Assistant
      media. These antibiotics in the doses and       course of therapy.2                             Professor of Medicine, Division of Infec-
      courses they are commonly prescribed                                                            tious Diseases, The Warren Alpert Medical
      would constitute effective therapy for early    PREGNANCY                                       School of Brown University.
      localized and disseminated disease.                  The epidemiology, presentation and
            As with adults, children may present      diagnosis of Lyme disease in pregnant           Disclosure of Financial Interests
      with erythema migrans in around 15% of          women is the same as for non-pregnant                 The author has no financial inter-
      cases. Other manifestations of disease in-      adults. Doxycycline, however, is absolutely     ests to disclose.
      clude fever, headache, arthritis, arthralgia,   contraindicated as therapy. The most ap-
      myalgia, cranial nerve palsies and menin-       propriate alternatives are amoxicillin 500      CORRESPONDENCE:
      gitis. Approximately 50% of children who        mg three times daily or cefuroxime 500mg        Jerome M. Larkin, MD
      do not receive appropriate antimicrobial        twice daily for 14 to 21 days.2                 Rhode Island Hospital
      therapy will develop arthritis. Abnormali-           In 1985 Schlesinger et al published        593 Eddy St.
      ties of the cardiac conduction system are       possible evidence of maternal fetal trans-      Providence, RI 02903
      possible later. Diagnosis is based on clini-    mission of B. burgdorgeri. Concerns were        Phone: (401) 444-8130
      cal signs and symptoms, appropriate epi-        raised regarding the possibility of fetal       e-mail:
      demiologic exposure and serologic testing.      malformations and stillbirth.3 Several large
      Antibody testing in early disease may be        studies have not, however, borne these
      negative and should not preclude treat-         concerns out. A prospective study of 2000
      ment in the appropriate setting. Demon-         pregnancies and outcomes in an endemic
      stration of seroconversion by repeated test-    area did not find an increased risk of preg-
      ing may be helpful in selected cases.1          nancy loss or congenital malformation.4,5
            For children under the age of eight,      A survey of pediatric neurologists in an
      amoxicillin at a dose of 50 mg/kg divided       endemic area did not detect a clinical syn-
      three times a day for 14 to 21 days is the      drome or pattern of abnormalities which
      drug choice for early localized and dis-        could be attributed to Lyme disease.6 Fi-
      seminated disease. Alternatives include         nally, there is no evidence that infection is
      cefuroxime 30 mg/kg day divided twice           transmitted via breast milk.

         Musculoskeletal Manifestations of Lyme Disease
                                                  Imad Bitar, MD, and Edward V. Lally, MD

In 1977, Dr. Allen Steere and colleagues            and synovial effusions are not evident. At         ease compared to more chronic illness.
reported an outbreak of arthritis in chil-          this stage, the patient’s illness resembled        Between the episodes of joint inflamma-
dren and adults in three small Connecti-            a typical viral syndrome.                          tion, the patients typically do not have
cut comminutes: Lyme, Old Lyme and                                                                     any joint symptoms.
East Haddam.1 These cases were first                LYME ARTHRITIS
noted in this small geographic region                    Frank arthritis develops months to            Chronic Arthritis
beginning in about 1972 and several of              a few years following the tick bite in un-              About 10% of untreated patients
the children were diagnosed with juve-              treated or inadequately treated patients           with recurrent attacks of arthritis lose the
nile rheumatoid arthritis (now called ju-           and Lyme arthritis is considered a mani-           typical periodicity of flares and develop
venile idiopathic arthritis). Steere and            festation of late Lyme disease (previously         chronic arthritis in one to three large
colleagues described this syndrome as a             referred to as Stage 3 Lyme disease). This         joints. This does not resemble the pat-
previously unrecognized disorder and                arthritis affects one or a few joints in two       tern of rheumatoid arthritis, and Lyme
coined the term “Lyme Arthritis.” There             distinctive patterns, intermittent arthri-         arthritis should not be considered in the
was a strong suspicion that the syndrome            tis and chronic arthritis.4                        differential diagnosis of chronic inflam-
was caused by an infectious agent, trans-                                                              matory polyarthritis, especially if the small
mitted by an arthropod vector.                      Intermittent Arthritis                             joints of the fingers and toes are involved.
       Subsequently, Lyme arthritis was                   Intermittent arthritis develops in at        Chronic Lyme arthritis clinically causes
found to be a major feature of a larger             least 60% of patients with Lyme disease            unremitting joint swelling and pain for
multi-systemic illness, Lyme disease,               who are not treated during the early               at least one year and one or both knees
caused by the spirochete Borrelia                   stages. The presence of prodromal symp-            are almost always involved.4 Due to the
Burgdorferi transmitted by a bite from              toms of polyarthralgia does not predict the        increased awareness of EM in endemic
the deer tick Ixodes damini. Following the          development of future arthritis. Patients          areas and the development of clearer
tick bite, the syndrome may involve mul-            develop episodes of severe joint inflamma-         treatment guidelines, the proportion of
tiple organs. Musculoskeletal symptoms              tion that are variable in frequency. The           patients with Lyme arthritis who do not
and findings are noted in the majority of           usual pattern of joint involvement is ei-          have a history of EM is increasing and
patients with Lyme disease.                         ther an asymmetric oligoarthritis or a             the lack of EM should not exclude pa-
       Arthritis was, and is, a dominant fea-       monoarthritis primarily affecting large            tients with characteristic arthritis in en-
ture in most patients with Lyme disease;            joints. The knee is the most common joint          demic areas from being tested for Lyme
however, the pattern of arthritis varies            involved and is almost always affected at          disease.
during different stages of this syndrome.           some point during the illness; the ankle
In fact, the pathogenesis of Lyme arthri-           and the wrist are the next most common             Synovial Pathology
tis is initially related directly to the spiro-     sites for arthritis.5                                    Unlike other forms of bacterial in-
chete infection and later, it is postulated,              During episodes of arthritis the af-         fections affecting the joint, Lyme arthri-
to immunologic abnormalities. This is               fected joint may become very swollen and           tis is indolent and damage is delayed for
particularly true in patients with chronic          warm although the patient usually com-             months or even years. The Borrelia spi-
Lyme arthritis. Lyme disease is said to be          plains only of mild pain. Patients with epi-       rochete lacks the enzymatic activity of
an infectious disease that behaves like a           sodes of arthritis that are severely painful       other bacterial pathogens that may affect
rheumatic disease.2                                 or associated with fever should be evalu-          the joints and it is believed that joint dam-
                                                    ated for other causes of joint inflammation        age occurs largely due to an exuberant
PRODROME                                            including crystal disease or even septic ar-       inflammatory response.
      Erythema migrans (EM), the classic            thritis; this is true even in patients that have         The synovial pathology of patients
skin manifestation of Lyme disease, is noted        previously proven Lyme arthritis.                  with Lyme arthritis is similar to that seen
in approximately 90% of patients, usually                 The presence of effusions in one or          in other types of non-bacterial inflamma-
within one month of the tick bite .3 Syn-           both knee joints is typical of the inter-          tory arthritis. This includes synovial hy-
chronously with, or subsequently to, the            mittent arthritis of Lyme disease. Very            pertrophy, vascular proliferation, and
skin rash, a prodrome develops consist-             large knee effusions, and Baker cysts for-         infiltration of the synovial membrane
ing of flu-like symptoms, fever, fatigue,           mation and spontaneous rupture in these            with mononuclear cells. However, it may
malaise, myalgias and polyarthralgias.              settings have been described.6                     be distinguished from the synovial pa-
Joint pain is typically polyarticular, involv-            The exacerbations of arthritis usu-          thology of rheumatoid arthritis in that
ing both large and small joints as well as          ally last weeks to months and typically            germinal centers and follicular hyperpla-
occasionally the back and neck. During              resolve spontaneously. In general the fre-         sia are not typically seen.
this early localized phase of Lyme disease,         quency and duration of arthritis attacks                 Synovial fluid analysis shows only
patients rarely developed frank arthritis           are greater in the early years of the dis-         mild elevations of white blood cells in the
                                                                                                                VOLUME 91      NO. 7     JULY 2008
      low inflammatory range. The synovial             (doxycycline or amoxicillin) are usually                Methotrexate and even tumor ne-
      fluid white blood cell count is usually less     given for 30 to 60 days; this is effective in    crosis factor a inhibitors have been con-
      than 50,000 cells/cubic millimeter.              about 90% of patients. Other recommen-           sidered for patients in this category.13.
                                                       dations are that patients who did not re-               A treatment strategy which is usually
      Laboratory                                       spond to 30-60 day course of oral antibi-        effective in patients with persistent arthri-
           Virtually all patients with Lyme ar-        otics should be treated with a 30 day            tis is arthroscopic synovectomy. Although
      thritis have serum immunoglobulin G              course of intravenous ceftriaxone.9 These        it is difficult to achieve a complete synovec-
      (IgG) antibodies to Borrelia burgdorferi         strategies are generally extremely effective     tomy with arthroscopy this should still be
      by Western blotting,7 but the presence of        in treating chronic Lyme arthritis.              considered as a treatment option.
      anti Borrelia antibodies within the synovial                                                              It should be further emphasized
      fluid by ELISA or Western blot is an ac-                                                           that although chronic Lyme arthritis may
      curate and reliable method of proving that             Lyme arthritis,                             be associated with joint erosions and car-
      arthritis is truly related to Lyme disease.                whether                                 tilage loss, the arthritis resolves eventu-
           In patients with chronic Lyme ar-                                                             ally in all patients.
      thritis cultures of the synovial fluid for             intermittent or
      the causative organism are usually nega-                 chronic, is a                            POST-LYME DISEASE SYNDROME
      tive but the genomic DNA of B.                                                                          Lyme disease at any stage may have
      burgdorferi can be identified in the syn-             hallmark of late                             associated nonspecific symptoms of fa-
      ovial fluid by Polymerase chain reaction               Lyme disease.                               tigue, myalgas, malaise, and wide spread
      (PCR) with sensitivity about 85%. The                                                              body pain. A fibromyalgia-like symp-
      conversion of a positive PCR to a nega-                                                           tom is well described in some of these pa-
      tive PCR after antibiotic therapy is used        Antibiotic-Refractor y Lyme                      tients even in those who received ad-
      to confirm successful treatment. PCR             Arthritis                                        equate antibiotic therapy for Lyme dis-
      analysis of synovial tissue has a higher yield        Approximately 5-10% of patients             ease.14 These patients have been referred
      than that of synovial fluid for the pres-        with Lyme arthritis do not respond to            to as having post-Lyme disease syndrome.
      ence of B. burgdorferi DNA.                      either oral or intravenous antibiotic            Additional symptoms include not only
                                                       therapy according to the prescribed rec-         fatigue, arthralgias, myalgias, and malaise
      Radiology                                        ommendations. These patients are felt            but symptoms of cognitive dysfunction
            In a study of 25 patients with Lyme        to have antibiotic-refractory (or slowly         including difficulty concentrating, poor
      arthritis8 who had active arthritis in the       resolving) arthritis. This condition is de-      attention and memory deficit. Head-
      knees for a median of 9 months (range 2          fined by persistent joint swelling for 3         aches, poor sleep and irritability also com-
      to 24 months), 20 patients (80%) were            or more months after the start of at least       prise this syndrome in many patients.
      found with radiographic abnormalities.           4 weeks of IV antibiotic therapy or at                 Although those patients have signifi-
      The most frequent findings were: soft tis-       least 8 weeks of oral antibiotic therapy         cant symptoms and functional disability,
      sue changes including knee effusions, syn-       or both. This condition could, theoreti-         they lack the objective findings of active
      ovial hypertrophy, edema of the                  cally, result from persistent infection,         inflammation, such as synovitis, on physi-
      infrapatellar fat pad and enthesitis. Other      but the identification of either spiro-          cal examination.
      findings included symmetrical articular          chetes or spirochetal DNA in these pa-                 The etiology of this syndrome is still
      cartilage loss, juxta-articular osteoporosis     tients is rare.10,11                             unclear and the actual incidence is very
      and erosions at bare areas at the margins             It is believed that persistent arthritis    variable. However, it does not seem to
      of the cartilage. However, radiographs of        in these patients results from immuno-           represent chronic active infection and it
      involved joints in the early stages of Lyme      logic abnormalities. Patients with this          does not benefit from prolonged courses
      arthritis are typically normal. No studies       condition have a higher incidence of             of antibiotics, whether orally or intrave-
      specifically evaluate the role of magnetic       HLA-DRB1 alleles (similar to the alleles         nously.15
      resonance imaging in Lyme arthritis.             associated with rheumatoid arthritis) and
                                                       are thought to have greater immune re-           OTHER     MANIFESTATIONS
      Treatment of Lyme Arthritis                      activity to Borrelia burgdorferi Outer-Sur-           Based on case reports, Lyme disease
            Antibiotic treatment early in the          face Protein A (OspA).12                         could be associated with myositis, osteo-
      course of Lyme disease is very effective in           Once the patients in this category have     myelitis, and panniculitis. 14,16 Patients
      preventing arthritis, and when started af-       a negative PCR for Borrelia Burgdorferi, the     with myositis may develop weakness and
      ter the presence of arthritis, shortens the      general recommendation is to treat these         muscle pain. The patients in this category
      duration of attacks with resolution of ar-       patients with oral non-steroidal anti-inflam-    have been found to have elevated muscle
      thritis within weeks to months. Oral anti-       matory drugs, hydroxychloroquine,                enzymes and other inflammatory mark-
      biotic therapy is preferred over intrave-        sulfasalazine or intraarticular steroids.        ers in their serum. In one report 16 a
      nous antibiotic therapy because both treat-      Intraarticular steroids should not be used       muscle biopsy showed tissue invasion with
      ments are equally effective, but oral treat-     for Lyme arthritis if the patient has not pre-   B. burgdorferi and an immune response
      ment is cheaper and probably associated          viously been treated with adequate antibi-       to this organism.
      with fewer side effects. Oral antibiotics        otic therapy.
SUMMARY                                        REFERENCES                                              Web references:
     Musculoskeletal symptoms in Lyme          1. Steere AC, et al. 1977. Lyme arthritis. Arthritis    Centers for Disease Control and Preven-
                                                   Rheum 1977; 20:7–17.
disease are very common at all stages of                                                                   tion:
                                               2. Stephen E. Malawista. Resolution of Lyme ar-
the disease. Lyme arthritis, whether in-           thritis, acute or prolonged. Inflammation 2000;     National Institute of Allergy and Infec-
termittent or chronic, is a hallmark of late       24 (6).                                                 tious Diseases (NIAID): http://
Lyme disease. This may cause severe joint      3. Linden Hu, MD. Lyme arthritis. Infect Dis Clin 
                                                   N Am 2005;19: 947–61.
pain and swelling especially confined to       4. Steere AC. Chronic Lyme arthritis. Ann Intern
one or a few joints, most notably the knee.        Med 1979; 90:896-901.                                    Edward V. Lally, MD, is Director,
Antibiotic therapy is very effective in        5. Steere AC, et al. The clinical evolution of Lyme     Division of Rheumatology, Rhode Island
treating Lyme arthritis in the majority of         arthritis. Ann Intern Med 1987; 107:725.            Hospital and the Warren Alpert Medical
                                               6. Massarotti EM. Lyme arthritis. Med Clin North
cases. However, a small proportion of              Am 2002 86:297-309.
                                                                                                       School, and Professor of Medicine, The
individuals will develop persistent            7. Weinstein, Britchkov. Lyme arthritis and post-       Warren Alpert Medical School at Brown
chronic arthritis which is likely mediated         Lyme disease syndrome. Curr Opin Rheumatol          University.
through immunologic mechanisms. In                 2002, 14:383-7.                                          Imad Bitar, MD, is a Rheumatology
                                               8. Lawson JP, Steere AC. Lyme arthritis. Radiol 1985;
these patients treatment strategies should         154:37.                                             Fellow, Roger Williams Medical Center.
include anti-inflammatory medications          9. Steere AC, Angelis SM. Therapy for Lyme arthri-
and possibly immunosuppressive treat-              tis. Arthritis Rheum 2006; 54: 3079–86.             Disclosure of Financial Interests
ments. Arthroscopic synovectomy ma             10. Sigal LH. Lyme arthritis. Arthritis & Rheumatism          The authors have no financial inter-
                                                   1999; 42: 1809–12.
ybe very helpful in some of these patients.    11. Steere AC, Gibofsky A, et al. Chronic Lyme ar-      ests to disclose.
Post Lyme disease syndrome and Lyme                thritis. Ann Intern Med 1979; 90:896.
myositis are two other sequelae that are       12. Steere AC. Medical progress. NEJM 2001;345          CORRESPONDENCE:
associated with Lyme disease.                      (2): July 12.                                       Edward V. Lally, MD
                                               13. Steere AC, et al. Therapy for Lyme arthritis.
                                                   Arthritis & Rheumatism 2006;54 (10).                Rhode Island Hospital
                                               14. Steere AC. Musculoskeletal manifestations of Lyme   2 Dudley St. Suite # 370
                                                   disease. Am J Med 1995; 95 (suppl 4 A).             Providence, RI 02905
                                               15. Sigal LH. Musculoskeletal manifestations of Lyme
                                                                                                       Phone: (401) 444-2248
                                                   arthritis. Rheum Dis Clin North Am 1998;24:323-
                                                   51.                                                 e-mail:
                                               16. Holmgren AR, Matteson EL. Lyme myositis.
                                                   Arthritis Rheum 2006;54:2697-700.

                                                                                                               VOLUME 91      NO. 7   JULY 2008
                    Neurological Complications of Lyme Disease
                                                 Syed Rizvi, MD, and Amanda Diamond, MD

      A tick-bite associated rash with later                 Radiculoneuropathy. Painful radicu-       The same patients have been discovered
      neurological manifestations, including pa-      litis is one of the most common early neu-       to develop an axonal neuropathy* in the
      ralysis and meningitis, had been docu-          rologic symptoms of Lyme disease in Eu-          affected limb.9, In the case of chronic
      mented in Europe for several years before       rope. Incidentally, it was also part of the      infection, it has been estimated that one
      Lyme arthritis was recognized in the            symptom-complex described in the first           in four patients may have peripheral
      1970s.1-4 The illness was later understood      patient reported with the syndrome.1 Usu-        nerve involvement. These patients may
      to be part of a multisystem disease caused      ally occurring within the first weeks to         present with mainly sensory symptoms.
                                                                                                       10, 11
      by spirochetae and transmitted by Ixodes        months in the infection, the
      ticks.5, 6 Borrelia burgdorferi, although       radiculoneuropathies of Lyme disease have
      initially thought to be a single species, has   included motor, sensory and mixed symp-          NEUROBORRELIOSIS OF THE
      been found to have several sub-species.         toms. They are usually self-limited and may      CENTRAL NERVOUS SYSTEM
      These subgroups may be responsible for          be easily mistaken for nerve-impingement                Meningitis. Although many syn-
      the variation in clinical symptoms observed     syndromes, with segmental symptoms of            dromes involving the central nervous sys-
      in different parts of the world.7               weakness, sensory or reflex changes.9 The        tem remain controversial, several have
            The pathophysiology of neuro-             symptoms may not occur in the region of          been well-defined. Certainly, the early
      borreliosis is difficult to demonstrate, but    the tick bit. Electrodiagnostic testing usu-     appearance of lymphocytic meningitis
      mimics other spirochetal infections. In-        ally shows multifocal mild sensorimotor in-      is well recognized. Mildly increased
      fection is local with subsequent dissemi-       volvement.10, 11                                 CSF pressure with headache and
      nation. During this time spirochete num-               Cranial neuropathies. Involvement of      papiledema may occur. The lympho-
      bers are high. B. burgdorferi components        cranial nerves, particularly the seventh         cytic pleocytosis usually includes tens to
      that induce cytokine production by T            nerve, may be present in up to 50%-75%           hundreds of lymphocytic cells per mL.
      and B cells produce immune activation           of all patients experiencing neurologic          A mild elevation of protein may also be
      and indirect cell damage. Central ner-          symptoms.4 Multiple cranial nerves may           seen, with CSF glucose usually remain-
      vous system involvement is common and           be involved simultaneously.9 Reports in-         ing within a normal range to minimally
      clinical syndromes tend to occur in             clude symptoms of every cranial nerve ex-        decreased. 12 The ‘typical’ symptoms
      stages.7                                        cept the olfactory nerve. The facial nerve       that usually occur with ‘aseptic’ menin-
            Lyme disease has been implicated in       involvement is reported to be bilateral in       gitis, such as photophobia, headache
      a variety of peripheral and central ner-        up to one third of cases.11 Facial nerve         and neck stiffness, are extremely variable
      vous system disorders. The neurological         symptoms may not affect taste or hearing,        with Lyme meningitis.11, 12
      syndromes are often accompanied by              indicating that involvement may be outside              Intracranial hypertension syn-
      more general complaints (arthralgias, fa-       the subarachnoid space. Additionally, CSF        drome. A rare complication of Lyme dis-
      tigue, myalgias). Earlier neurological          analysis in isolated Lyme disease facial palsy   ease resulting in headache and potential
      symptoms, or those occurring during dis-        may be normal. Complete recovery occurs          papilledema, this syndrome seems to be
      semination within weeks to months, tend         in 80-90% of patients within weeks to            associated more often with children and
      to be more clinically obvious and develop       months.                                          adolescents. CSF abnormalities may oc-
      in an estimated 15% to 20% of patients.4               “Guillain Barré-like” syndrome.           cur. There does not appear to be a cor-
      Several late syndromes seem to follow a         Although rare, an acute and severe syn-          relation with female sex or obesity, as with
      more insidious course.8 For purposes of         drome of diffuse polyneuropathy, includ-         pseudotumor cerebri. 11, 13
      simplification, disorders of the peripheral     ing bifacial weakness, may mimic the                    Encephalomyelitis. A chronic
      and central nervous systems will be re-         symptoms of Guillan Barré. A CSF lym-            manifestation of Lyme disease, encepha-
      viewed separately.                              phocytic pleocytosis and/or neurophysi-          litis is rare in North American (nearly all
                                                      ologic testing may help differentiate be-        cases have been reported in Europe). On
      NEUROBORRELIOSIS OF THE                         tween the syndromes.7                            MRI there is evidence of parenchymal
      PERIPHERAL NERVOUS SYSTEM                              Peripheral neuropathy. Symptoms           involvement. This can include hemi-
           The most common peripheral mani-           of peripheral neuropathies in patients           spheric or brainstem abnormalities and
      festations of Lyme disease are cranial neu-     with Lyme disease tend to be primarily           is usually nonspecific, although may
      ropathies, peripheral neuropathies and          sensory, occurring in a stocking-glove fash-     mimic ischemic patterns.11
      radicultis. However, many other syn-            ion, although patchy paresthesias may                   Myelopathy. Patients may present
      dromes, including a “Guillian Barré-like”       also be noted. In some European pa-              with symptoms of transverse myelitis so
      syndrome, motor neuron disease,                 tients, a dermatologic manifestation is          that Lyme disease should be considered
      axonopathies, brachial and lumbar               often associated with the neuropathy.            in the diagnosis of these patients.11, 14
      plexopathies, mononeuropathy multiplex          Labeled acrodermatitis atrophicans, the          Rarely, a transverse myelopathy may ac-
      and even myositis have been described. 7        skin becomes tissue-thin and discolored.         company Lyme radiculoneuritis. This
typically occurs at the same level as radicu-   testing. Spinal fluid can, however, be                Given the high incidence of B.
lar involvement and may be preceeded            tested for the presence of anti-B.              burgdorferi antibody in the CSF of pa-
by a leptomeningitis.12                         burgdorferi antibodies.19                       tients who are seropostive but without
      Lyme encephalopathy. This may be               The American Academy of Neurol-            neuroborreliosis, other tests for the di-
the most common late neurologic mani-           ogy (AAN) guidelines for the diagnosis          agnosis of central nervous system disease
festation of Lyme disease. Patients express     of neurologic Lyme disease include the          have been evaluated. A recent study by
difficulties with concentration, sleep dis-     consideration of exposure to ticks in an        Blanc, suggested the use of an
turbance, emotional lability, memory and        endemic region, clinical abnormalities          anti-Borrelia antibody index (AI). The
attention.11, 15, 16 Despite studies includ-    other than those affecting the nervous          AI is the ratio of anti-Borrelia IgG in
ing requirements for CSF abnormalities          system (including cardiac, rheumatologic        CSF to anti-Borrelia IgG in the serum
and SPECT imaging, the definitive di-           and dermatologic symptoms), and ad-             and is considered positive if greater than
agnosis of Lyme encephalopathy remains          equate laboratory support (proof of the         or equal to two. The study noted 74 pa-
elusive.16 In the consideration of acute        presence of B. burgdorferi or immuno-           tients with diagnoses of other neurologic
encephalopathy, one should note that            logic evidence of exposure) in addition         diseases all had positive CSF Lyme anti-
persons with Lyme-induced cognitive             to the causally-related neurologic disease      bodies; only two of those patients had a
changes likely have a mild encephalitis;        or syndrome.20                                  positive AI (specificity of 97%). The sen-
these patients should not be confused                                                           sitivity of positive AI was determined to
with mental status changes associated           …prolonged courses                              be 75%. The authors suggested the fol-
with systemic symptoms.17 Such patients                                                         lowing criteria for diagnosis of
are likely to have objective findings on        of antibiotics do not                           neuroborreliosis: presence of four of the
neuropsychiatric testing and such a di-          improve outcomes                               following five items. 1) no past history
agnosis should only be made in the pres-                                                        of neuroborreliosis, 2) positive CSF anti-
ence of appropriate findings after test-             and are not                                Borrelia antibodies, 3) positive anti-Bor-
ing has been performed by a qualified              recommended.                                 relia antibody index, 4) favorable out-
professional. This is distinct from the                                                         come after specific antibiotic treatment,
more subjective symptoms patients often                                                         5) no other etiologic diagnosis.22
experience for weeks to months follow-                Additionally, the US Centers for                Researchers have also described a
ing an episode of acute infection with B.       Disease Control and Prevention (CDC)            B-cell-tropic chemokine, CXCL13,
burgdorferi (discussed below).                  has recommended a two-tier system to test       which appears abnormally elevated in
      Post-Lyme disease. Several patients       for anti-B. burgdorferi antibodies. Sero-       CSF of patients with Lyme
who have had Lyme disease have been             logic testing starts with enzyme-linked         neuroborreliosis. If confirmed, this
noted to have other psychiatric and cog-        immunosorbent assay (ELISA), with               cytokine might serve as a marker to as-
nitive symptoms, such as fatigue, cogni-        usually high sensitivity depending on           sist in the confirmation of the diagnosis
tive slowing and depression. These pa-          acuity of infection and organ systems in-       of neuroborreliosis.23
tients are sometimes diagnosed with post-       volved, and low specificity due to cross-
Lyme disease. It is unlikely that these         reacting antigens.21 Seropositivity may         TREATMENT     OF NEUROBORRELIOSIS
symptoms indicate persistent neurologic         remain for years and can occur in up to              Although the general recommen-
infection, and studies have not shown           10% of the asymptomatic population in           dation in the US is to use parenteral an-
that antimicrobial therapy is helpful in        endemic areas. The antibody may not             tibiotics whenever the nervous system is
these patients.18                               be detected within the first 2 to 6 weeks       involved, there is considerable evidence
                                                after exposure, so retesting (or treatment      in the European literature suggesting
DIAGNOSIS OF NEUROLOGIC           LYME          without testing in cases with Erythema          oral doxycycline (200-400mg/day) may
DISEASE                                         migricans) may be important in cases of         be equally effective in most patients. At
      The crucial element for the consid-       high clinical suspicion. Borderline or          the recommended doses it appears that
eration of neurologic Lyme disease is the       positive results are then confirmed by          the CSF concentrations of doxycycline
presence of an indicative neurologic            Western blot. IgM testing is recom-             exceed minimum inhibitory concentra-
symptom. Laboratory data should be              mended only acutely in disease, when            tion for most strains. Although there are
complimentary and supportive of clini-          clinical history is limited to 1 to 2 months,   strain differences between United States
cal findings. In evaluating response to         and requires 2 of 3 possible bands (sensi-      and Europe, there probably is not a sig-
therapy, the clinician must remember            tivity 32%). Confirmatory testing of IgG        nificant difference in antimicrobial sus-
that many neurologic illnesses improve          presence requires 5 of 10 possible bands        ceptibility. 24 Also, prolonged courses of
with time, regardless of treatent.17 Un-        (sensitivity 83%). Given lower sensitivi-       antibiotics do not improve outcomes and
fortunately, sensitivity of culture in ner-     ties, clinical judgment should in used in       are not recommended. The duration of
vous system infections is low (only about       patients with positive ELISA whom do            parenteral treatment suggested is 2 to 4
10% in CSF in Lyme meningitis). The             not meet Western blot criteria. Also,           weeks, with no data showing any definite
sensitivity of PCR testing appears to be        positive Western blot performed without         advantage of prolonged treatment. 25, 26
low as well. Confirmation of the diagno-        ELISA may be deceptive and should not           Oral regimens are generally given for 30
sis, therefore, relies largely on serologic     be used.19, 20, 21                              days.
                                                                                                        VOLUME 91      NO. 7   JULY 2008
                                                                                                              22. Blanc F, Jaulhac B, , Neurol 2007;69:
                Table 1. Antimicrobial regimens for the treatment of                                              953-8.
                           nervous system Lyme disease                                                        23. Rupprecht TA, Pfister HW, Neurol
                                                                                                              24. KarlssonM, Hammers S, et al. Antimicrobial agents
        Medication                                                                                                Chemother 1996; 40:1104-7.
        Oral regimens                 Adult dose                  Pediatric dose                              25. Klempner M, Hu L. et al. NEJM 2001;345:85-
        Doxycycline                   100 (-200) mg BID           Aged = 8 years:                                 92.
                                                                  4 mg/kg/day in                              26. Krupp LB, Hymann LG, et al. Neurol 2003;
                                                                  2 divided doses;                                60:1923-60.
                                                                  max 200mg/dose
        Amoxicillin (when             500 mg TID                  50 mg/kg/day in
                                                                                                                   Syed Rizvi, MD, is Director, Rhode
        doxycycline                                               3 divided doses;                            Island Hospital Multiple Sclerosis Center,
        contraindicated)                                          max 500 mg/dose                             and Assistant Professor of Clinical Neuro-
        Cefuroxime (when              500 mg BID                  30 mg/kg/day in                             sciences. Warren Alpert Medical School of
        doxycycline                                               2 divided doses;                            Brown University.
        contraindicated)                                          max 500 mg/dose                                  Amanda Diamond, MD, is a Neu-
                                                                                                              rolog y Fellow, Warren Alpert Medical
        Parenteral regimens                                                                                   School of Brown University.
        Ceftriaxone                   2 g IV daily                50-75 mg/kd/d in
                                                                  single dose, max 2 g                        Disclosure of Financial
        Cefotaxime                   2 g IV Q8H                   150-200 mg/kg/day in                        Interests
                                                                  3-4 divided doses;                               Syed Rizvi, MD, has no financial
                                                                  max 6 g/day                                 interests to disclose.
        Penicillin G                  18-24 MU/day,               200-400,000 U/kg/day                             Amanda Diamond, MD. Consult-
                                      divided doses Q4H           divided Q4H, max 18-24                      ant: Guidant, Teva, Berlex (Bayer),
                                                                  MU/day                                      Genentech, Cordis.

          The AAN published practice pa-             REFERENCES                                               Discussion of drug used off-
      rameters for the treatment of nervous sys-     1. Garin B. J Med Lyon 1922;71:765-7.                    label or under investigation:
                                                     2. Bannwarth A. Arch Psychiatr Nervenkr                       Doxycycline, amoxicillin, ceftriaxone,
      tem Lyme disease in March, 2007. It rec-
      ommended:                                      3. Steere, AC, Malawista SE, et .al. Arthritis Rheum
                                                                                                              ceftriaxime and penicillin are not FDA-
                                                         1977;20:7-17.                                        approved for the treatment of Lyme dis-
      1) Parenteral penicillin, ceftriaxone,         4. Said, G. Neurol Clinics 2007;25:115-37.               ease, but all have been shown either effec-
                                                     5. Burgdorfer W, Barbour AG, et .al. Science             tive or have evidence indicating efficacy.
         and cefotaxime are probably safe                1982;216:1317-9.
         and effective treatments for periph-        6. Steere, AC, Grodzidki, RL, NEJM
         eral nervous system Lyme disease                1983;308:733-40.                                     CORRESPONDENCE:
         and for CNS Lyme disease with or            7. Halperin, JJ. J Neurol Sci 1998;153:182-91.           Syed Rizvi, MD
                                                     8. Halperin, JJ, Luft, BJ, Neurol 1989;39:        2 Dudley Street, suite 555
         without parenchymal involvement                 753-9.
         (Level B recommendation).                   9. Halperin, JJ. Muscle Nerve 2003;28:133-43.            Providence RI 02903
      2) Oral doxycycline is probably a safe         10. Halperin, JJ, Luft, B, Brain                  Phone: (401) 444-3799
         and effective treatment for periph-             1990;113;1207-21.                                    e-mail:
                                                     11. Coyle, PK. Lyme disease. Curr Neurol Neurosci
         eral nervous system Lyme disease                Rep 2002;2:479-87.
         and for CNS Lyme disease without            12. Pachner, AR, Steere, AC. Neurol 1985;35:47-
         parenchymal involvement (Level B                53.
         recommendation). Amoxicillin and            13. Kan, L, Sood, SK, Maytal, J Pediatr Neurol
         cefuroxime axetil may provide alter-        14. Mantienne, C, Albucher, JF, Neuroradiol
         natives but supporting data are                 2001;43:485-8.
         lacking.                                    15. Logigian EL, Kaplan RF, Steere, AC.. J Infect Dis
      3) Prolonged courses of antibiotics do
                                                     16. Logigian EL, Johnson KA, Neurol
         not improve the outcome of post-                1997;49:1661-70.
         Lyme syndrome, are potentially as-          17. Halperin, JJ. Vector Borne Zoonotic Dis
         sociated with adverse events, and are           2002;2:241-7.
                                                     18. Halperin JJ, Shapiro ED, Logigian E, Neurol
         therefore not recommended (Level                2007;69: 91-102.
         A recommendation).                          19. Halperin, JJ. Curr Treat Options Neurol 2007;9:93-
          Treatment regimens are listed in           20. Halperin JJ, Logigian EL, et al. Neurol
      Table 1.                                       21. Aguero-Rosenfeld ME, Wang G, Clin
                                                         Microbiol Rev 2005;18:484-509.

Updates and Controversies In the Treatment of Lyme Disease
                                         Jennifer Mitty, MD, MPH, and David Margolius

Lyme disease is the most commonly               have published treatment guidelines for        ing the diagnosis. 3 Conversely, the
reported vector-borne disease in the            Lyme disease. The guidelines, which dif-       ILADS guidelines rely on physician
United States, with approximately 20,000        fer significantly, can be confusing to pa-     judgement coupled with a list of symp-
cases diagnosed each year.1 A majority of       tients and providers. The IDSA guide-          toms, of which most, if not all, can be
these cases occur in the Northeast and          lines have generally been derived from         present in other infectious and non-in-
upper Midwest, with a significant num-          controlled clinical trials especially with     fectious disease states. Per the ILADS
ber of cases each year in Rhode Island.2        regard to choice of antibiotic and dura-       guidelines, antibody assays are not sensi-
According to the Rhode Island Depart-           tion of treatment. Conversely, the ILADS       tive enough to be used clinically and
ment of Health, 736 cases were reported         guidelines are largely symptom-based           Lyme disease is a suspected diagnosis in
in 2003, the last year for which it has pub-    and eschew the use of diagnostic testing       many circumstances. This is especially
lished data. Because patients with Lyme         to confirm cases, relying on physician         true when there are both musculoskel-
disease can present to primary care pro-        judgement on when, with what and how           etal and neuropsychiatric symptoms, and
viders, subspecialists or providers in urgent   long to treat a given patient.                 when there is no evidence to indicate
care centers and emergency departments,                                                        another illness.5 Accordingly, many pa-
all Rhode Island physicians should under-       DIAGNOSIS                                      tients may be treated with antibiotics
stand the diagnosis and management of                 Both the IDSA and ILADS guide-           without clear lab-based or objective
Lyme disease. Similarly, they should have       lines agree that the presence of an            physical evidence of a specific disease.
knowledge of the controversies surround-        erythema migrans type rash is highly sug-      This can lead to overuse of antibiotics and
ing diagnosis and the use of antimicrobial      gestive of Lyme disease and, when              the resulting complications of drug reac-
therapy.                                        present, constitutes sufficient evidence       tions and the development of resistant
      Lyme borreliosis is caused by a spi-      to make a diagnosis of acute infection.        bacteria, with the attendant negative im-
rochete, Borrelia burgdorferi, which is         Yet such a rash is not present in all          pact on both the patient and the com-
transmitted by the Ixodes scapularis tick,      cases.3,5 Accordingly, the IDSA guide-         munity.
commonly known as the deer tick. The            lines maintain that in the absence of
disease consists of three stages. The first     erythema migrans, a positive serologic         LABORATORY TESTING
stage is usually localized, and presents as     test is necessary to make a diagnosis of             IDSA and Centers for Disease Con-
erythema migrans (EM), the character-           Lyme disease. The joint and other sys-         trol and Prevention (CDC) recommen-
istic “bullseye rash.” This rash is an ex-      temic symptoms of infection are too            dations consist of a two-test approach us-
panding skin lesion that appears at the         nonspecific, and overlap with other            ing a sensitive ELISA or immunofluores-
site of the tick bite, presents within 7-14     types of, usually viral, infections..3 Ad-     cent assay (IFA) followed by a confirma-
days after removing the engorged tick,          ditionally, the majority of patients pre-      tory Western blot test.3,6 If the ELISA or
and is usually at least 5cm in largest di-      senting with systemic symptoms, i.e. early     IFA is negative, these guidelines state that
ameter.3 Although helpful for diagnosis         disseminated disease, are seropositive at      a Western blot should not be performed.
when present, not all patients develop a        the time of presentation. Those patients       The need for confirmatory Western blot
rash. Additionally, some patients may           who still may not have seroconverted           is supported by the results of a study by
have an atypical rash; i.e., smaller and        may be reasonably treated empirically,         Engstrom et al. where 29% of positive
without central clearing. Relatively few        especially if the case is highly suggestive    ELISA tests were recorded in persons with
patients recall a tick bite. Stage 2 or dis-    and in an area of high endemicity, with        illnesses other than Lyme disease.7 Al-
seminated infection may begin several           follow-up testing used to demonstrate          though the western blot is highly specific,
days or weeks after the rash, as the spiro-     seroconversion and confirm the diagno-         false positives do exist, particularly in the
chete spreads hematogenously. Manifes-          sis. The ILADS guidelines, in contrast,        IgM immunoblot.8,9 The one exception
tations of disseminated infection include       hold that clinical judgment alone stands       to this algorithm is in the acute phase of
multiple erythema migrans, meningitis,          as the only alternative basis for the diag-    infection. Most of the current tests are too
cranial or peripheral neuritis, carditis,       nosis of Lyme disease.                         insensitive to be helpful diagnostically,
atrioventricular nodal block, or migra-               In terms of late stage Lyme, where       given the time lapse in developing an im-
tory musculoskeletal pain.4 Stage 3, the        the time from initial bite to presentation     mune response to the spirochete antigens.
late stage disease, may present as chronic      is relatively long, a diagnosis per the IDSA         The ILADS guidelines state that a
arthritis or chronic neurologic distur-         guidelines requires a positive blood en-       seronegative patient may present with
bances.                                         zyme-linked immunosorbent assay                Lyme disease, especially if evidence does
      Two national organizations, the In-       (ELISA) confirmed with a Western blot.         not indicate another disease. 5 Citing
fectious Diseases Society of America            A lumbar puncture or joint aspiration          unpublished surveillance data, the
(IDSA) and the International Lyme and           yielding a positive polymerose chain re-       ILADS guidelines state that laboratory
Associated Diseases Society (ILADS),            action (PCR) may be helpful in confirm-        testing advocated by the CDC fails to
                                                                                                        VOLUME 91      NO. 7    JULY 2008
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                                                                              VOLUME 91       NO. 6     JUNE 2008

A Clearer Vision of Health ™                                  
      identify up to 90% of cases of Lyme dis-         even without objective values. To sup-        months, or even years. Chronic Lyme
      ease.10 ILADS proposes to increase sen-          port their recommendations, the authors       and Post-Treatment Lyme Disease Syn-
      sitivity of the test by registering a serop-     cite 2 non randomized studies: one in-        drome refer to a set of non-specific symp-
      ositive case when only 2 of the                  volves 43 acute psychiatric patients with     toms that can occur after initial treatment
      immunoblot bands are positive rather             a positive Lyme serology who improved         for Lyme disease. The real question is
      than the CDC recommended 5 IgG                   after 90 or more days of concurrent an-       whether these symptoms are due to ac-
      bands. ILADS maintains that other tests,         tibiotic and antipsychotic pharmacologic      tive spirochetal infection, or a post-infec-
      including antigen capture, urine antigen,        therapy;15 and another, where 18/23 pa-       tious disease state.
      and PCR on fluids other than CSF and             tients previously treated for Lyme had              ILADS describes Chronic Lyme as
      synovial remain options for Lyme diag-           better outcomes in cognition, but simi-       a set of permanent symptoms that include
      nosis. Although the ILADS guidelines             lar improvement in depression and anxi-       fatigue, cognitive dysfunction, headaches,
      acknowledge that these tests have not            ety as compared to the 5 who were not         sleep disturbance, demyelinating disease,
      been standardized,5 the CDC has taken            retreated with antibiotics.16                 neuropsychiatric presentations, cardiac
      this a step further and put out an advi-                                                       presentations, and musculoskeletal prob-
                                                                                                     lems that seems to be a growing epidemic.
      sory warning against the use of these tests,
      as the accuracy and clinical usefulness of
                                                        …at this time there                          ILADS maintains that chronic Lyme and
      these assays have not been adequately es-         are no randomized                            its symptoms may continue despite a 30
                                                                                                     day treatment course (persistent), may re-
                                                        controlled studies                           lapse in the absence of a new tick bite
      TREATMENT                                            that show a                               (recurrent), and may be poorly respon-
                                                                                                     sive to antibiotic therapy (refractory).5 In
            The IDSA guidelines recommend
      doxycycline, amoxicillin, or cefuroxime
                                                         sustained benefit                           these cases, ILADS guidelines state that
      axetil for 14 days for adult patients with           of long term                              the Lyme disease is often resistant to treat-
                                                                                                     ment and may require higher and longer
      early Lyme disease associated with an EM,
      and state that macrolides should only be
                                                            antibiotics.                             doses of antibiotics to produce clear evi-
      used when the patient has contraindications                                                    dence of improvement.
      for all of the medications listed above. These         To summarize, IDSA proposes a                 In an exhaustive review of the litera-
      recommendations are based on the re-             fixed treatment course for each stage of      ture, the authors of the IIDSA guidelines
      sults of randomized controlled trials.12,13      Lyme disease based on the results of con-     found no convincing biologic evidence
      Late Lyme disease should be treated with         trolled studies, while ILADS avoids spe-      of the persistence of the spirochete in
      a full 28 days of the oral antibiotics listed    cific recommendations, arguing to treat       humans following recommended treat-
      or parenteral therapy with ceftriaxone,          the patient, often with long courses of       ment regimens for Lyme disease. 3 In-
      cefotaxime, or penicillin G for 14-28            antibiotics, based on clinical response.      stead, they propose that the symptoms fol-
      days. In cases where symptoms such as            Given the growing concern of antibiotic       lowing treatment of Lyme be entitled
      arthritis persist, a second cycle of antibi-     resistance, and the substantial morbidity     Post-Treatment Lyme Disease Syn-
      otics may be given. However, clinicians          and even mortality16 associated with per-     drome. Chronic symptoms following
      are advised by the IDSA to wait several          sistent antibiotic usage, physicians and      Lyme disease most likely represent either
      months to allow for the slow resolution          patients should understand that at this       an autoimmune phenomenon or stem
      of inflammation associated with this dis-        time there are no randomized controlled       from the slow resolution of the initial
      ease. As a general rule, these guidelines        studies that show a sustained benefit of      immune response to the infection. They
      state that response to treatment is slow,        long term antibiotics.                        also note that there are a high rate of simi-
      and re-treatment in most cases is not rec-                                                     lar complaints in the general population,
      ommended unless objective measures in-           LATE STAGE VS. CHRONIC VS.                    as is supported by population-based sur-
      dicate relapse.3,14                              POST-LYME DISEASE SYNDROME                    veillance data.3, 18
            In contrast, ILADS states that giv-              Often the terms late stage, chronic,          The concept of a post- infectious
      ing antibiotics for a fixed amount of time       and post-treatment Lyme disease are used      state is supported by a landmark study
      based on recommendations is “arbitrary”.         interchangeably; however, it is important     that randomized individuals with a his-
      Instead, the patient’s symptoms and clini-       to note that they describe very different     tory of Lyme disease and persistent symp-
      cal response should guide the duration           disease states, and that there is disagree-   toms to placebo or an additional 90 days
      of the treatment. ILADS defends this             ment regarding the presence of chronic        of antibiotic therapy; in this study, ex-
      ambiguity by stating that in an ideal situ-      lyme disease. Late stage Lyme disease is      tended antibiotic therapy showed no ad-
      ation treatment would be halted when             generally a point of consensus between        ditional benefits but did have slightly in-
      the Lyme spirochete is cleared from the          IDSA and ILADS and is defined as the          creased adverse events over the placebo
      body; however, without such a test clini-        late manifestations of the disease such as    group.14 Two recent studies, published
      cians must rely on symptom based diag-           arthritis, encephalopathy, encephalomy-       since the IDSA guidelines in November
      nosis and treatment.5 The ILADS panel            elitis, and peripheral neuropathy.3,5 This    2007, also argue against the use of long
      writes that treatment should be initiated        stage of Lyme can arise from a spirochete     term antibiotics. A randomized, placebo-
      at once upon suspicion of a diagnosis,           infection that has gone untreated for         controlled trial of 10 weeks of IV
                                                                                                                     Jennifer Mitty, MD,MP H, is
     Table 1. Web Sites That Provide Information for Patients and                                              Assisstant Professor of Medicine at the War-
                      Clinicians on Lyme Disease                                                               ren Alpert Medical School of Brown Uni-
                                                                                                               versity and the Director of the Lyme Clinic
        •                          •                                                   at Rhode Island Hospital.
        •                    •                                                David Margolius, is a student in the
                                                                                                               Warren Alpert Medical School of Brown

ceftriaxone,19 showed slight cognitive           at this time that support their use.                          Disclosure of Financial Interests
improvement in patients on intravenous           Through education, patients can under-                              The authors have no financial inter-
antibiotics versus the intravenous placebo       stand the risks of prolonged antibiotics,                     ests to disclose.
at 12 weeks, but this difference was not         and through such understanding, can
maintained at 24 weeks post treatment;           embrace alternative forms of treatment                        CORRESPONDENCE:
and more than one quarter of the patients        for symptoms that can often be quite dis-                     Jennifer A. Mitty, MD, MPH
experienced adverse effects attributed to        abling. Physicians in Lyme endemic ar-                        The Miriam Hospital
IV ceftriaxone. Another double-blind,            eas can play a central role helping pa-                       164 Summit Avenue
randomized, placebo controlled study,            tients negotiate the controversies and                        Providence, RI 02906
from Finland, demonstrated that an ad-           choose safe and studied treatments.                           phone: (401) 793-4851?
ditional 100 days of oral amoxicillin                                                                          e-mail:
showed no benefit over placebo after             REFERENCES
both groups were treated with 3 weeks            1. CDC. MMWR 2007; 56: 573-6.
                                                 2. Health RID.o. Lyme Disease. 2008 [cited 2008
of IV ceftriaxone.20 Based on the results            January 16];
of these studies, physicians should explore          ease/communicable/lyme/index.php.
other treatment modalities, similar to                               .
                                                 3. Wormser GP et al. Clin Infect Dis 2006; 43:1089-
those used for patients with fibromyalgia,           134.
                                                 4. Harrison TR, Kasper KL, ebrary Inc., Harrison’s
such as increased physical activity, anti-           principles of internal medicine. 2005, McGraw-
depressants and alternative/complimen-               Hill, Medical Pub. Division: New York. p. xxvii,
tary medicine.                                       2754 p.
                                                 5. Cameron D., et al., Expert Rev Anti Infect Ther
CONCLUSION                                           2004. 2(1 Suppl): p. S1-13.
                                                 6. CDC. MMWR 1995;44: 590-1.
      The nature of the spirochete that          7. Engstrom SM., Shoop E, Johnson RC. J Clin
causes Lyme disease has to date prevented            Microbiol 1995; 33: 419-27.
the development of laboratory testing            8. Dressler F, et al. J Infect Dis 1993; 167:392-400.
                                                 9. Aguero-Rosenfeld ME., et al.. Clin Microbiol Rev
that would allow us to accurately moni-              2005; 18(3): 484-509.
tor disease activity. Controversy stems          10. Cameron D. Monitoring Lyme disease in the com-
from differing interpretations of the avail-         munity in 12th Annual International Scientific
able data. Whereas the ILADS guide-                  Conference on Lyme Disease and Other Spiro-
                                                     chetal and Tick-Borne Disorders. 1999.
lines rely primarily on small, clinically        11. CDC. MMWR 2005; 54: 125.
based studies, the IDSA guidelines were          12. Luft BJ, et al. Ann Intern Med 1996; 124:785-
evidence-based, using data from random-              91.
                                                 13. Wormser, GP. Ramanathan R, et al. Ann Intern
ized, controlled, and open-label trials.
                                                     Med 2003;138;697-704.
Given the non-specific symptoms of               14. Klempner MS, et al. NEMJ 2001l 345: 85-92.
many patients, following the ILADS rec-          15. Battaglia, H, et al. J Spirochetal and Tick-Borne
ommendations could lead to a rise in the             Dis 2000;7:22-5.
                                                 16. Fallon B., et al. J Spirochetal and Tick-Borne Dis
misdiagnosis of Lyme disease with a re-              1999; 6:94-102.
sultant overuse of antibiotics. Therefore,       17. Patel R, et al. Clin Infect Dis 2000; 31: 1107-9.
it is important that we educate our pa-          18. Zahran HS, et al. MMWR Surveill Summ 2005;
tients (Table 1) regarding the significant           54:1-35.
                                                 19. Fallon BA, et al. Neurol 2008; 70:992-1003
negative effects of prolonged antibiotics,       20. Oksi, J., et al., Eur J Clin Microbiol Infect Dis 2007;
and the lack of convincing scientific data           26: 571-81.

                                                                                                                       VOLUME 91       NO. 7    JULY 2008

                                              GERIATRICS FOR THE
      Division of Geriatrics
      Department of Medicine
                                            PRACTICING PHYSICIAN                                                               Quality Partners of RI
                                                                                                                          EDITED BY ANA T UYA FULTON, MD

               Dementia Screening: Should We Screen Asymptomatic
                                 Older Adults?
                                                                Ana Tuya Fulton, MD
      A 76-year-old woman comes to your office for her routine                 improvements in cognition as measured by several rating scales
      annual visit. She’s been doing well since you last saw her, has          (Alzheimer’s disease Assessment scale and Clinician’s global rat-
      no complaints, and is in her usual state of health. She has a            ings)3. There was no effect on quality of life scores. A second
      history of hypertension that has been well controlled on hy-             placebo controlled trial, AD2000, showed a small but signifi-
      drochlorothiazide. She attends the local senior center weekly,           cant improvement in cognition (Mini Mental Status Exam score
      participates in Tai Chi every morning and volunteers at the              up by an average of 0.8 points).3 These effects are consistent
      local elementary school on weekdays. You have seen her regu-             with several other studies.3 However, the study did not dem-
      larly and she is up to date with influenza and pneumococcal              onstrate a delay in institutionalization.3 Other studies have
      vaccines, had a normal colonoscopy 4 years ago, and normal               demonstrated delays in the decline of performance of activities
      yearly mammograms, which she has decided to continue as                  daily living. More consistently demonstrated is that cholinest-
      long as she is active and independent. Today, she asks you about         erase inhibitors have a positive effect on the behavioral compli-
      dementia screening, because her best friend was just diagnosed           cations of dementia.
      with Alzheimer’s and is now on donepezil. You ask her tar-                     An additional argument in favor of dementia screening is
      geted questions about her memory, functional status and ask              that there are conditions, albeit rare, that cause dementia but
      whether she or her family have noted any deficits or problems;           are not due to underlying neurodegeneration or stroke. These
      she reports none.                                                        rare situations result from an array of metabolic disorders, CNS
            Dementia is a major cause of morbidity and mortality in            infections, nutritional deficiencies, drug toxicities and even
      the older patient population, as well as in younger, more active         psychiatric conditions. But even if these “reversible dementias”
      adults, who are just beginning their “leisure years”. It is esti-        are rare, the more common circumstance is that the dementia
      mated that about 8% of adults over 65 years old have demen-              due to neurodegeneration or stroke is made worse by the ef-
      tia; for those over 85 years old, the number jumps to 30-40%.1           fects of the superimposed comorbidity.
      This translates to more than 4 million people.1                                The question to the patient then becomes a personal one:
            Dementia care is estimated to exceed $100 billion per year.2       “when would you want to know”? As discussed above, the ar-
      The per person, per year cost for formal health care (long term          gument for screening is colored by the fact that we cannot
      care, medications, acute care and emergency visits) is estimated         alter the outcome, only delay it at best. However, allowing
      at $27,672, and the cost of informal care (caregiver and pri-            patients and families to do advance care and estate planning in
      vate home care) ranges from $10,400 to $34,5172. These fig-              the earlier, more functional stages is often argued as a large
      ures do not include the social costs of a debilitating disease that      benefit of earlier detection. There are people who prefer to
      can ravage a family, and almost always results in permanent              know, regardless of the answer, and who would worry more
      nursing home placement and loss of independence, personal-               about the chance of the disease than the disease itself. But
      ity and the most basic of functional activities. Due to dementia’s       some might be crippled by the knowledge and lose day-to-day
      dramatic impact, many are considering instituting screening              enjoyment and quality of life due to their anxiety about the
      programs. Screening programs would involve asking asymp-                 future. No studies demonstrate psychosocial benefits to patients
      tomatic patients questions about their memory and functional             or their caregivers through earlier detection.4
      status, and performing cognitive assessment tests (e.g, Mini                   A good screening test is evaluated by its sensitivity and
      Mental Status Exam, 7 minute screen, Mini-Cog).                          specificity for the disease or condition. Many of the cognitive
            The discussion of screening is difficult, because the treat-       tests that are routinely used to evaluate for cognitive impair-
      ments we can offer are not curative. The purpose of a screen-            ment have met the desired sensitivity and specificity cut offs.
      ing test is early identification to permit early initiation of therapy   However, a valuable screening test must also have a high posi-
      that will improve outcomes. Data indicate that cholinesterase            tive predictive value4 to be sure that patients are correctly iden-
      inhibitors at best temporarily slow or delay progression of dis-         tified as having the disease. The positive predictive value should
      ease and improve measures of cognition on some scales. Most              be higher than the disease prevalence, a criterion on which
      experts describe a delay in progression of approximately 6 to12          many cognitive tests for dementia fail. In addition, there must
      months with use of cholinesterase inhibitors. Studies of                 follow a discussion of cost-effectiveness. A screening study
      donepezil, for example, have demonstrated mixed results. A               should, thinking pragmatically, not only impact mortality and
      24-week, placebo controlled trial demonstrated significant               morbidity, but also the financial and resource burden on the
health care system. No evidence supports the hypothesis that               Further reading and practice guidelines:
earlier diagnosis will ameliorate costs to our health care system.
In fact, many speculate that early detection will increase costs           American Geriatrics Society Position Statement:
due to increased physician and support staff time, longer du-              h t t p : / / w w w. a m e r i c a n g e r i a t r i c s . o r g / p r o d u c t s /
ration of use of medications (6 month cost of Aricept is almost                   positionpapers/stopscreening.shtml
$1000 5), and longer use of community and health care re-
sources.4 For many of the reasons discussed, the current rec-              American Academy of Neurology Guidelines:
ommendation by the US Preventative Services Task Force is an      ofessionals/practice/pdfs/
“I” recommendation, indicating insufficient evidence to rec-                   dementia_guideline.pdf
ommend for or against dementia screening.6
     “Rationale: The USPSTF found good evidence that some                  USPSTF rationale:
screening tests have good sensitivity but only fair specificity in         http://www.ahrq.go v/clinic/3rduspstf/dementia/
detecting cognitive impairment and dementia. There is fair to                  dementrr.htm
good evidence that several drug therapies have a beneficial ef-
fect on cognitive function (equivalent to delaying the natural        REFERENCES
progression of Alzheimer’s disease from 2 to 7 months), but           1. NIA Alzheimer’s Disease Fact Sheet:
                                                                         lications/adfact.htm. Accessed May 13, 2008.
the evidence of their beneficial effects on instrumental activi-
                                                                      2. Rice DP, Fillit HM, et. al. Prevalence, costs, and treatment of Alzheimer’s
ties of daily living is mixed, with the benefit being small, at          Disease and related dementia. Am J Manag Care 2001; 7: 809-18.
best. There is insufficient evidence to determine whether the         3. Press D, Alexander M. Cholinesterase inhibitors in dementia. In DeKosky ST,
benefits observed in drug trials are generalizable to patients           Schmader KE, Wilterdink J: UpToDate Online 16.1. Updated January 2008.
                                                                         Accessed May 13, 2008.
whose disease would be detected by screening in primary care          4. Brayne C, Fox C, Boustani M. Dementia screening in primary care. JAMA
settings. The accuracy of diagnosis, the feasibility of screening        2007; 298: 2409-11.
and treatment in routine clinical practice, and the potential         5. Drugstore: Accessed May 18, 2008
harms of screening (e.g., labeling effects) are also unknown.         6. Boustani M, Peterson B, et al. Screening for dementia. Systematic evidence
                                                                         review. Accessed May 13, 2008.
The Task Force therefore could not determine whether the
benefits of screening for dementia outweigh the harms. “ http:/
                                                                          Ana Tuya Fulton, MD, is Assistant Professor, Division of
                                                                      Geriatrics, Warren Alpert Medical School of Brown University.
     Using objective criteria to evaluate a screening test, de-
mentia screening does not pass the bar. However, many pro-
                                                                      Disclosure of Financial Interests
fessional organizations recommend screening and early inter-
                                                                           The author has no financial interests to disclose.
vention. As better treatments emerge, a concerted screening
effort will follow. For now, individualized conversations with
patients, discussing the evidence for screening, the likely re-
sults of treatment and the impact on quality of life are the best       THE ANALYSES UPON WHICH THIS PUBLICATION IS BASED were
course of action.                                                       performed under Contract Number 500-02-RI02, funded by
                                                                        the Centers for Medicare & Medicaid Services, an agency of
     What to do with our patient? She has no symptoms of                the U.S. Department of Health and Human Services. The con-
cognitive impairment, and is high functioning and active.               tent of this publication does not necessarily reflect the views
Reassurance with a discussion of the rationale above, and plans         or policies of the Department of Health and Human Services,
to follow closely with screening if she strongly desires, or devel-     nor does mention of trade names, commercial products, or
ops any symptoms or concerns would be a reasonable approach.            organizations imply endorsement by the U.S. Government.
                                                                        The author assumes full responsibility for the accuracy and
                                                                        completeness of the ideas presented.

                                                                                                               VOLUME 91            NO. 7       JULY 2008
                         The Creative Clinican
                                Rituximab In Treating Refractory Thrombotic
                               Thrombocytopenic Purpura: Three Case Reports
                                             Samir Dalia, MD, Brendan McNulty, MD, Gerald A. Colvin, DO
            Thrombotic thrombocytopenic purpura (TTP), previ-               twice daily PE on hospital day five with subsequent improve-
      ously often fatal, today is managed effectively with corticoster-     ment in platelet count. After one week of twice daily PE, her
      oids and plasma exchange (PE); but a subset of patients will          platelet count fell again, and a rituximab course of four weekly
      require further treatment. Though the classic pentad charac-          doses of 375mg/m2 was initiated in addition to a prednisone
      teristic of TTP includes microangiopathic hemolytic anemia,           taper. Her platelet count normalized within a week. On hos-
      thrombocytopenia, neurological deficits, fever, and renal im-         pital day twenty-one she was discharged home following her
      pairment, only one sixth of cases have all these features. 1 Treat-   third dose of rituximab with close follow-up and a weaning
      ment is often initiated based on the findings of microangiopathic     course of PE. After twelve months, she had no signs of relapse
      hemolytic anemia, including significant schistocytes on periph-       without any medications.
      eral blood smear, in combination with thrombocytopenia un-
      explained by disseminated intravascular coagulation or other          CASE 2
      processes.                                                                  A 23 year-old woman with history of hydrocephalus,
            The additional therapy may include immunosuppressive            treated at age 8 with a VP shunt, presented to the emergency
      agents, including vincristine, cyclophosphamide, and                  department with a week of progressive spontaneous bruising,
      cyclosporine, which have been used with variable success.2            dizziness, blurry vision, headache, and intermittent numbness
      Rituximab, a chimeric monoclonal antibody against CD20, a             on the right side of her body. Her roommate noticed a right-
      phosphoprotein that is expressed on the surface of all mature         sided facial droop on the day prior to her admission. On ad-
      B-cells, has increasingly been shown to induce remission in re-       mission, the patient’s physical exam was notable for diffuse trun-
      fractory TTP.2,3 In fact, a retrospective review of TTP cases         cal petechiae with multiple ecchymoses on the legs. Her neu-
      treated with rituximab demonstrated a decrease in the titer of        rologic exam was normal. A CT scan of the head revealed no
      antibodies of ADAMTS13, a metalloproteinase that regulates            acute abnormalities, as did a subsequent MRI. She had an
      the biological breakdown of Von Willebran factor (vWF), a             initial hemoglobin of 9.2 g/dL, a platelet count of 16,000/µL,
      platelet aggregation regulator.4                                      haptoglobin was <5.83 mg/dL and normal renal function.
            We report three cases of refractory TTP in which the early      Coagulation studies and fibrogen level were within normal lim-
      use of rituximab, combined with PE and corticosteroids, led to        its. An assay of ADAMTS13 was <5% with an inhibitor unit
      favorable outcomes.                                                   level of 1.0. Review of the peripheral blood smear revealed
                                                                            multiple schistocytes.
      CASE 1                                                                      Daily PE with prednisone 100mg daily was started, and
           A 28 year-old woman with no significant medical his-             her platelet count rapidly improved along with her symptoms.
      tory presented with a two-week history of worsening, sponta-          She was weaned to every other day PE when her platelet count
      neous bruising of her limbs and left breast. She reported             reached 173,000 on hospital day four. However, her platelet
      malaise and generalized abdominal pain with nausea, but               count decreased again and daily PE was restarted. Her disease
      denied any history of fever, diarrhea, or numbness. She had           became refractory to once daily exchange, and the patient was
      mild diffuse abdominal tenderness, truncal petechiae, and             then transferred to the intensive care unit for twice-daily PE
      ecchymoses on the extremities and left breast. She was alert,         on hospital day nine because of falling platelet counts. By hos-
      oriented and had no neurologic deficits. Imaging of the ab-           pital day fifteen her platelet count response remained poor so
      domen by CT revealed no abnormal findings. Initial labora-            weekly rituximab was initiated with a prednisone taper. Her
      tory studies showed a hemoglobin of 10.5 g/dL, a platelet             platelet count increased to the low normal range within the
      count of 11,000/µL, and normal renal function, PT/PTT,                first week of treatment with rituximab and this trend contin-
      and fibrinogen levels. Hemolysis studies were notable for an          ued after the second dose. She was discharged home for out-
      LDH of 892 IU/L, an undetectable haptoglobin, and an el-              patient PE three times per week, and two further doses of
      evated indirect bilirubin of 1.6. Review of a peripheral blood        weekly rituximab therapy. PE was weaned slowly and after six
      smear revealed numerous schistocytes supporting the diag-             months of follow-up, she remained relapse-free on no medica-
      nosis of TTP. An assay for ADAMTS13 was at <5% (refer-                tions.
      ence range > or = 67%) with a protease inhibitor level >8.0
      inhibitor units.                                                      CASE 3
           The patient was transferred to the medical intensive care             A 25 year-old man with a history of schizophrenia,, hy-
      unit where once daily PE was initiated with prednisone 100mg.         pertension and pancreatitis secondary to hypertriglyceridemia
      Due to suboptimal platelet response the patient was started on        presented initially to an outside hospital with renal failure and
                                                                                                                                                             slight improvement in his renal function
                                                                                      Patie nt 1- Plate le t Count
                                                                                                                                         Rituximab           and on post hospital day six rituximab
                                                        210                                Rituximab                                                         therapy was started for continued renal fail-
                                                                                                                     Rituximab                               ure thought to be from the TTP. After four
                             Platelet Count x 1000/µL

                                                        150                                                                                                  doses of weekly rituximab therapy the
                                                                                                                                                             patient’s creatinine improved to 1.3 mg/dl
                                                                                                                                                             from a high of 5.0 mg/dl with a stable plate-
                                                                                                                                                             let count. He has been disease free for four
                                                                                                                                                             months on no medications.
                                                              1   2   3   4   5   6   7    8    9 10 11 12 13
                                                                                          Hospital C ourse (D ays)
                                                                                                                     14   15   16   17   18   19   20   21   DISCUSSION
                                                                                                                  Treatment of TTP with PE has been
                                                                                                            accepted since PE was compared with
                                        Patie nt 2- Plate le t Count
                                                                                                            plasma infusion for treatment in 1991.5 In
                                                                                  Rituximab                 refractory cases immunosuprpression is of-
                                                                                                            ten utilized based on the rationale that TTP
                             Platelet Count x 1000/µL

                                                                       Rituximab                            may be caused by autoantibodies that in-

         150                                2xdPE
                                                                                                            hibit ADAMTS13 activity. Several differ-
                                                                                                            ent immunosuppressant medications have
                                                                                                            been tried but none seem as promising and
          60                                                                                                safe as rituximab. Rituximab’s efficacy as
          30                                                                                                an adjunct to plasma exchange and corti-
           0                                                                                                costeroids in the treatment of TTP is de-
               1   2   3   4   5    6   7   8    9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
                                                                                                            scribed in multiple case reports.3-4,6-13 One
                                             Hospi tal C ou rse (D ays )
                                                                                                            case study demonstrated the use of
                                             Patie nt 3- Plate le t Count                                   rituximab as a first line treatment in TTP.8
      350                          2xdPE                                                                    Another study demonstrated that prophy-
                                                                                                            laxis with rituximab in patients with previ-
  Platelet Count x 1000/µL

      250                                                                                                   ous TTP was beneficial.3 Unlike other im-
      200                                                                                                   munosuppressants, rituximab is generally
           1xd PE
                                                                      3xW                                   safe and well tolerated though it does have
      100                                                                                                   a common adverse effect of infusion reac-
       50                                                                                                   tions.
                                                                                Discharge                         Our case reports illustrate that early
             1   2   3   4   5   6    7   8   9 10 11 12 13 14 15 16 17 18 19 21 22 25 27 30 60
                                            Hos pital Cours e (Days )
                                                                                                            intervention with rituximab may provide
                                                                                                            rapid improvement of refractory TTP. In
    Figure 1: Platelet Count of Patients while in the hospital. 1xd PE: Once daily plasma                   these cases use of rituximab may have con-
 exchange. 2xd PE: Twice daily plasma exchange, 3xW: Three times a week plasma exchange.                    tributed to a decrease in length of hospital
                                                                                                            stay as well as the associated morbidity and
                                                                                                            mortality of refractory TTP. The benefits
hyperkalemia requiring emergent dialysis. The patient had a of early rituximab therapy in TTP management will need to be
hemoglobin of 9.1 g/dL, platelet count of 8,000/µL and mul- established through a prospective clinical trial. The Transfu-
tiple shistocytes on peripheral smear. He was transferred to our sion Medicine and Hemostatis Clinical Trials Network, spon-
institution for management of TTP. An assay of ADAMTS13, sored by the National Heart, Lung and Blood Institute
drawn during PE therapy, revealed proteases activity level (NHLBI), has initiated a multi-center, randomized clinical trial,
>67%.                                                                                   designed to determine whether rituximab, in addition to stan-
      The patient received twice daily PE with Solu-Medrol dard treatment of PE and corticosteroids, decreases initial treat-
125mg intravenous every 6 hours for one week. The patient ment failure rates as well as subsequent relapses of TTP over
was tapered to once daily PE and the Solu-Medrol was changed three years. Data from this study will establish rituximab’s role
to a prednisone taper. The patient’s hospital course was com- in the first line treatment in TTP.
plicated by an intra-abdominal infection and continued wors-                                 Data are mounting in regard to the efficacy of rituximab
ening of his renal function. The week prior to discharge the in TTP management. In our experience rituximab has pro-
patient was tapered to prednisone 10mg once a day receiving vided considerable benefit for patients with refractory TTP by
thrice weekly PE. On hospital day nineteen the patient had a facilitating the rapid wean of PE and systemic corticosteroid
platelet count of 175,000/µL and was discharged with outpa- therapy. It shows promise for reducing the morbidity and
tient dialysis and thrice weekly PE.                                                    mortality of this dangerous immune-mediated disorder.
      His platelets stayed between 160,000-190,000/µL with

                                                                                                                                                                       VOLUME 91      NO. 7    JULY 2008
      REFERENCES                                                                                 Samir Dalia, MD, is a resident in Internal Medicine, Rhode
      1. Eldor A. Thrombotic thrombocytopenic purpura. Baillieres Clin Haematol            Island Hospital/ Warren Alpert Medical School of Brown Uni-
          1998;11:475-95.                                                                  versity.
      2. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. NEJM
          2006; 354:1927-35.                                                                     Brendan McNulty, MD, is a Clinical Fellow in Hematol-
      3. Fakhorui F, Vernat JP, et al. Efficiency of curative and prophylactic treatment   ogy/Oncology Brown University Hematology/Oncology Fellowship
          with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic pur-            Program.
          pura.. Blood 2005;106:1932-7.
                                                                                                 Gerald A. Colvin, DO, is Associate Professor of Medicine,
      4. Scully M, Cohen H, et al. Remission in acute refractory and relapsing throm-
          botic thrombocytopenic purpura following rituximab. Br J Haematol                Warren Alpert Medical School of Brown University.
      5. Rock GA, Shumak KH, et al. Comparison of plasma exchange with plasma              Disclosure of Financial Interests
          infusion in the treatment of thrombotic thrombocytopenic purpura. NEJM
                                                                                               The authors have no financial interests to disclose.
      6. Millward PM, Bandarenko N, et al. Cardiogenic shock complicates successful
          treatment of refractory thrombotic thrombocytopenia purpura with rituximab.      Discussion of use of off-label or investigational
          Transfusion 2005; 45:1481-6.                                                     product:
      7. Scott SM, Szczepiorkowski ZM. Rituximab for TTP. Am J Hematol
          2005;80:87-8.                                                                        Rituximab
      8. Patino W, Sarode R. Successful repeat therapy with rituximab for relapsed
          thrombotic thrombocytopenic purpura. J Clin Apheresis 2007;22:17-20.
      9. George JN, Woodson RD, et al. Rituximab therapy for thrombotic thromb-
          ocytopenic purpura. J Clin Apheresis 2006;21:49-56.
      10. Chow KV, Carroll R, et al. Anti-CD20 antibody in thrombotic thrombocy-           CORRESPONDENCE:
          topenic purpura refractory to plasma exchange. Intern Med J 2007;37:329-         Samir Dalia, MD
          32.                                                                              Rhode Island Hospital
      11. Basquiera AL, Damonte JC, et al. Long-term remission in a patient with           593 Eddy Street
          refractory thrombotic thrombocytopenic purpura treated with rituximab and
          plasma exchange. Ann Hematol 2007 Set 27 (Epub ahead of print).                  George Building, 3rd floor
      12. Darabi K. Berg AH. Rituximab can be combined with daily plasma ex-               Providence, RI 02903
          change to achieve effective B-cell depletion and clinical improvement in acute   Phone: (401) 444-4000
          autoimmune TTP. Am J Clin Pathol 2006;125:592-7.
      13. Koulova L, Alexandrescu D, et al. Rituximab for the treatment of refractory
          idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocy-
          topenic purpura (TTP). Am J Hematol 2005;78:49-54.


         Estimating the Incidence of New Onset Lyme Disease
                            in Rhode Island
                                                            John P. Fulton, PhD

     Lyme disease (LD), a tick-borne illness caused by the bac-           lance. Between 2002 and 2006 (inclusive), the New Jersey
terium Borrelia burgdorferi, is prevalent along the northeast-            Department of Health (NJDH) mandated electronic report-
ern seaboard of the US and in Wisconsin and Minnesota.1 It is             ing of all positive laboratory tests for LD among New Jersey
reported with much less frequency in other parts of the nation.           residents.6 Compared to the year preceding mandated labora-
(Figures 1 and 2.1,2) According to the Centers for Disease                tory reporting (2001), the average annual number of LD re-
Control and Prevention (CDC):                                             ports quintupled in 2002-2006, creating a significant strain
                                                                          on human resources in local health departments. Nonetheless,
    Typical symptoms include fever, headache, fatigue, and                the results of this natural experiment are quite instructive, and
    a characteristic skin rash called erythema migrans. If left           may be compared—albeit roughly—with Connecticut’s expe-
    untreated, infection can spread to joints, the heart, and             rience. Laboratory reporting increased the average annual in-
    the nervous system. Lyme disease is diagnosed based                   cidence of confirmed LD in New Jersey by 18%, less than
    on symptoms, physical findings (e.g., rash), and the                  Connecticut’s increase (~50%). About 29% of New Jersey’s
    possibility of exposure to infected ticks; laboratory test-           laboratory reports yielded confirmed LD cases, slightly less than
    ing is helpful in the later stages of disease.3                       Connecticut’s yield (36%).4,6 Thus, even though the net yield
                                                                          of confirmed LD cases from laboratory-initiated reports (the
      Because laboratory tests are not definitive for the diagno-         yield over and above physician-initiated reports) was lower in
sis of LD, public health agencies must rely on reports from               New Jersey than Connecticut—18% versus ~50%—the gross
clinicians containing detailed information “on symptoms, physi-           yield was roughly the same—29% versus 36%. Ultimately,
cal findings (e.g., rash), and the possibility of exposure to in-         New Jersey changed its surveillance practices to conserve hu-
fected ticks”3 in order to establish the burden of LD in a de-            man resources. It now follows up only on those laboratory
fined population. Obtaining timely, accurate, and complete                reports that are linked to physician-initiated reports.6
reporting of LD is labor intensive for both clinician reporters                Like its neighbors in the northeastern United States, Rhode
and public health agencies; and the result, to no one’s surprise,         Island has struggled to muster sufficient resources to follow up
has been significant under-reporting of new onset LD. 4-8                 on mandated laboratory reports for LD. In common with vir-
      Connecticut is a case in point, as revealed in the results of       tually all jurisdictions in which LD is prevalent, cases of new
a study undertaken by the Connecticut Department of Public                onset disease are known to be undercounted and under-re-
Health (CDPH) from 1998 through 2002.4 By means of la-                    ported to the CDC. Nonetheless, from 1992-1998, Rhode
bor-intensive investigation during those five years, the CDPH             Island had the second highest state LD incidence rate in the
identified an average of 3755 new onset cases of LD
per year, of which only about half (approximately Figure 1. Number* of newly reported Lyme disease cases by
1830 per year) were identified through “physician county** – United States, 2006
initiated” reporting. The rest of the cases were iden-
tified by following up on every positive laboratory test
for LD reported to the CDPH. Of more than 10,000
positive tests per year reported to the CDPH by man-
date, “only 36% of reports received through required
laboratory surveillance resulted in identification that
met the national surveillance case definition [as de-
fined by the CDC] for LD.” 4 The CDPH could not
sustain this intensity of effort for the long term, and
dropped mandatory laboratory reporting for LD in
2003. The number of cases reported to the CDC
from Connecticut dropped from a high of about
4600 in 2002, the last year of intense case finding, to
an average of about 1500 per year in 2003, 2004,
and 2005.4
      New Jersey provides another documented illus- *N=23,174; county not available for 131 other cases. **One dot placed
tration of the difficulties associated with LD surveil- randomly within the county of patient residence for each reported case.
                                                                                                         VOLUME 91         NO. 7        JULY 2008
      Figure 2. Number of reported cases of Lyme disease by                            LD counts recorded for Rhode Island in previous years
      county – United States, 1982-1998*                                               – 789 cases in 1998, 852 cases in 2002, and 736
                                                                                       cases in 2003.1,2 As well, the estimated Rhode Island
                                                                                       rate of 96 per 100,000 population (computed from
                                                                                       Connecticut’s yield) compares favorably with
                                                                                       Connecticut’s rate for the 1998-2002 period, 109 per
                                                                                       100,000 persons (an average of 3730 confirmed LD
                                                                                       cases per year, with a mid-period population of
                                                                                       3,409,549).4 On the basis of all LD surveillance in-
                                                                                       formation collected to date, it is reasonable to expect
                                                                                       similar LD rates in the two states, with Connecticut
                                                                                       having a marginally higher rate than Rhode Island.
                                                                                            If the high-end estimate for Rhode Island is
                                                                                       roughly correct – 96 LD cases per 100,000 per year
                                                                                       in 2005 (the estimate computed from Connecticut’s
                                                                                       1998-2002 experience) – then at best (e.g., in 2002,
                                                                                       when Rhode Island confirmed 852 cases) Rhode Is-
                                                                                       land has been able to confirm and report about 83%
                                                                                       of LD cases meeting CDC’s case definition.

      *Includes Pennsylvania cases for 1994-1998 and Oregon cases for 1993-1998.       DISCUSSION
                                                                                             Surveillance for LD is costly, because it is neces-
      nation, 44.8 per 100,000 population,2 and by 2004, had sur-             sary to obtain clinical information on signs and symptoms
      passed all other states in new onset cases of LD per capita: 68.39      from clinician’s records, and because so many clinicians are
      per 100,000 population.1                                                involved. In Rhode Island, more than 400 physicians were
           Just how high is the actual LD incidence rate in Rhode             responsible for generating the 2881 LD laboratory reports
      Island? Can it be estimated? It can, because Rhode Island               transmitted to HEALTH in 2005. Connecticut, New Jersey,
      mandates reporting of positive LD laboratory tests, and be-             and Rhode Island all tried to enhance surveillance by man-
      cause two of Rhode Island’s sister states (Connecticut and New          dating LD laboratory reporting, and found it too labor-in-
      Jersey) have evaluated the yield of confirmed LD cases from             tensive to sustain the follow-up necessary to identify LD cases
      positive laboratory reports. It is reasonable to employ the find-       meeting the CDC’s case definition. In the recently published
      ings of Connecticut’s and New Jersey’s LD reporting evalua-             evaluation of its LD surveillance system, New Jersey public
      tions to Rhode Island because the three states share similar geo-       health officials reported that “LD investigations required a
      graphic features and LD history (Figures 1 and 2), and be-              median of 2 months to complete follow-up and classify the
      cause the LD case yields from positive LD laboratory tests were         report… representing approximately 1 hour of active infor-
      roughly similar in Connecticut and New Jersey.4,6                       mation collection per case.” 6 This experience closely paral-
                                                                              lels informal observations of the same activity as undertaken
      METHODS                                                                 in Rhode Island. Applying New Jersey’s “1 hour of active
            Positive LD laboratory reports transmitted to the Rhode Is-       information collection per case” finding to Rhode Island,
      land Department of Health (HEALTH) in 2005 were carefully               835-1037 cases would consume one well-trained, full-time
      evaluated for address (of the patient, or, lacking that, of the or-     employee for the entire year – for just one of many report-
      dering clinician), test (several tests for other tick-borne illnesses   able diseases. Furthermore, because LD activity is much more
      were discovered in this manner and removed), and positivity of          common in the warmer months, it would actually require more
      result. 2881 contained an authentic Rhode Island address and            than one full-time employee to keep pace with clinical prac-
      at least one of several positive test results for LD.                   tice. Keeping pace with receipt of laboratory tests is an im-
            The number of positive test results was multiplied by pro-        portant time-saver for clinicians, especially the many who see
      portions of yield (for confirmed LD) as reported by the States          one or two possible LD cases per year, so that they may re-
      of Connecticut (for the 1998-2002 reporting years) and New              spond to public health requests for case information without
      Jersey (for the 2002-2006 reporting years) to estimate the num-         having to search through old records. Keeping pace also as-
      ber of new onset LD cases meeting the CDC’s case definition,            sures timely reporting of confirmed cases to the CDC. Every
      as used in the 1998-2002 and 2002-2006 periods.                         year, public health agencies have a window of opportunity to
                                                                              report calendar year cases to the CDC. Cases that are con-
      RESULTS                                                                 firmed outside the window are never counted in national sta-
           In 2005, an estimated 835-1037 cases of new onset LD (meet-        tistics. From its evaluation of LD surveillance activities in
      ing CDC’s case definition for that year) occurred in Rhode Island,      2001-2006, New Jersey concluded that 24% of its LD cases
      yielding crude incidence rates of 78-96 per 100,000 population.         were confirmed outside the window of opportunity for re-
           The estimates have good face validity. The number of               porting, and therefore were omitted from statistics published
      estimated cases approximates (or exceeds) the highest annual            by the CDC.6
     The CDC has recently attempted to address the costliness                 Additional information on LD is available on HEALTH’s
of LD surveillance by permitting public health agencies to re-            website. ( /disease/communicable/
port LD cases in several categories:                                      lyme/index.php)

                      Case classification 9                               1. Bacon RM, Kugeler KJ, et al. Lyme disease — United States, 2003—2005.
                                                                             MMWR (Weekly) June 15, 2007 / 56(23);573-6.
   •   Confirmed: a) a case of EM [erythema migrans] with                 2. Orloski KA, Hayes EB, Campbell GL. Surveillance for Lyme disease — United
       a known exposure, or b) a case of EM with laboratory                  States, 1992—1998. MMWR (Surveillance Summaries) April 28, 2000 /
       evidence of infection* and without a known exposure                   49(SS03);1-11.
       or c) a case with at least one late manifestation that             3. Centers for Disease Control and Prevention, Division of Vector-Borne Infec-
       has laboratory evidence of infection.*                                tious Diseases. Lyme Disease.
   •   Probable: any other case of physician-diagnosed
                                                                          4. Cartter ML, Mshar P, Hadler JL. The epidemiology of Lyme disease in Con-
       Lyme disease that has laboratory evidence of infec-                   necticut. Conn Med 1989;53:320-3.
       tion.*                                                             5. Coyle BS, et al. The public health impact of Lyme disease in Maryland. J Infect
   •   Suspected: a) a case of EM where there is no known                    Dis 1996;173:1260-2.
       exposure and no laboratory evidence of infection,* or              6. McHugh LA, Semple S, et al. Effect of electronic laboratory reporting on the
       b) a case with laboratory evidence of infection but no                burden of Lyme disease surveillance — New Jersey, 2001—2006. MMWR
       clinical information available (e.g. a laboratory report).            (Weekly) January 18, 2008 / 57;42-5.
                                                                          7. Meek JI, et al. Underreporting of Lyme disease by Connecticut physicians,
   [Lyme disease reports will not be considered cases if the medi-           1992. J Public Health Management Practice 1996;2:61-5.
                                                                          8. Naleway AL, Belongia EA, et al. Lyme disease incidence in Wisconsin. Am J
   cal provider specifically states this is not a case of Lyme dis-
                                                                             Epidemiol 2002;155:1120-7.
   ease, or the only symptom listed is “tick bite” or “insect bite.”]
                                                                          9. Centers for Disease Control and Prevention, Division of Vector-Borne Infec-
                                                                             tious Diseases. Lyme Disease 2008 Case Definition.
   * For a definition of “laboratory evidence of infection,” please see      disss/nndss/ casedef/lyme_disease_2008.htm
   criteria as established in: Centers for Disease Control and Pre-
   vention. Recommendations for test performance and interpreta-
                                                                              John P. Fulton, PhD, is Chief Health Program Evaluator,
   tion from the Second National Conference on Serologic Diagno-
   sis of Lyme Disease. MMWR (Weekly) 1995; 44:590-1. http://
                                                                          Center for Epidemiology and Infectious Diseases, Rhode Island                         Department of Health, and Clinical Associate Professor of Com-
                                                                          munity Health, The Warren Alpert Medical School of Brown
     Using this convention (the 2008 Case Definition) allows
public health agencies to report all information to CDC with-             Disclosure of Financial Interests
out having to confirm each individual case. This, in turn, will                 The author has no financial interests to disclose.
allow the CDC to estimate the true burden of Lyme disease
incidence, much as Rhode Island has done by applying esti-
mates of LD yield (and other measures) to numbers of positive
LD laboratory reports. Nonetheless, individual clinician re-
porting of LD cases remains the backbone of LD surveillance.
Therefore, health care providers in Rhode Island are strongly
urged to report all new onset LD to the Center for Epidemiol-
ogy and Infectious Diseases on the standard reporting form.
LymeReportForm2005.pdf )

                                                                                                                 VOLUME 91         NO. 7      JULY 2008
                                                                                                            DAVID GIFFORD, MD, MPH, DIRECTOR OF HEALTH
                                                                 RHODE ISLAND DEPARTMENT OF HEALTH                         EDITED BY J OHN P. FULTON, PHD

                              The RI Board of Medical Licensure and Discipline,
                                            2007 Year Summary
               Robert S. Crausman, MD, Mary E. Salerno, MA, Linda Julian, Lauren Dixon, and Bruce McIntyre, JD

      Few professions involve the unique privileges and responsibilities            In 2007 a total of 332 completed applications were pro-
      that medicine and osteopathy require of practitioners in mod-            cessed: 320 MD and 11 DO licenses granted with 1 rejection.
      ern American society. So extraordinary is this role and so nec-
      essary is this commitment, that every state operates a govern-           Complaints and discipline
      mental agency to monitor and enforce the professional con-                     The Board serves as a clearinghouse for written complaints
      duct of physicians. These Boards of Medicine in turn have the            regarding unprofessional conduct. Complaints may come from
      obligation to be open to performance review by the physician             individuals, institutions, public officers, other physicians,
      community and society at large.                                          healthcare professionals or anyone who has contact with medi-
                                                                               cal professionals—including the Board itself. All complaints and
      THE   RHODE ISLAND BOARD            OF   MEDICAL LICENSURE               investigations remain confidential prior to final Board action.1
      AND   DISCIPLINE                                                               The Board reviews all complaints and refers those meriting
            The Board is an agency of state government established, by         further investigation to a three-member subcommittee. The sub-
      law, to protect the public and to assure high practice and profes-       committee—including at least one physician and one layper-
      sional standards in the nearly 4000-member physician commu-              son—investigates and makes a recommendation to the full Board.
      nity.1 The Board discharges these responsibilities primarily through     Written Board decisions include findings of fact and law. A ma-
      the licensing process, receiving and investigating complaints, and       jority of Board members must concur for an individual to be
      serving as a disciplinary body. Chapter 5-37 of the RI General           found guilty of unprofessional conduct. A variety of sanctions
      Laws describes the Board’s composition, the appointment of mem-          may be administered, including: a reprimand; a suspension, limi-
      bers, its mandate, powers and functions. The 12-member Board             tation or restriction to practice medicine; probation subject to
      includes equal appointment of physicians and public members.             conditions and requirements; indefinite revocation of the medi-
      The Governor appoints members with input from the medical or             cal license; mandatory participation in a remedial continuing
      osteopathic societies and the Health Department.                         medical education program; compelled submission to care, coun-
            The Director of the RI Department of Health (HEALTH)               seling or treatment; and assessment of fees to cover the adminis-
      serves as Chair. The Board’s Physician Chief Administrator and           trative costs of proceedings. Appeals receive judicial review by
      Legal Counsel serve in vital support roles.                              the RI Superior Court. In cases of egregious misconduct consti-
                                                                               tuting an immediate danger to the public, the Director of Health
      BOARD ACTIVITIES                                                         may immediately suspend the individual’s license.
      Licensing                                                                      The law speaks in terms of negative examples, i.e. behav-
           A license to practice medicine in the State of Rhode Is-            iors or activities that constitute “unprofessional conduct.” Ex-
      land is considered a privilege, not a right. The essential require-      amples include: conviction of a crime arising from the practice
      ments include: graduation from a school of medicine, success-            of medicine; patient abandonment; medical practice while
      ful completion of no less then two years of postgraduate train-          under the influence of alcohol or illicit drugs; volitional falsifi-
      ing or three years of postgraduate training for ECFMG (Edu-              cation or misrepresentation of medical reports records or treat-
      cation Commission for Foreign Medical Graduates) certified               ments; fee splitting; willful overcharging for professional ser-
      international graduates, successful completion of the USMLE              vices; deceptive billing practices or collection of fees for ser-
      licensing examination (no greater than 3 attempts per section,           vices not rendered; malpractice or incompetence; negligent or
      all complete in 7 years), evidence of a high moral and ethical           willful misconduct in the practice of medicine; sexual contact
      standard and payment of the application fee. The Board en-               in the context of a physician/patient relationship; and failure
      deavors to render a decision on a complete license application           to comply with requests from the Board or its agents.1-4
      within 30-90 days.                                                             The national advocacy group Public Citizen ranks State
           In 2006 the Board adopted electronic licensing renewal.             Medical Boards according to the number of sanctions made
      In 2008 the Board plans to adopt web-based licensing with a              per 1000 licensed physicians. For years 2004-2006, RI ranked
      common application recognized by other states and linked with            38 out of 51 jurisdictions with a serious action rate of 2.75.
      nationally accepted credentials verification via FCVS (Federa-           The range for jurisdictions was Alaska at 7.30 through Missis-
      tion Credentials Verification Service), testing, USMLE and               sippi at 1.41. [
      ECFMG certification to further speed processing.                         release.cfm?ID=7525]
           In 2007 the State legislature increased the licensing fee struc-          In 2007, 279 new complaints were received and reviewed;
      ture to: $570 for initial license, $650 for the two-year renewal,        182 were opened for investigation; 126 investigations were
      and $140 for the RI controlled substances registration.                  closed, with an average time-to-close of 117 days.
     In 2007 the Board issued 23 public orders regarding phy-         - A physician involved with the Physician’s Health Com-
sicians. Six orders related to medical negligence, 4 to drugs or        mittee received a reprimand for willfully making a false
alcohol, 3 to reciprocal actions recognizing unprofessional con-        report when applying for hospital privileges.
duct findings in another State on a RI licensed physician, 2 to
                                                                      - A physician received a reprimand and was placed on pro-
medical/psychiatric illness rendering a physician unable to prac-
                                                                        bation for prescribing a medication for one family mem-
tice safely, 2 to Boundary violations (e.g. inappropriate rela-
                                                                        ber using the insurance member identification number
tionship with a patient or key third party), 3 to crime in the
                                                                        of another. No physician-patient relationship existed.
practice of medicine, 3 to falsification of records, 2 to inappro-
priate prescribing – 1 via the internet, and 1 to facilitating the    - A physician received a reprimand and was directed to
medical practice of an unlicensed physician.*                           complete an ethics program for facilitating the unlicensed
     Below are short summaries. These orders are public docu-           practice of another physician who had previously had his
ments. []        license revoked by the Board.
 - Two physicians were relicensed on probation and required           - Three physicians were issued reciprocal actions to reflect
   to comply with a treatment and monitoring program.                   sanctions and findings of unprofessional conduct by other
   They are each required to have a chaperone present for               State medical boards for their practice outside of RI.
   all examinations of female patients.
                                                                      - An immediate compliance order was issued to a physician to
 - A physician voluntarily surrendered his medical license              prohibit the prescription of sublingual midazolam as treatment
   while under investigation for inappropriately purchasing             for agitation in unmonitored nursing home patients. This was
   approximately 50,000 Vicodin tablets, not for patient use.           not associated with any sanction against the physician.
 - A physician voluntarily surrendered his license while un-          - An immediate compliance order was issued to a physi-
   der investigation by the RI Attorney General.                        cian to discontinue the operation of an illegal physician
                                                                        operatory. The physician was subsequently sanctioned
 - A physician voluntarily surrendered his medical license
                                                                        with a 3-month suspension and reinstated on probation.
   owing to medical illness. It was found that his continued
   practice posed a significant risk to his patients.**
                                                                     * Total greater than the 23 orders issued due to several re-
 - A physician voluntarily surrendered his license due to               lating to multiple categories
   health-related problems. He was subsequently reinstated           ** N.B. physicians are not generally required to surrender
   with a 5-year treatment and monitoring contract with                 their medical license upon retirement or infirmity. Un-
   the Physician’s Health Committee.                                    fortunately the nature of some illness occasionally forces
                                                                        the Board to intervene with a public order for the pro-
 - A physician previously suspended by the Director of
                                                                        tection of both the physician and the public.
   Health for failing to comply with a Board Consent Or-
   der settled the outstanding case with a revocation retro-
                                                                     Policy Statements
   active to 1998. Of note, a physician who has been re-
                                                                          The Board is empowered by statute to identify the Standard
   voked may reapply after 5 years.
                                                                     of Care in the practice of medicine. In the course of case investiga-
 - A physician previously revoked by the State of Massa-             tion the Board occasionally finds areas of practice where there is a
   chusetts, who had also been imprisoned for crimes re-             perceived need for clear articulation of the Standard. The Board
   lated to healthcare fraud, was suspended for one year by          issues ‘policy statements’ to disseminate this standard. Statements
   order of a hearing committee for moral unfitness, inap-           are on the web [
   propriate prescribing, making false statements to the             positions.php]. RI licensed physicians are expected to review these
   Board, and falsification of a medical record.                     statements at least biannually with their license renewal.
 - A physician first voluntarily consented to cease all surgical          In 2007 the Board articulated 3 new statements.
   cases while under investigation for his role in a wrong-site
                                                                     12/12/2007 - Physician or Advanced Practice Clinician Pa-
   surgery. He subsequently consented to a retroactive sus-
                                                                        tient Visits in a Hospital Setting – In general, when caring
   pension of surgical privileges to the date of the initial order
                                                                        for inpatients in an acute general medicine/surgical hospi-
   and was allowed to resume full and unrestricted practice.
                                                                        tal, at least daily visits by either the attending physician, his/
 - A physician was placed on probation for three years and              her physician cross-coverage, or advanced practice clinician
   required to undergo a skills and competency assessment               should occur and be documented in the medical record.
   in his area of specialty surgery. He was required to dis-
                                                                     12/12/2007 - The Physician/Patient Relationship – “It is
   continue all surgery in the interim. Conditions were
                                                                        inappropriate to prescribe medications via the Internet or
   placed upon his supervision of physician assistants and
                                                                        similar venue without an appropriate physician/patient re-
   nurse practitioners.
                                                                        lationship that would typically include: 1) patient history,
 - A physician with undergraduate training as a pharmacist              2) physical and/or mental health assessment, 3) legitimate
   received a reprimand for approving prescriptions for an              records kept, 4) licensed and trained practitioners, 5) ele-
   Internet pharmacy.
                                                                                                       VOLUME 91       NO. 7    JULY 2008
         ments of informed consent wherever appropriate and rea-          REFERENCES
         sonable, and 6) AMA/AOA code of ethics followed.”                1. Crausman RS. Protecting the public and assuring high practice and profes-
                                                                             sional standards in the physician community. Med Health RI 2003:279-81
      12/12/2007 - Physician Self-Treatment or Treatment of               2. Crausman RS, Savoretti A, Conroy J. Disruptive physician behaviors. Med
         Immediate Family MembersThe Board endorses the                      Health RI 2007:48-9
                                                                          3. Crausman RS. Sexual boundary violations in the physician-patient relation-
         AMA Statement E-8.19 [                 ship. Med Health RI 2004:255-6
         pub/category/8510.html]. Specifically, the Board em-             4. Crausman RS, Baruch JM. Abandonment in the physician-patient relation-
         phasizes that, “Except in emergencies, it is not appropri-          ship. Med Health RI 2004:154-6
         ate for physicians to write prescriptions for controlled sub-    5. RI BMLD website
         stances for themselves or immediate family members.”
                                                                               Robert S. Crausman, MD, is Chief Administrative Officer,
      CONCLUSION                                                          RI Board of Medical Licensure and Discipline, Interim Direc-
            The Board of Medical Licensure and Discipline contin-         tor, Center for Epidemiology and Infectious Disease, and Associ-
      ues to protect the high standards of professionalism and ethics     ate Professor of Medicine, Warren Alpert Medical School of Brown
      that characterize medical practice, to safeguard the public wel-    University.
      fare, to provide an efficient yet thorough licensing process, and        Mary E. Salerno, MA, is Associate Administrator, RI Board
      to provide balanced review and investigation of complaints.         of Medical Licensure and Discipline.
      The challenges associated with new technologies, telemedicine,           Linda Julian is a Complaint Investigator, RI Department of
      emergency preparedness and an increasingly international            Health.
      physician workforce have fostered improved collaboration                 Lauren Dixon is a Medical License Coordinator, RI De-
      across State jurisdictions and led to recognition that there are    partment of Health.
      national standards for practice and licensure. The Board’s role          Bruce McIntyre, JD, is Deputy Legal Counsel, Rhode Island
      in patient safety continues to evolve.                              Department of Health.

                                                                          Disclosure of Financial Interests
                                                                               The authors have no financial interests to disclose.

                                                                          Robert S. Crausman, MD, MMS
                                                                          RI Board of Medical Licensure and Discipline
                                                                          3 Capitol Hill, Room 205
                                                                          Providence, RI 02908
                                                                          Phone: (401) 222-7888

                          Physician’s Lexicon
                                                    The Eight Little Wrist Bones
In an era where gene deletions, neu-                    Capitate: From the Latin, capitatus,               “Open Sesame !” unlocks the cave hold-
rotransmitters and folding proteins domi-          meaning headlike in shape; cognate                      ing the treasures of the forty thieves.
nate the content of newer medical text-            words include capitation, decapitation,                      Trapezium: From the Latin mean-
books, the study of the morphology of              capital and Capitol [originally, Jupiter’s              ing a four-sided plane figure with no two
the eight wrist bones seems at best ar-            Temple in Rome.]                                        sides parallel. Earlier from a Greek word,
chaic. Since wiser heads have fashioned                 Hamate: From the Latin, hamatus,                   trapezion, meaning a table with four legs.
the curricula of yesteryear, perhaps this          meaning hook-shaped.                                    Cognate words include trapeze and the
exercise in memorization, if nothing else,              Pisiform: From the Latin, pisum,                   voluntary muscle, trapezius.
taught us something about patience, for-           meaning pea-like.                                            Trapezoid: Shaped like a trapezium.
bearance and discipline.                                Scaphoid: From the Greek, scaphos,                      Tr iquetrum: From the Latin,
     Yes, there were eight of them; and            meaning boat-like [an older term for a                  triquestris, meaning having three corners
other than some orthopedic surgeons per-           submarine is a bathyscaphe]; and from                   or angles.
forming hand repair and a cadre of                 an older Greek term, scaphoi, meaning                        The other bones of the hand and
rheumatologists, it is unlikely that many          shaped like a shovel [which led to the                  wrist employ such terms as phalanx [From
physicians remember their names, con-              anatomic name, scapula and the name of                  the Greek, meaning a trunk or log; and
tours or juxtapositions let alone evolution.       a short cloak, scapulary.]                              the Latin describing an infantry unit];
Nor is it likely that these eight names will            Sesamoid: Shaped like a sesame seed.               and metacarpal [meta- from the Greek
arise in casual conversation except, per-          Derived from the Aramaic, shimshim.                     meaning after or beyond or above; and
haps, in recounting the details of a night-        Why a street has also been named Sesame                 carpus, meaning wrist.]
mare. In no order other than alphabetic,           is unclear, but perhaps related to the Ali
these eight carpal bones are:                      Baba tale wherein the secret message,                                  – STANLEY M. ARONSON, MD

               DAVID G IFFORD, MD, MPH
                                                                                           V I TA L S TAT I S T I C S
               DIRECTOR OF HEALTH                                                                    EDITED BY COLLEEN FONTANA, STATE REGISTRAR

                                                       Underlying                                              Reporting Period
 Rhode Island Monthly                                Cause of Death                             July
                                                                                                                 12 Months Ending with July 2007
 Vital Statistics Report                                                                    Number (a)     Number (a)             Rates (b)           YPLL (c)
Provisional Occurrence                                  Diseases of the Heart                        216          2,768                258.8          3,764.0
                                                       Malignant Neoplasms                           213          2,279                213.0          5,792.5
     Data from the                                 Cerebrovascular Diseases                           25            388                 36.3            619.5
Division of Vital Records                           Injuries (Accidents/Suicide/Homicde)              48            559                 52.3          9,015.5
                                                                                COPD                  31            436                 40.8            375.0

                                                         Reporting Period                                  (a) Cause of death statistics were derived from

     Vital Events                                                                                          the underlying cause of death reported by
                                          January                 12 Months Ending with                    physicians on death certificates.
                                           2008                       January 2008
                                                                                                           (b) Rates per 100,000 estimated population of
                                           Number                  Number                   Rates
                       Live Births             1,112               13,219                   12.4*
                           Deaths                870                9,880                    9.3*          (c) Years of Potential Life Lost (YPLL)
                   Infant Deaths                  (2)                 (96)                   7.3 #
                 Neonatal Deaths                  (1)                 (76)                   5.7 #         Note: Totals represent vital events which occurred in Rhode
                   Marriages                     200                6,771                    6.3*          Island for the reporting periods listed above. Monthly pro-
                    Divorces                     265                2,966                    2.8*          visional totals should be analyzed with caution because the
                                                                                                           numbers may be small and subject to seasonal variation.
        Induced Terminations                     458                5,087                  384.8 #
    Spontaneous Fetal Deaths                       39                 920                   69.6 #         * Rates per 1,000 estimated population
      Under 20 weeks gestation                   (35)               (842)                   63.7 #         # Rates per 1,000 live births

          20+ weeks gestation                     (4)                 (78)                   5.9 #
                                                                                                                       VOLUME 91           NO. 7       JULY 2008
                                 The Official Organ of the Rhode Island Medical Society
                           Issued Monthly under the direction of the Publications Committee
            VOLUME 1                                                                     PER YEAR $2.00
            NUMBER 1      PROVIDENCE, R.I., JANUARY, 1917                        SINGLE COPY, 25 CENTS

      NINETY YEARS AGO, JULY 1918                                                   ground radiation compared to which radioactive fallout is of
           John Champlin, MD, in the President’s Annual Address,                    very minor significance.”
      briefly discussed Society business, then turned “to the consid-                    The Honorable John D. Pastore, in “The Atom – Its Ulti-
      eration of patriotic and medical questions concerning the war.”               mate Promise,” reflected: “We know that all power God shares
      The usual agenda was not appropriate, “when we have been                      with man is power for good. We know that the power and the
      participants in the most destructive war the world has ever                   promise of the atom is – peace.”
      known, when our country is calling for more and still more                         Johannes Virks, MD, and Baruth B. Motola, MD, in
      medical men for its service.” In 1918 the Medical Society had                 “Megimide and Daptazole in Treatment of Barbituate Poison-
      460 members (dues: $10.00); the total number of physicians                    ing,” reviewed 4 cases: all recovered, with no serious side ef-
      in Rhode Island came to 751; 18.2% of physicians in the state                 fects from the treatment.
      accepted military commissions.
           W. Louis Chapman, MD, in “Roentgen Method of Gas-                        TWENTY-FIVE YEARS AGO, JULY 1983
      trointestinal Investigation,” cautioned that patients’ histories                   Thomas C. McOsker, in “Subdural Hematomas in Sub-
      were often unreliable: “The patient’s story should be elicited                teens,” declared: “A subteen child with mild to moderate
      with as little coaching as possible. It should be verified by ques-           trauma to the head is unlikely to develop a subdural collec-
      tions on succeeding days and will often be found to change                    tion.” He drew his conclusion from chart review of 64 cases of
      with surprising frequency.” The Roentgen examination was                      children, aged up to 12, admitted with intracranial bleeding
      essential to understanding the patient’s complaint. He suggested              at Rhode Island Hospital, 1973-82. For 47 cases, the cause
      clinicians begin investigating gastrointestinal concerns with                 was not trauma. One 11 year-old child, an “exceptional case,”
      mouth x-rays: “The first step ought to be a study of the mouth,               had struck his head on frozen ground, but not lost conscious-
      and in any case that is at all obscure this should be an x-ray                ness. For five weeks he had no symptoms, then he developed
      study…if one takes a set of x-rays of the teeth in…cases of ar-               headaches, which was attributed to migraines (his family had
      thritis and gastric ulcer the results may be surprising.” He                  had migraines). A CT scan, though, showed a “large left fronto-
      judged subjective symptoms “misleading.”                                      temporal mass which proved at craniotomy to be hygroma.”
           An Editorial, “The Surgeon General of the Army,” praised                 After the operation, the CT scan still showed subdural collec-
      General Gorgas, who was nearing retirement age. “No one re-                   tion, but it finally was reabsorbed.
      alizes that he is old, for in reality he is young in body as well as               Duane Golomb, MD, in “Attitudes toward Pelvic Exami-
      in mind.” The Editorial urged physicians “as a patriotic mea-                 nations in Two Primary Care Settings,” found that the exams
      sure” to lobby the President, their Congressional representa-                 “…are tolerated, but not with enthusiasm.”
      tives, and their state legislators to urge the reappointment of                    Joseph Chazan, MD, contributed a Commentary: “Insti-
      General Gorgas.                                                               tutional Prerogatives and the Private Practicing Physician: A
                                                                                    Changing Partnership or the Development of Adversarial
      FIFTY YEARS AGO, JULY 1958                                                    Roles?”
            Shields Warren, MD, Professor of Pathology, Harvard                          Norman A. Baxter, PhD, Executive Director, RI Medical
      Medical School, delivered the 17th Charles Value Chapin Ora-                  Society, in Special Report: “The RIMS Federation: A Neces-
      tion: “The Prevention of Somatic and Genetic Radiation In-                    sary Step Forward,” explained the decision of the Medical So-
      jury.” He stressed the persistence of radiation in normal life.               ciety (a 501c6 organization) to create a separate 501c3 organi-
      Providence had 4.5r per generation “at least since the days of                zation focused on education.
      the Narragansett Indians. Radioactive fallout to date is adding
      about 1/40 of that amount. The amount added by industrial
      utilization of atomic energy…is at present insignificant, and
      appears likely to be adequately controlled.” As for why deaths
      from radiation still occurred, he cited “ignorance.” For instance,
      he cited a professor who carried in his vest pocket a piece of
      radium. As for bomb testing, he reassured readers: “…radio-
      active fallout at the present time is not likely to cause harm
      from continued bomb testing, because it is less significant than
      the changes in background radiation that are produced from
      changes in altitude alone. Thus the move from Providence to
      Denver involves the receipt of an increased amount of back-


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