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Chronic Neurologic Manifestations of Lyme Disease
Eric L. Logigian, M.D., Richard F. Kaplan, Ph.D., and Allen C. Steere,
M.D.
N Engl J Med 1990; 323:1438-1444November 22, 1990
Abstract
Article
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Abstract
Background and Methods.
Lyme disease, caused by the tick-borne spirochete Borrelia
burgdorferi, is associated with a wide variety of neurologic
manifestations. To define further the chronic neurologic abnormalities
of Lyme disease, we studied 27 patients (age range, 25 to 72 years)
with previous signs of Lyme disease, current evidence of immunity to
B. burgdorferi, and chronic neurologic symptoms with no other
identifiable cause. Eight of the patients had been followed
prospectively for 8 to 12 years after the onset of infection.
Full Text of Background and Methods....
Results.
Of the 27 patients, 24 (89 percent) had a mild encephalopathy that
began 1 month to 14 years after the onset of the disease and was
characterized by memory loss, mood changes, or sleep disturbance. Of
the 24 patients, 14 had memory impairment on neuropsychological tests,
and 18 had increased cerebrospinal fluid protein levels, evidence of
intrathecal production of antibody to B. burgdorferi, or both.
Nineteen of the 27 patients (70 percent) had polyneuropathy with
radicular pain or distal paresthesias; all but two of these patients
also had encephalopathy. In 16 patients electrophysiologic testing
showed an axonal polyneuropathy. One patient had leukoencephalitis
with asymmetric spastic diplegia, periventricular white-matter
lesions, and intrathecal production of antibody to B. burgdorferi.
Among the 27 patients, associated symptoms included fatigue (74
percent), headache (48 percent), arthritis (37 percent), and hearing
loss (15 percent). At the time of examination, chronic neurologic
abnormalities had been present from 3 months to 14 years, usually with
little progression. Six months after a two-week course of intravenous
ceftriaxone (2 g daily), 17 patients (63 percent) had improvement, 6
(22 percent) had improvement but then relapsed, and 4 (15 percent) had
no change in their condition.
Full Text of Results....
Conclusions.
Months to years after the initial infection with B. burgdorferi,
patients with Lyme disease may have chronic encephalopathy,
polyneuropathy, or less commonly, leukoencephalitis. These chronic
neurologic abnormalities usually improve with antibiotic therapy. (N
Engl J Med 1990; 323:1438–44.)
Full Text of Conclusions....
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68 articles have cited this article
LYME disease, which is caused by the tick-borne spirochete Borrelia
burgdorferi, is associated with a wide variety of neurologic
abnormalities.1 2 3 4 5 6 7 Early in the illness, many patients have
episodes of headache and mild meningism.8 Within several weeks, about
15 percent have objective neurologic abnormalities, most commonly
lymphocytic meningitis, motor or sensory radiculoneuritis, or cranial
neuropathy, particularly facial palsy.2 , 3 A similar syndrome of
meningoradiculitis occurs in Europe.4 , 9 , 10 These early neurologic
abnormalities can be cured with antibiotic therapy,11 , 12 and even if
untreated, they usually resolve within months.4
Chronic neurologic involvement, affecting either the central or
peripheral nervous system, may also occur in Lyme borreliosis. In
Germany, Ackermann et al. described 44 patients with progressive
borrelial encephalomyelitis, a severe neurologic disorder
characterized by spastic paraparesis or tetraparesis, ataxia,
cognitive impairment, bladder dysfunction, and cranial neuropathy,
particularly deficits of the seventh or eighth cranial nerve.5 In all
cases, the diagnosis was proved by the demonstration of intrathecal
production of IgG antibody to B. burgdorferi. In addition,
acrodermatitis chronica atrophicans, a late skin manifestation of Lyme
borreliosis reported primarily in Europe, has been associated with a
sensory polyneuropathy13 , 14 and with mental disturbances.15
In the United States, Halperin et al. described two chronic neurologic
syndromes associated with Lyme disease: one involved the peripheral
nervous system and was characterized by paresthesias and
electrophysiologic evidence of axonal polyneuropathy,6 and the other
involved the central nervous system and was manifested by
encephalopathy with memory impairment.7 The patients with central
nervous system involvement usually had intrathecal production of
antibodies to the spirochete, but those with abnormalities of the
peripheral nervous system did not. A few patients have been described
with other neurologic abnormalities thought to be due to Lyme disease,
including encephalitis,16 17 18 dementia,18 , 19 psychiatric syndromes,
17 possible demyelinating disease,17 , 19 stroke,20 , 21 brain-stem
abnormalities,17 and extrapyramidal syndromes.22 In some instances,
however, the evidence linking these syndromes to infection with B.
burgdorferi was incomplete.
The goal of the current study was to define further the chronic
neurologic abnormalities of Lyme disease. We describe the clinical
courses, diagnostic studies, and treatment responses of 27 patients in
whom chronic neurologic syndromes developed months to years after the
onset of Lyme disease.
Methods
Neurologic Evaluation
From October 1987 through December 1989, we evaluated a total of 37
patients with chronic neurologic symptoms following well-recognized
manifestations of Lyme disease. Eight of them had been entered
previously into clinical studies of Lyme disease and had been followed
prospectively for 8 to 12 years after the onset of infection. The 37
patients had detailed neurologic evaluations, including lumbar
puncture, neuropsychological testing, electrophysiologic studies, and
magnetic resonance imaging of the head. The antibody responses to B.
burgdorferi in serum were determined by indirect enzyme-linked
immunosorbent assay23 and in serum and cerebrospinal fluid samples
obtained simultaneously, by capture enzyme immunoassay.24 If the
patient was seronegative according to these methods, the serum was
further tested by immunoblotting,25 and peripheral-blood mononuclear
cells were tested for reactivity with borrelial antigens by
proliferative assay.26
Neuropsychological tests were selected to provide measures of
immediate and delayed memory, conceptualization, copying, perceptual
discrimination, and language. These tests included the Wechsler Memory
Scales, California Verbal Learning Test, Wisconsin Card-Sorting Test,
Trailmaking Test, Rey—Osterrieth Complex Figure Test, Finger-Tapping
Test, Benton Face-Discrimination Test, Hooper Visual Organization
Test, Boston Naming Test, Token Test, and Oral Word-Association Test.
In addition, intelligence quotient was estimated with either the
Wechsler Adult Intelligence Scale—Revised or the Shipley Hartford
Institute of Living Scale. Finally, symptoms of concurrent
psychopathology, such as depression, were assessed by the Minnesota
Multiphasic Personality Inventory. The test scores were transformed
into standard scores that were calculated from published, age-
corrected normative data. According to a previously described system,
27 evidence of memory impairment was defined as scores that were 2 SD
below the normative mean on any one of the three tests of memory
(Wechsler Memory Scales, California Verbal Learning Test, or Rey—
Osterrieth Complex Figure Test) or more than 1 SD below the mean on
two of the tests. A score of 70 or above on the Minnesota Multiphasic
Personality Inventory was considered indicative of depression.
A detailed electromyographic examination of limb and paraspinal
muscles was performed with concentric needle electrodes. Motor-nerve
and sensory-nerve conduction studies of the median, ulnar, peroneal,
and tibial nerves were performed with 10-mm surface recording and
stimulating electrodes. For magnetic resonance imaging of the brain,
T1-weighted sagittal and axial images were obtained on a 1.0-tesla
Siemens Magnetom with a repetition time to echo time of 650/20 msec,
and T2-weighted axial images were obtained with a repetition time to
echo time of 3000/45 and 90 msec.
Criteria for Case Inclusion
Of the 37 patients, 5 who had memory difficulties, depression, or
headache after erythema migrans were excluded because they had normal
neurologic tests, negative or indeterminate antibody responses to B.
burgdorferi, and no reactivity of mononuclear cells to borrelial
antigens. Five additional patients who had dementia, demyelinating
disease, or headache were excluded because Alzheimer's disease,
multiple sclerosis, or brain tumor was the likely diagnosis. Four of
these five patients still had antibody responses to B. burgdorferi. We
believe that the remaining 27 patients had neurologic abnormalities
caused by infection with B. burgdorferi. All 27 had previously had
signs of Lyme disease, had neurologic symptoms lasting at least three
months that could not be attributed to another cause, and had current
evidence of humoral or cellular immunity to B. burgdorferi, as shown
by an elevated serum IgG or IgM antibody titer of at least 1:400,23
five or more IgG antibody bands to spirochetal polypeptides,25 or a
stimulation index of 10 or more in response to borrelial antigens.26
Treatment Regimen and Follow-up Examinations
The patients were treated with 2 g of ceftriaxone intravenously once a
day for 14 days. Complete blood counts and liver-function tests were
done on days 0, 7, and 14 to monitor the effect of therapy. Follow-up
examinations were performed three and six months later. Serologic
testing for B. burgdorferi was repeated at each follow-up visit, and
all samples were tested again on a single plate to assess the change
in titer. If possible, neurologic tests whose results had been
abnormal in the initial examination were repeated at the six-month
follow-up examination.
Results
Course of Lyme Disease
Of the 27 patients with chronic neurologic abnormalities due to Lyme
disease, 23 (85 percent) had erythema migrans at the beginning of the
illness and 2 others (7 percent) had an influenza-like illness without
rash during the summer, days to weeks before the onset of early
neurologic involvement (Table 1Table 1Course of Lyme Disease in the 27
Study Patients.*). The two patients who did not have symptoms of early
infection did have arthritis followed by neurologic abnormalities. In
11 patients (41 percent), early symptoms included severe headache,
mild neck stiffness, or spinal pain. Eight patients (30 percent) had
early neurologic abnormalities consisting of facial palsy, sometimes
with meningitis or thoracic radiculoneuritis, a median of one month
after the onset of erythema migrans. These abnormalities resolved
within one to two months except in one patient, who had mild residual
facial weakness and a unilateral hearing impairment. A median of six
months after the onset of disease, 19 patients (70 percent) began to
have brief episodes of arthritis affecting primarily the knees.
Arthritis occurred in all these patients before the chronic neurologic
symptoms developed, and it was still present in 10 patients (37
percent) when the chronic neurologic abnormalities were noted.
Symptoms of chronic involvement of the peripheral nervous system
developed a median of 16 months after the onset of infection, whereas
symptoms of central nervous system involvement usually began later, a
median of 26 months after the onset of disease (Table 1). At the far
end of the spectrum, these abnormalities began 10 or more years after
the onset of disease, after long periods of latent infection (Fig.
1Figure 1Interval between the Onset of Lyme Disease and the Occurrence
of Encephalopathy, Polyneuropathy, or Leukoencephalitis and the
Duration of These Complications in the 25 Patients in Whom the Onset
of Infection Could Be Determined.). At the time of the current
evaluation, chronic neurologic involvement had usually been present
for more than 1 year, and in several patients for 10 or more years.
Fifteen of the 27 patients (56 percent) had already been treated with
one or more courses of antibiotic therapy before this evaluation; in
six cases, they had received two-week courses of intravenous
penicillin or ceftriaxone.
Chronic Neurologic Abnormalities
Seventeen of the patients (63 percent) had abnormalities of both the
central and peripheral nervous systems manifested as subacute
encephalopathy and axonal polyneuropathy, seven patients (26 percent)
had encephalopathy alone, two (7 percent) had polyneuropathy alone,
and the remaining patient (4 percent) had leukoencephalitis.
Subacute Encephalopathy
Of the 27 patients, 24 had a mild encephalopathy. Twenty-two of them
had difficulty remembering things (Table 2Table 2Signs and Symptoms of
Chronic Neurologic Abnormalities.). They forgot names, missed
appointments, or misplaced objects. To compensate, they often made
daily lists. Ten patients had symptoms of depression, and three of
them sought psychiatric help or received antidepressant medication.
Eight patients had excessive daytime sleepiness, and seven had extreme
irritability. They became angry over circumstances that previously
caused only minor annoyance. Finally, five patients had subtle
symptoms of a language disturbance, with difficulty finding words. No
one had seizures, myoclonus, or a change in the level of
consciousness. Although most patients were able to remain employed,
three quit their jobs, three decreased their work hours to part-time,
and two retired early.
All 24 patients had at least 12 years of education; they had
intelligence quotients that were average or above, and none had a
history of neuropsychological impairment. Of the 22 patients with
symptoms of memory loss, 12 had evidence of memory impairment on
neuropsychological tests, and the 2 with encephalopathy who did not
notice any memory changes also had evidence of such impairment on
these tests (Table 3Table 3Results of Neurologic Tests in 27 Patients
with Chronic Neurologic Abnormalities.). In only six patients was
memory dysfunction marked enough to be apparent on neurologic
evaluation at the bedside. On the Minnesota Multiphasic Personality
Inventory, 9 of the 10 patients with symptoms of depression had scores
indicative of depression. Only two patients scored 1 SD below the mean
on any other neuropsychological test.
Of the 24 patients with encephalopathy, 21 had elevated serum IgG
antibody responses to B. burgdorferi (Fig. 2Figure 2Pretreatment and
Follow-up Serum IgG Antibody Responses to B. burgdorferi,
Cerebrospinal Fluid (CSF):Serum Ratios of IgG Antibody to the
Spirochete, and Cerebrospinal Fluid Protein Concentrations in the 27
Patients with Encephalopathy (●), Polyneuropathy Alone (○), or
Leukoencephalitis ().). Of the remaining three patients, all of whom
received antibiotic therapy for erythema migrans, one had only an IgM
response (1:3200) to the spirochete; one had an IgG response in the
indeterminate range (1:200), but the immunoblot showed antibody to six
spirochetal polypeptides; and one had only a cellular immune response
to borrelial antigens (stimulation index, 28). On analysis of the
cerebrospinal fluid, 11 patients (46 percent) had evidence of slight
intrathecal production of antibody to B. burgdorferi: 8 had only IgG
antibody to the spirochete, 1 had both IgG and IgA antibodies, 1 had
only IgA antibody, and 1 had only IgM antibody (Fig. 2, Table 3). In
addition, 11 patients had increased cerebrospinal fluid protein
levels, but only 1 had a pleocytosis of 7 lymphocytes per cubic
millimeter. Thus, a total of 18 patients had increased cerebrospinal
fluid protein levels, evidence of intrathecal production of antibody
to B. burgdorferi, or both. Only one patient had an elevated IgG index
and an increased rate of IgG synthesis in cerebrospinal fluid. None of
the patients had low glucose levels in cerebrospinal fluid,
oligoclonal bands, or a positive Venereal Disease Research Laboratory
test. Four of the 24 patients, who were 34, 61, 64, and 72 years of
age, had abnormal magnetic resonance imaging scans of the head. They
had numerous small, rounded areas of increased T2-signal intensity,
primarily in the peripheral white matter (Fig. 3Figure 3Magnetic
Resonance Imaging Scans of the Brain of a 34-Year-Old Woman with
Encephalopathy (Left Panel) and a 40-Year-Old Man with
Leukoencephalitis (Right Panel).).
Overall, 23 of the 24 patients had objective evidence of memory
impairment, abnormal cerebrospinal fluid findings, or both. Of the 10
patients in whom memory impairment could not be demonstrated on
neuropsychological tests, 9 (90 percent) had abnormal cerebrospinal
fluid analyses. All four patients with abnormal magnetic resonance
imaging scans of the head had objective signs of memory loss, and
three of them had abnormal cerebrospinal fluid findings.
Axonal Polyneuropathy
Of the 27 patients, 19 (70 percent) had polyneuropathy; all but 2 of
these patients also had encephalopathy. Eighteen of the 19 patients
had sensory symptoms: 11 had pain in the cervical, thoracic, or
lumbosacral area of the spine, usually accompanied by tingling,
burning, spasms, or shooting pain in the limbs or trunk, and 7 had
only distal paresthesia, with intermittent tingling or "pins and
needles" sensations in the hands or feet (Table 2). On examination, 12
patients had diminished sensation in response to light touch or
pinprick within affected cutaneous areas, 2 had ankle hyporeflexia,
and 2 had mild weakness of the limbs. The one patient who did not have
sensory symptoms had "stocking" sensory loss (affecting the feet and
areas of the legs usually covered by stockings) on examination.
Sensory signs or symptoms were symmetric in 13 patients and asymmetric
in 6.
On electrophysiologic testing, 16 of the 19 patients had evidence of
an axonal polyneuropathy (Table 3). Electromyography showed that 9 of
the 11 patients with spinal pain and 6 of the 7 patients with only
distal symptoms had active or chronic denervation both in proximal
paraspinal and in more distal limb muscles. In contrast, only 3 of the
11 patients with spinal pain and 4 of the 7 patients with distal
paresthesia had slightly slow conduction velocities of the motor or
sensory peroneal and tibial nerves or slightly prolonged motor
latencies to the intrinsic muscles of the foot. The single patient
with asymptomatic polyneuropathy had slight slowing of conduction
velocities in the legs and denervation in the paraspinal and limb
muscles. Of the three patients with normal electrophysiologic studies,
two had typical radicular pain and one had distal paresthesia.
Leukoencephalitis
Six years after the onset of Lyme disease, after erythema migrans and
several brief attacks of arthritis that were treated with erythromycin
and penicillin V benzathine, respectively, 1 of the 24 patients
experienced progressive stiffness and then moderate weakness and
increased tone in the muscles of his right arm and of both legs. His
gait showed reduced arm swing on the right. Tendon jerks were
diffusely brisk, with bilateral ankle clonus and Babinski signs. He
had urinary urgency and frequency, with occasional episodes of
incontinence.
Magnetic resonance imaging of the brain showed numerous small areas of
increased T2-signal intensity in the periventricular regions (Fig. 3).
The scan of the spinal cord was normal, as were visual and brain-stem
auditory evoked potentials. The serum IgG antibody response to B.
burgdorferi was 1:12,800. The patient's cerebrospinal fluid showed 6
lymphocytes per cubic millimeter, an increased protein level of 0.64 g
per deciliter, a cerebrospinal fluid:serum ratio of IgA antibody to B.
burgdorferi of 4, and an IgG ratio of 0.98 (Fig. 2, Table 3). Analysis
of the cerebrospinal fluid did not show a low glucose level,
oligoclonal bands, myelin basic protein, or an increased rate of IgG
synthesis. The patient scored 1 SD below the mean on two separate
tests of memory. Electrophysiologic studies were normal.
Associated Symptoms
Of the 27 patients, 20 had marked fatigue, which was often a major
symptom of their illness. Thirteen patients had mild-to-severe,
episodic, non-pounding headache in a global, hemicranial,
bifrontotemporal, or occipital distribution. They did not have nausea
or visual or somatosensory aura. In two of them, headache was the
primary symptom. Four patients, from 35 to 67 years of age, had mild-
to-moderate unilateral hearing loss, sometimes accompanied by
tinnitus. In all four, the hearing loss was apparent on physical
examination, and in the two patients tested, audiometry confirmed a
mild, high-frequency, sensorineural hearing loss. During the course of
neurologic involvement, four patients had symptoms of fibromyalgia, a
chronic pain syndrome associated with tender points in multiple
locations, most commonly over spinal or paraspinal areas. However, all
four of these patients had abnormal results of cerebrospinal fluid
analyses or white-matter lesions on magnetic resonance imaging scans
of the brain.
Treatment
The 27 patients were treated with 2 g of intravenous ceftriaxone a day
for 14 days. Near the end of therapy, four patients had diarrhea and
three had slightly elevated enzyme levels on liver-function tests. At
the evaluation six months later, 17 patients (63 percent) were better,
including the patient with leukoencephalitis. Improvement often did
not begin until several months after the completion of therapy, and
recovery was seldom complete. Of the remaining 10 patients, 6 (22
percent) improved but then relapsed, and 4 (15 percent) were no
better. The response to treatment among patients with polyneuropathy
was slightly better than that among patients with encephalopathy (68
vs. 58 percent).
In general, an improvement in symptoms was accompanied by an
improvement in neuropsychological tests (five of six patients) and in
nerve-conduction studies (five of seven patients). Regardless of the
response to antibiotics, the cerebrospinal fluid protein levels often
declined, and the serum and cerebrospinal fluid antibody responses
frequently remained the same (Fig. 2). However, the one patient whose
cerebrospinal fluid protein levels increased, the one in whom evidence
of intrathecal antibody production subsequently developed, and two of
the three whose serum antibody titers increased had recurrent
symptoms. Although there was objective clinical improvement in the
five patients with abnormal magnetic resonance imaging scans of the
brain, the lesions showed no change. When pretreatment characteristics
were analyzed according to the response to treatment, there was a
trend toward a longer duration of infection, higher serum antibody
titers, increased cerebrospinal fluid protein levels, and objective
evidence of memory impairment in patients who did not respond, but
these differences were not statistically significant.
Discussion
In this study of patients with chronic neurologic symptoms following
well-recognized manifestations of Lyme disease, three neurologic
syndromes emerged: encephalopathy, polyneuropathy, and
leukoencephalitis, alone or in combination. These chronic neurologic
abnormalities began months to years after the onset of infection,
sometimes after long periods of latency, as in neurosyphilis. In some
cases, patients had erythema migrans during the summer followed within
weeks by early neurologic abnormalities. Months later, arthritis often
dominated the picture, and years later, chronic neurologic involvement
became apparent, which often showed little progression for several
years. In other cases, however, this chronology was condensed, the
system involvement was incomplete or overlapped, chronic neurologic
symptoms began early in the illness, or the neurologic abnormalities
progressed more rapidly.
The most common form of chronic central nervous system involvement in
our patients was subacute encephalopathy affecting memory, mood, and
sleep, sometimes with subtle disturbances in language. Diagnosis of
this condition may be difficult because the typical symptoms are
nonspecific. In addition to evidence of immunity to B. burgdorferi,
however, most of our patients had memory impairment on
neuropsychological tests and abnormal results of cerebrospinal fluid
analyses, frequently accompanied by axonal polyneuropathy and
arthritis — a clinical picture that is very suggestive of Lyme
disease. Although the anatomical and pathological basis for Lyme
encephalopathy is not yet known, spirochete-like structures have been
seen in brain-biopsy samples from two patients with apparent Lyme
encephalitis.17 , 28 By analogy with the general-paresis form of
neurosyphilis, which may begin with impairment of memory and
concentration, irritability, depression, sleep disorder, and fatigue,
29 30 31 we suspect that the pathologic process of Lyme encephalopathy
may be mild, multifocal, and generalized, affecting both the gray and
white matter. We excluded three elderly women from our series who had
dementia several years after Lyme disease because we could not rule
out the diagnosis of Alzheimer's disease. It remains possible that B.
burgdorferi, like Treponema pallidum, may occasionally cause severe
cognitive deficits.
In addition to encephalopathy, most of our patients had peripheral
sensory symptoms, either distal paresthesias or spinal or radicular
pain. Electrophysiologic testing, particularly in those with distal
paresthesias, often showed an axonal polyneuropathy, with subtle
abnormalities of distal motor-nerve or sensory-nerve conduction.
Demyelinating features were not seen. Most of our patients, however,
including those with only distal symptoms, also had extensive
abnormalities of the proximal nerve segments on electromyography. The
pathoanatomical basis for this symmetric or asymmetric polyneuropathy
may be mononeuritis multiplex. In support of this idea, sural-nerve
biopsies in affected patients have shown predominantly axonal injury
with perivascular infiltration of lymphocytes and plasmacytes around
epineural vessels.6 , 32 , 33
One patient in our series had an asymmetric spastic diplegia, upper-
motor-neuron bladder dysfunction, subtle memory impairment,
pleocytosis, and lesions of the periventricular white matter. This
clinical picture is partially compatible with either European
borrelial encephalomyelitis5 or multiple sclerosis. Against the
diagnosis of multiple sclerosis was the patient's progressive course
involving only the motor system, normal evoked potentials, and the
absence of myelin basic protein or oligoclonal bands in cerebrospinal
fluid. Most important for the diagnosis of borrelial leukoencephalitis
were the findings of lesions of the periventricular white matter and
intrathecal production of antibody to B. burgdorferi. In two previous
studies, patients with classic multiple sclerosis did not have
antibody to B. burgdorferi.34 , 35
The typical response of our patients to antibiotic therapy supports
the role of spirochetal infection in the pathogenesis of each of the
syndromes described here. However, our results were not as good as
those in previous reports.6 , 7 Six months after treatment, more than
one third of the patients either had relapsed or were no better. In
addition, more than half had previously received antibiotic therapy
thought to be appropriate for their stage of disease and still had
progression of the illness. The likely reason for relapse is failure
to eradicate the spirochete completely with a two-week course of
intravenous ceftriaxone therapy. On the other hand, the patients whose
conditions did not improve may have had irreversible damage to the
nervous system, particularly since the response to therapy tended to
be worse in patients with longer durations of disease.
@@@@@@@@@@@@@@@@@@@@
This is reminiscent of far-advanced neurosyphilis, in which the
response to penicillin may be minimal.36
Supported by a grant (AM-20358) from the National Institutes of
Health.
We are indebted to Mr. Bruce Reinhardt, Ms. Karen Weeks, and Ms.
Jennifer Whalen for laboratory assistance; to Ms. Linda Vincent and
Ms. Mary-Ellen Meadows for assistance with neuropsychological testing;
to the neurology residents for their help with patient care; and to
Drs. John Halperin and Louis Caplan for their helpful advice.
Source Information
From the Departments of Neurology and Medicine, Tufts University
School of Medicine, New England Medical Center, #406, 750 Washington
St., Boston, MA 02111, where reprint requests should be addressed to
Dr. Steere.
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Chronic Neurologic Manifestations of Lyme Disease
N Engl J Med 1991; 324:1137April 18, 1991
Article
To the Editor:
In our opinion, the data provided by Logigian and coworkers (Nov. 22
issue)* are not sufficient to prove that chronic disease of the
central nervous system was caused by Borrelia burgdorferi. Our main
criticism concerns the interpretation of the cerebrospinal fluid
(CSF):serum ratio of specific antibodies. If total IgG and specific
antibodies could be measured with absolute accuracy, the ratio should
have a value of 1 in all patients without a Central-nervous-system
immune response. If the accuracy is lower, as in practice it always
will be, a logarithmic gaussian distribution with a mean value of 1
has to be expected. In the absence of normal values, the cut-off
values should be defined on the basis of statistical considerations.
Because values below 1 can only be interpreted by statistical
dispersion, the cut-off for positivity should be drawn at the
reciprocal of the lowest value measured. Since Logigian et al. found
values as low as 0.5, only ratios higher than 2.0 can be considered
definitely positive.
Because the study lacks case controls or a population-based estimate
of incidence, the possibility cannot be excluded that the neurologic
disease represented the accidental coincidence of a history of Lyme
disease with another disease. Even if the neurologic disease was
caused by B. burgdorferi, a partial recovery from the acute disease
seems more probable than progressive disease. In two of our patients
reporting similar symptoms after Lyme disease, antibiotic therapy
seemed to improve some of the symptoms, even though objective
improvement could not be documented. During a follow-up period of one
year, the patients presented with the same symptoms again, although
the clinical findings did not change at all. We believe that the
importance of chronic neuroborreliosis is overestimated.
This summary of the neurosurgical procedures available for the
treatment of pain, written by two specialists in the field, is well
organized, detailed, critical, and presented fairly. It is a book that
neurosurgeons should read. Every specialist in the management of pain
should be familiar with its contents. It will be an important
reference for anyone who wishes to understand specific surgical
procedures or the diseases in which they are used for pain control.
The book itself is timely. There have been great advances in our
understanding of the pathophysiology of pain in the past 10 years.
Much emphasis has been placed on the complexities of clinical problems
in pain, stressing medical, social, psychological, and even economic
mediators of chronic pain. The authors have carried out an extensive
review of the literature and have reassessed traditional and newer
procedures for pain control in the light of this new information.
The introduction is an outstanding philosophical and practical review
of the complexities of the problem of pain. The definitions of somatic
pain and neurogenic pain, with a subgroup called "central pain"
denoting pain from primary lesions in brain or spinal cord, is a
practical simplification of the problem of pain semantics. The
arguments concerning the long-term control of pain through the use of
narcotics in patients with nonlethal diseases are summarized
succinctly. The purpose of the book is to define the current role of
neurosurgical procedures in the management of persistent pain —
procedures based on our new understanding of the anatomical,
physiologic, and pharmacologic features of the pain pathways.
The book is organized on an anatomical and procedural basis. The first
topic details the experience of surgical interruption of nociceptive
pathways and is divided in the traditional way into operations on
cranial and peripheral nerves or their roots and ganglia. Interruption
of spinal-cord pathways, brain-stem lesions, and more central pain-
pathway interruptions follow. There is a major section reviewing the
neurosurgical approaches to the sympathetic nervous system. The newer
techniques of electrical stimulation for pain perception and the
administration of pharmacologic agents for pain in the spinal or
cranial compartments are also described in detail.
Individual sections begin with a useful historical note, discuss the
pathophysiology of the pain state involved, and then describe the
treatments available. The actual techniques are presented in some
detail. The authors then finish with a summary statement of their own
philosophy on the use of each procedure. When the data are
insufficient for a conclusion, they say so. Most important, they
present all the information, so the reader can agree, disagree, or
modify the authors' conclusions after a comprehensive review of the
available material.
Not surprisingly, the book begins with an exhaustive review of the
question of trigeminal neuralgia and procedures performed on the
trigeminal nerve. This reflects both the historical importance of
trigeminal neuralgia in neurosurgery and the great expertise of the
authors. Thermal coagulation of the trigeminal ganglion was introduced
into the United States by Sweet. His leadership in this field is well
recognized. The comparative data concerning radiofrequency thermal
coagulation, glycerol injection, and posterior fossa microvascular
decompression can be made against the background of an excellent
historical review. The arguments presented are not likely to sway the
proponents of these three techniques from their current practice, but
the information is available for all neurosurgeons who read the book
to make decisions concerning their own philosophy on the treatment of
this recurring neurosurgical problem.
In several areas the authors describe a technique and the sparse
supporting literature in enough detail to conclude that there are
insufficient data for any conclusive statement. The treatment of
cluster headache, medial-branch neurotomy for chronic back pain, and
dorsal-root ganglionectomy are examples of this balanced presentation.
Their review should serve as a spur for those who have been using
these procedures to examine the existing data and present information
rigorously.
There are other less well known procedures that the authors present as
worthy of wider use. Selective posterior rhizotomy is one such
operation. In other procedures, such as destruction of the dorsal-root
entry zone, the review serves to illustrate the usefulness of the
operation in some situations, principally in the treatment of pain of
brachial plexus avulsion, while reemphasizing its lack of utility in
others. The authors remind us that the success of a pain procedure in
one disease does not change its investigative status in others in
which it remains unproved.
The usefulness of cordotomy has diminished greatly in the recent past.
Improved oral narcotics and the use of intrathecal narcotic
medications for patients with terminal cancer have eliminated the use
of cordotomy in most centers. It is good to be reminded periodically
of how effective the operation can be, so that appropriate candidates
are not deprived of an excellent procedure for relieving pain.
The extensive review of lesions in the pain pathways in the brain
stem, hypothalamus, and thalamus are of historical and anatomical
value. They serve to remind us that this is a business for a limited
number of experts. The data remain sparse in spite of many years of
application.
By contrast, the review of the field of sympathectomy for pain
reemphasizes that this is an excellent operation for specific
indications. On the other hand, sympatholytic drugs have the potential
of accomplishing the same results, and the number of surgical
sympathectomies continues to decline. The new percutaneous techniques
are described, but as the authors tell us, their long-term denervation
potential remains to be assessed.
There is an excellent review of the stimulation techniques in
peripheral nerve, spinal cord, and brain for pain control. The data
are comprehensive and the conclusions balanced. The review of so-
called deep-brain stimulation is particularly useful. In the past five
years there has been an even greater interest in this field. The
detailed maps of the thalamus being presented by Tasker and Lenz have
the potential to make brain stimulation even more useful in its
current position as the last resort.
The book concludes with a review of the intraspinal and
intraventricular infusion of opioids for pain control. This has become
the standard technique for the treatment of patients with chronic pain
of cancer, and it is now being explored for its usefulness in pain
that complicates nonlethal disease.
The authors did not plan this book to be a comprehensive review of the
treatment of pain. It is a detailed account of the usefulness of
specific procedures. The assessment includes the historical data that
are so important in understanding the outcome of the application of
these procedures. The pathophysiology is described in modern terms,
and a balanced appraisal of the outcome of each procedure is
presented. This book should be required reading for all neurosurgeons
in training and any neurosurgeon who deals with problems of pain. It
is of equal value to pain specialists who need to know the potential
for these procedures to benefit their patients. If specialists do not
have this knowledge, patients can be both deprived of valuable help
and subjected to operations that have little chance of benefit. While
the authors make their own philosophy quite clear throughout the book,
they do so in a balanced fashion presenting all the data and allowing
the reader to come to individual conclusions concerning each
procedure. The reference list is extensive and well chosen. This book
is an invaluable resource to all those committed to the care of
patients with persistent pain.
E. Stark, M.D.
U. Wurster, Ph.D.
Hannover Medical School, 3000 Hannover 61, Germany
1 Reference
*
Logigian EL, Kaplan RF, Steere achéal. Chronic neurologic
manifestations of Lyme disease . N Engl J Med 1990; 323:1438–44.
The above letter was referred to the authors of the article in
question, who offer the following reply:
To the Editor: In diagnosing infection of the central nervous system
in Lyme borreliosis, Drs. Stark and Wurster question the validity of a
cut-off value of 1 for the CSF:serum ratio of antibody to B.
burgdorferi. We have published a separate study on the evaluation of
the intrathecal antibody response to B. burgdorferi in 37 American and
30 German patients with Lyme borreliosis and in 12 control subjects.1
The antibody responses were determined by capture enzyme immunoassay,
which measures directly the proportion of specific to total antibody.
Unlike the indirect systems commonly used, this method does not
require the adjustment of serum and CSF concentrations in order to
compare specific antibody titers.
In that study, American patients with neuroborreliosis had
significantly lower CSF:serum ratios of antibody to B. burgdorferi
than German patients. Even among the patients with meningitis, which
is known to be caused by intrathecal infection with the spirochete,
the mean CSF:serum ratio of specific IgG antibody to the spirochete
was 17 in the European patients as compared with 2 in the American
patients (P<0.05). Of 12 American patients with chronic
encephalopathy, only 5 (42 percent) had CSF:serum ratios above 1 but
not usually more than 2. In comparison, 6 seropositive patients with
peripheral neuropathy due to Lyme disease and 6 seropositive patients
with chronic fatigue after Lyme disease had a mean ratio of 0.7
(range, 0.3 to 1), and none of the 12 patients with other inflammatory
neurologic diseases had a ratio above 1. Thus, the mean values among
patients with Lyme disease who did not have central nervous system
abnormalities were not normally distributed around 1, as hypothesized
by Drs. Stark and Wurster.
For a number of reasons, only one of which concerns the central
nervous system immune response, we believe that the 27 patients
described in our recent article in the Journal had chronic neurologic
manifestations due to Lyme disease.2 Most of the patients had symptoms
of both an encephalopathy and a polyneuropathy, manifested primarily
by memory impairment, distal paresthesias, or radicular pain. In most
instances, memory impairment could be demonstrated on
neuropsychological tests, total protein levels in CSF were elevated,
and electromyograms showed evidence of an axonal polyneuropathy.
Although all the patients had current evidence of immunity to B.
burgdorferi, only about half of those with encephalopathy had
CSF:serum ratios of IgG antibody to the spirochete between 1 and 2.
Determination of the intrathecal antibody response to B. burgdorferi
has limitations as a diagnostic test. First, demonstration of an
intrathecal antibody response is an inconsistent finding among our
patients with central nervous system abnormalities. Perhaps in some
patients with this systemic illness, more antibody is produced in
peripheral lymph nodes than in the central nervous system, and
therefore selective concentration of specific antibody cannot be
demonstrated in CSF. Second, we agree that a positive test does not
prove the presence of a live spirochete; selective concentration of
specific antibody in CSF may still be found for at least months,
albeit at lower levels, in patients who have apparently been treated
successfully for neuroborreliosis.2 We do not think, however, that
this is the explanation for the elevated CSF:serum ratios in our
patients with encephalopathy, since elevated ratios were not found
more frequently in the subgroup of these patients who had previously
had early neurologic manifestations of the illness.
In their introduction, the authors state clearly that this second
edition bears little similarity to the first. The focus and format
have been both improved and amplified, with the result being a very
good small, functional manual for interpreting renal biopsies.
Throughout the book the diagrams are excellent, and they provide a
helpful guide to the photographs. While most of the pictures are very
good, several appear to lack appropriate contrast and are a bit out of
focus. The text is clear, concise, and well written, and it relates
well to the diagrams and photographs. The selected readings after the
discussion of each disease category are particularly well chosen and
very convenient for the reader. It is important to emphasize that The
Renal Biopsy is not a primer or an introduction to nephrology. A basic
understanding of normal and pathologic anatomy is required to maximize
its use.
As an aid to the interpretation of renal biopsies, this small book
succeeds admirably, and it should be useful to any knowledgeable
physician interested in understanding the morphologic and clinical
correlations of renal diseases. The authors' preface provides an up-to-
date list of comprehensive references for those desiring a more
detailed description.
Allen C. Steere, M.D.
New England Medical Center, Boston, MA 02111
Eric L. Logigian, M.D.
Brigham and Women's Hospital, Boston, MA 02115
2 References
1
Steere achéal, Berardi VP, Weeks KE, Logigian EL, Ackerman R.
Evaluation of the intrathecal antibody response to Borrelia
burgdorferi as a diagnostic test for Lyme neuroborreliosis . J Infect
Dis 1990; 161:1203–9.
2
Logigian EL, Kaplan RF, Steere achéal. Chronic neurologic
manifestations of Lyme disease . N Engl J Med 1990; 323:1438–44.
Eric L. Logigian, M.D., Richard F. Kaplan, Ph.D., and Allen C. Steere,
M.D.
N Engl J Med 1990; 323:1438-1444November 22, 1990
Abstract
Article
References
Citing Articles (68)
Letters
Abstract
Background and Methods.
Lyme disease, caused by the tick-borne spirochete Borrelia
burgdorferi, is associated with a wide variety of neurologic
manifestations. To define further the chronic neurologic abnormalities
of Lyme disease, we studied 27 patients (age range, 25 to 72 years)
with previous signs of Lyme disease, current evidence of immunity to
B. burgdorferi, and chronic neurologic symptoms with no other
identifiable cause. Eight of the patients had been followed
prospectively for 8 to 12 years after the onset of infection.
Full Text of Background and Methods....
Results.
Of the 27 patients, 24 (89 percent) had a mild encephalopathy that
began 1 month to 14 years after the onset of the disease and was
characterized by memory loss, mood changes, or sleep disturbance. Of
the 24 patients, 14 had memory impairment on neuropsychological tests,
and 18 had increased cerebrospinal fluid protein levels, evidence of
intrathecal production of antibody to B. burgdorferi, or both.
Nineteen of the 27 patients (70 percent) had polyneuropathy with
radicular pain or distal paresthesias; all but two of these patients
also had encephalopathy. In 16 patients electrophysiologic testing
showed an axonal polyneuropathy. One patient had leukoencephalitis
with asymmetric spastic diplegia, periventricular white-matter
lesions, and intrathecal production of antibody to B. burgdorferi.
Among the 27 patients, associated symptoms included fatigue (74
percent), headache (48 percent), arthritis (37 percent), and hearing
loss (15 percent). At the time of examination, chronic neurologic
abnormalities had been present from 3 months to 14 years, usually with
little progression. Six months after a two-week course of intravenous
ceftriaxone (2 g daily), 17 patients (63 percent) had improvement, 6
(22 percent) had improvement but then relapsed, and 4 (15 percent) had
no change in their condition.
Full Text of Results....
Conclusions.
Months to years after the initial infection with B. burgdorferi,
patients with Lyme disease may have chronic encephalopathy,
polyneuropathy, or less commonly, leukoencephalitis. These chronic
neurologic abnormalities usually improve with antibiotic therapy. (N
Engl J Med 1990; 323:1438–44.)
Full Text of Conclusions....
Read the Full Article...
Article Activity
68 articles have cited this article
LYME disease, which is caused by the tick-borne spirochete Borrelia
burgdorferi, is associated with a wide variety of neurologic
abnormalities.1 2 3 4 5 6 7 Early in the illness, many patients have
episodes of headache and mild meningism.8 Within several weeks, about
15 percent have objective neurologic abnormalities, most commonly
lymphocytic meningitis, motor or sensory radiculoneuritis, or cranial
neuropathy, particularly facial palsy.2 , 3 A similar syndrome of
meningoradiculitis occurs in Europe.4 , 9 , 10 These early neurologic
abnormalities can be cured with antibiotic therapy,11 , 12 and even if
untreated, they usually resolve within months.4
Chronic neurologic involvement, affecting either the central or
peripheral nervous system, may also occur in Lyme borreliosis. In
Germany, Ackermann et al. described 44 patients with progressive
borrelial encephalomyelitis, a severe neurologic disorder
characterized by spastic paraparesis or tetraparesis, ataxia,
cognitive impairment, bladder dysfunction, and cranial neuropathy,
particularly deficits of the seventh or eighth cranial nerve.5 In all
cases, the diagnosis was proved by the demonstration of intrathecal
production of IgG antibody to B. burgdorferi. In addition,
acrodermatitis chronica atrophicans, a late skin manifestation of Lyme
borreliosis reported primarily in Europe, has been associated with a
sensory polyneuropathy13 , 14 and with mental disturbances.15
In the United States, Halperin et al. described two chronic neurologic
syndromes associated with Lyme disease: one involved the peripheral
nervous system and was characterized by paresthesias and
electrophysiologic evidence of axonal polyneuropathy,6 and the other
involved the central nervous system and was manifested by
encephalopathy with memory impairment.7 The patients with central
nervous system involvement usually had intrathecal production of
antibodies to the spirochete, but those with abnormalities of the
peripheral nervous system did not. A few patients have been described
with other neurologic abnormalities thought to be due to Lyme disease,
including encephalitis,16 17 18 dementia,18 , 19 psychiatric syndromes,
17 possible demyelinating disease,17 , 19 stroke,20 , 21 brain-stem
abnormalities,17 and extrapyramidal syndromes.22 In some instances,
however, the evidence linking these syndromes to infection with B.
burgdorferi was incomplete.
The goal of the current study was to define further the chronic
neurologic abnormalities of Lyme disease. We describe the clinical
courses, diagnostic studies, and treatment responses of 27 patients in
whom chronic neurologic syndromes developed months to years after the
onset of Lyme disease.
Methods
Neurologic Evaluation
From October 1987 through December 1989, we evaluated a total of 37
patients with chronic neurologic symptoms following well-recognized
manifestations of Lyme disease. Eight of them had been entered
previously into clinical studies of Lyme disease and had been followed
prospectively for 8 to 12 years after the onset of infection. The 37
patients had detailed neurologic evaluations, including lumbar
puncture, neuropsychological testing, electrophysiologic studies, and
magnetic resonance imaging of the head. The antibody responses to B.
burgdorferi in serum were determined by indirect enzyme-linked
immunosorbent assay23 and in serum and cerebrospinal fluid samples
obtained simultaneously, by capture enzyme immunoassay.24 If the
patient was seronegative according to these methods, the serum was
further tested by immunoblotting,25 and peripheral-blood mononuclear
cells were tested for reactivity with borrelial antigens by
proliferative assay.26
Neuropsychological tests were selected to provide measures of
immediate and delayed memory, conceptualization, copying, perceptual
discrimination, and language. These tests included the Wechsler Memory
Scales, California Verbal Learning Test, Wisconsin Card-Sorting Test,
Trailmaking Test, Rey—Osterrieth Complex Figure Test, Finger-Tapping
Test, Benton Face-Discrimination Test, Hooper Visual Organization
Test, Boston Naming Test, Token Test, and Oral Word-Association Test.
In addition, intelligence quotient was estimated with either the
Wechsler Adult Intelligence Scale—Revised or the Shipley Hartford
Institute of Living Scale. Finally, symptoms of concurrent
psychopathology, such as depression, were assessed by the Minnesota
Multiphasic Personality Inventory. The test scores were transformed
into standard scores that were calculated from published, age-
corrected normative data. According to a previously described system,
27 evidence of memory impairment was defined as scores that were 2 SD
below the normative mean on any one of the three tests of memory
(Wechsler Memory Scales, California Verbal Learning Test, or Rey—
Osterrieth Complex Figure Test) or more than 1 SD below the mean on
two of the tests. A score of 70 or above on the Minnesota Multiphasic
Personality Inventory was considered indicative of depression.
A detailed electromyographic examination of limb and paraspinal
muscles was performed with concentric needle electrodes. Motor-nerve
and sensory-nerve conduction studies of the median, ulnar, peroneal,
and tibial nerves were performed with 10-mm surface recording and
stimulating electrodes. For magnetic resonance imaging of the brain,
T1-weighted sagittal and axial images were obtained on a 1.0-tesla
Siemens Magnetom with a repetition time to echo time of 650/20 msec,
and T2-weighted axial images were obtained with a repetition time to
echo time of 3000/45 and 90 msec.
Criteria for Case Inclusion
Of the 37 patients, 5 who had memory difficulties, depression, or
headache after erythema migrans were excluded because they had normal
neurologic tests, negative or indeterminate antibody responses to B.
burgdorferi, and no reactivity of mononuclear cells to borrelial
antigens. Five additional patients who had dementia, demyelinating
disease, or headache were excluded because Alzheimer's disease,
multiple sclerosis, or brain tumor was the likely diagnosis. Four of
these five patients still had antibody responses to B. burgdorferi. We
believe that the remaining 27 patients had neurologic abnormalities
caused by infection with B. burgdorferi. All 27 had previously had
signs of Lyme disease, had neurologic symptoms lasting at least three
months that could not be attributed to another cause, and had current
evidence of humoral or cellular immunity to B. burgdorferi, as shown
by an elevated serum IgG or IgM antibody titer of at least 1:400,23
five or more IgG antibody bands to spirochetal polypeptides,25 or a
stimulation index of 10 or more in response to borrelial antigens.26
Treatment Regimen and Follow-up Examinations
The patients were treated with 2 g of ceftriaxone intravenously once a
day for 14 days. Complete blood counts and liver-function tests were
done on days 0, 7, and 14 to monitor the effect of therapy. Follow-up
examinations were performed three and six months later. Serologic
testing for B. burgdorferi was repeated at each follow-up visit, and
all samples were tested again on a single plate to assess the change
in titer. If possible, neurologic tests whose results had been
abnormal in the initial examination were repeated at the six-month
follow-up examination.
Results
Course of Lyme Disease
Of the 27 patients with chronic neurologic abnormalities due to Lyme
disease, 23 (85 percent) had erythema migrans at the beginning of the
illness and 2 others (7 percent) had an influenza-like illness without
rash during the summer, days to weeks before the onset of early
neurologic involvement (Table 1Table 1Course of Lyme Disease in the 27
Study Patients.*). The two patients who did not have symptoms of early
infection did have arthritis followed by neurologic abnormalities. In
11 patients (41 percent), early symptoms included severe headache,
mild neck stiffness, or spinal pain. Eight patients (30 percent) had
early neurologic abnormalities consisting of facial palsy, sometimes
with meningitis or thoracic radiculoneuritis, a median of one month
after the onset of erythema migrans. These abnormalities resolved
within one to two months except in one patient, who had mild residual
facial weakness and a unilateral hearing impairment. A median of six
months after the onset of disease, 19 patients (70 percent) began to
have brief episodes of arthritis affecting primarily the knees.
Arthritis occurred in all these patients before the chronic neurologic
symptoms developed, and it was still present in 10 patients (37
percent) when the chronic neurologic abnormalities were noted.
Symptoms of chronic involvement of the peripheral nervous system
developed a median of 16 months after the onset of infection, whereas
symptoms of central nervous system involvement usually began later, a
median of 26 months after the onset of disease (Table 1). At the far
end of the spectrum, these abnormalities began 10 or more years after
the onset of disease, after long periods of latent infection (Fig.
1Figure 1Interval between the Onset of Lyme Disease and the Occurrence
of Encephalopathy, Polyneuropathy, or Leukoencephalitis and the
Duration of These Complications in the 25 Patients in Whom the Onset
of Infection Could Be Determined.). At the time of the current
evaluation, chronic neurologic involvement had usually been present
for more than 1 year, and in several patients for 10 or more years.
Fifteen of the 27 patients (56 percent) had already been treated with
one or more courses of antibiotic therapy before this evaluation; in
six cases, they had received two-week courses of intravenous
penicillin or ceftriaxone.
Chronic Neurologic Abnormalities
Seventeen of the patients (63 percent) had abnormalities of both the
central and peripheral nervous systems manifested as subacute
encephalopathy and axonal polyneuropathy, seven patients (26 percent)
had encephalopathy alone, two (7 percent) had polyneuropathy alone,
and the remaining patient (4 percent) had leukoencephalitis.
Subacute Encephalopathy
Of the 27 patients, 24 had a mild encephalopathy. Twenty-two of them
had difficulty remembering things (Table 2Table 2Signs and Symptoms of
Chronic Neurologic Abnormalities.). They forgot names, missed
appointments, or misplaced objects. To compensate, they often made
daily lists. Ten patients had symptoms of depression, and three of
them sought psychiatric help or received antidepressant medication.
Eight patients had excessive daytime sleepiness, and seven had extreme
irritability. They became angry over circumstances that previously
caused only minor annoyance. Finally, five patients had subtle
symptoms of a language disturbance, with difficulty finding words. No
one had seizures, myoclonus, or a change in the level of
consciousness. Although most patients were able to remain employed,
three quit their jobs, three decreased their work hours to part-time,
and two retired early.
All 24 patients had at least 12 years of education; they had
intelligence quotients that were average or above, and none had a
history of neuropsychological impairment. Of the 22 patients with
symptoms of memory loss, 12 had evidence of memory impairment on
neuropsychological tests, and the 2 with encephalopathy who did not
notice any memory changes also had evidence of such impairment on
these tests (Table 3Table 3Results of Neurologic Tests in 27 Patients
with Chronic Neurologic Abnormalities.). In only six patients was
memory dysfunction marked enough to be apparent on neurologic
evaluation at the bedside. On the Minnesota Multiphasic Personality
Inventory, 9 of the 10 patients with symptoms of depression had scores
indicative of depression. Only two patients scored 1 SD below the mean
on any other neuropsychological test.
Of the 24 patients with encephalopathy, 21 had elevated serum IgG
antibody responses to B. burgdorferi (Fig. 2Figure 2Pretreatment and
Follow-up Serum IgG Antibody Responses to B. burgdorferi,
Cerebrospinal Fluid (CSF):Serum Ratios of IgG Antibody to the
Spirochete, and Cerebrospinal Fluid Protein Concentrations in the 27
Patients with Encephalopathy (●), Polyneuropathy Alone (○), or
Leukoencephalitis ().). Of the remaining three patients, all of whom
received antibiotic therapy for erythema migrans, one had only an IgM
response (1:3200) to the spirochete; one had an IgG response in the
indeterminate range (1:200), but the immunoblot showed antibody to six
spirochetal polypeptides; and one had only a cellular immune response
to borrelial antigens (stimulation index, 28). On analysis of the
cerebrospinal fluid, 11 patients (46 percent) had evidence of slight
intrathecal production of antibody to B. burgdorferi: 8 had only IgG
antibody to the spirochete, 1 had both IgG and IgA antibodies, 1 had
only IgA antibody, and 1 had only IgM antibody (Fig. 2, Table 3). In
addition, 11 patients had increased cerebrospinal fluid protein
levels, but only 1 had a pleocytosis of 7 lymphocytes per cubic
millimeter. Thus, a total of 18 patients had increased cerebrospinal
fluid protein levels, evidence of intrathecal production of antibody
to B. burgdorferi, or both. Only one patient had an elevated IgG index
and an increased rate of IgG synthesis in cerebrospinal fluid. None of
the patients had low glucose levels in cerebrospinal fluid,
oligoclonal bands, or a positive Venereal Disease Research Laboratory
test. Four of the 24 patients, who were 34, 61, 64, and 72 years of
age, had abnormal magnetic resonance imaging scans of the head. They
had numerous small, rounded areas of increased T2-signal intensity,
primarily in the peripheral white matter (Fig. 3Figure 3Magnetic
Resonance Imaging Scans of the Brain of a 34-Year-Old Woman with
Encephalopathy (Left Panel) and a 40-Year-Old Man with
Leukoencephalitis (Right Panel).).
Overall, 23 of the 24 patients had objective evidence of memory
impairment, abnormal cerebrospinal fluid findings, or both. Of the 10
patients in whom memory impairment could not be demonstrated on
neuropsychological tests, 9 (90 percent) had abnormal cerebrospinal
fluid analyses. All four patients with abnormal magnetic resonance
imaging scans of the head had objective signs of memory loss, and
three of them had abnormal cerebrospinal fluid findings.
Axonal Polyneuropathy
Of the 27 patients, 19 (70 percent) had polyneuropathy; all but 2 of
these patients also had encephalopathy. Eighteen of the 19 patients
had sensory symptoms: 11 had pain in the cervical, thoracic, or
lumbosacral area of the spine, usually accompanied by tingling,
burning, spasms, or shooting pain in the limbs or trunk, and 7 had
only distal paresthesia, with intermittent tingling or "pins and
needles" sensations in the hands or feet (Table 2). On examination, 12
patients had diminished sensation in response to light touch or
pinprick within affected cutaneous areas, 2 had ankle hyporeflexia,
and 2 had mild weakness of the limbs. The one patient who did not have
sensory symptoms had "stocking" sensory loss (affecting the feet and
areas of the legs usually covered by stockings) on examination.
Sensory signs or symptoms were symmetric in 13 patients and asymmetric
in 6.
On electrophysiologic testing, 16 of the 19 patients had evidence of
an axonal polyneuropathy (Table 3). Electromyography showed that 9 of
the 11 patients with spinal pain and 6 of the 7 patients with only
distal symptoms had active or chronic denervation both in proximal
paraspinal and in more distal limb muscles. In contrast, only 3 of the
11 patients with spinal pain and 4 of the 7 patients with distal
paresthesia had slightly slow conduction velocities of the motor or
sensory peroneal and tibial nerves or slightly prolonged motor
latencies to the intrinsic muscles of the foot. The single patient
with asymptomatic polyneuropathy had slight slowing of conduction
velocities in the legs and denervation in the paraspinal and limb
muscles. Of the three patients with normal electrophysiologic studies,
two had typical radicular pain and one had distal paresthesia.
Leukoencephalitis
Six years after the onset of Lyme disease, after erythema migrans and
several brief attacks of arthritis that were treated with erythromycin
and penicillin V benzathine, respectively, 1 of the 24 patients
experienced progressive stiffness and then moderate weakness and
increased tone in the muscles of his right arm and of both legs. His
gait showed reduced arm swing on the right. Tendon jerks were
diffusely brisk, with bilateral ankle clonus and Babinski signs. He
had urinary urgency and frequency, with occasional episodes of
incontinence.
Magnetic resonance imaging of the brain showed numerous small areas of
increased T2-signal intensity in the periventricular regions (Fig. 3).
The scan of the spinal cord was normal, as were visual and brain-stem
auditory evoked potentials. The serum IgG antibody response to B.
burgdorferi was 1:12,800. The patient's cerebrospinal fluid showed 6
lymphocytes per cubic millimeter, an increased protein level of 0.64 g
per deciliter, a cerebrospinal fluid:serum ratio of IgA antibody to B.
burgdorferi of 4, and an IgG ratio of 0.98 (Fig. 2, Table 3). Analysis
of the cerebrospinal fluid did not show a low glucose level,
oligoclonal bands, myelin basic protein, or an increased rate of IgG
synthesis. The patient scored 1 SD below the mean on two separate
tests of memory. Electrophysiologic studies were normal.
Associated Symptoms
Of the 27 patients, 20 had marked fatigue, which was often a major
symptom of their illness. Thirteen patients had mild-to-severe,
episodic, non-pounding headache in a global, hemicranial,
bifrontotemporal, or occipital distribution. They did not have nausea
or visual or somatosensory aura. In two of them, headache was the
primary symptom. Four patients, from 35 to 67 years of age, had mild-
to-moderate unilateral hearing loss, sometimes accompanied by
tinnitus. In all four, the hearing loss was apparent on physical
examination, and in the two patients tested, audiometry confirmed a
mild, high-frequency, sensorineural hearing loss. During the course of
neurologic involvement, four patients had symptoms of fibromyalgia, a
chronic pain syndrome associated with tender points in multiple
locations, most commonly over spinal or paraspinal areas. However, all
four of these patients had abnormal results of cerebrospinal fluid
analyses or white-matter lesions on magnetic resonance imaging scans
of the brain.
Treatment
The 27 patients were treated with 2 g of intravenous ceftriaxone a day
for 14 days. Near the end of therapy, four patients had diarrhea and
three had slightly elevated enzyme levels on liver-function tests. At
the evaluation six months later, 17 patients (63 percent) were better,
including the patient with leukoencephalitis. Improvement often did
not begin until several months after the completion of therapy, and
recovery was seldom complete. Of the remaining 10 patients, 6 (22
percent) improved but then relapsed, and 4 (15 percent) were no
better. The response to treatment among patients with polyneuropathy
was slightly better than that among patients with encephalopathy (68
vs. 58 percent).
In general, an improvement in symptoms was accompanied by an
improvement in neuropsychological tests (five of six patients) and in
nerve-conduction studies (five of seven patients). Regardless of the
response to antibiotics, the cerebrospinal fluid protein levels often
declined, and the serum and cerebrospinal fluid antibody responses
frequently remained the same (Fig. 2). However, the one patient whose
cerebrospinal fluid protein levels increased, the one in whom evidence
of intrathecal antibody production subsequently developed, and two of
the three whose serum antibody titers increased had recurrent
symptoms. Although there was objective clinical improvement in the
five patients with abnormal magnetic resonance imaging scans of the
brain, the lesions showed no change. When pretreatment characteristics
were analyzed according to the response to treatment, there was a
trend toward a longer duration of infection, higher serum antibody
titers, increased cerebrospinal fluid protein levels, and objective
evidence of memory impairment in patients who did not respond, but
these differences were not statistically significant.
Discussion
In this study of patients with chronic neurologic symptoms following
well-recognized manifestations of Lyme disease, three neurologic
syndromes emerged: encephalopathy, polyneuropathy, and
leukoencephalitis, alone or in combination. These chronic neurologic
abnormalities began months to years after the onset of infection,
sometimes after long periods of latency, as in neurosyphilis. In some
cases, patients had erythema migrans during the summer followed within
weeks by early neurologic abnormalities. Months later, arthritis often
dominated the picture, and years later, chronic neurologic involvement
became apparent, which often showed little progression for several
years. In other cases, however, this chronology was condensed, the
system involvement was incomplete or overlapped, chronic neurologic
symptoms began early in the illness, or the neurologic abnormalities
progressed more rapidly.
The most common form of chronic central nervous system involvement in
our patients was subacute encephalopathy affecting memory, mood, and
sleep, sometimes with subtle disturbances in language. Diagnosis of
this condition may be difficult because the typical symptoms are
nonspecific. In addition to evidence of immunity to B. burgdorferi,
however, most of our patients had memory impairment on
neuropsychological tests and abnormal results of cerebrospinal fluid
analyses, frequently accompanied by axonal polyneuropathy and
arthritis — a clinical picture that is very suggestive of Lyme
disease. Although the anatomical and pathological basis for Lyme
encephalopathy is not yet known, spirochete-like structures have been
seen in brain-biopsy samples from two patients with apparent Lyme
encephalitis.17 , 28 By analogy with the general-paresis form of
neurosyphilis, which may begin with impairment of memory and
concentration, irritability, depression, sleep disorder, and fatigue,
29 30 31 we suspect that the pathologic process of Lyme encephalopathy
may be mild, multifocal, and generalized, affecting both the gray and
white matter. We excluded three elderly women from our series who had
dementia several years after Lyme disease because we could not rule
out the diagnosis of Alzheimer's disease. It remains possible that B.
burgdorferi, like Treponema pallidum, may occasionally cause severe
cognitive deficits.
In addition to encephalopathy, most of our patients had peripheral
sensory symptoms, either distal paresthesias or spinal or radicular
pain. Electrophysiologic testing, particularly in those with distal
paresthesias, often showed an axonal polyneuropathy, with subtle
abnormalities of distal motor-nerve or sensory-nerve conduction.
Demyelinating features were not seen. Most of our patients, however,
including those with only distal symptoms, also had extensive
abnormalities of the proximal nerve segments on electromyography. The
pathoanatomical basis for this symmetric or asymmetric polyneuropathy
may be mononeuritis multiplex. In support of this idea, sural-nerve
biopsies in affected patients have shown predominantly axonal injury
with perivascular infiltration of lymphocytes and plasmacytes around
epineural vessels.6 , 32 , 33
One patient in our series had an asymmetric spastic diplegia, upper-
motor-neuron bladder dysfunction, subtle memory impairment,
pleocytosis, and lesions of the periventricular white matter. This
clinical picture is partially compatible with either European
borrelial encephalomyelitis5 or multiple sclerosis. Against the
diagnosis of multiple sclerosis was the patient's progressive course
involving only the motor system, normal evoked potentials, and the
absence of myelin basic protein or oligoclonal bands in cerebrospinal
fluid. Most important for the diagnosis of borrelial leukoencephalitis
were the findings of lesions of the periventricular white matter and
intrathecal production of antibody to B. burgdorferi. In two previous
studies, patients with classic multiple sclerosis did not have
antibody to B. burgdorferi.34 , 35
The typical response of our patients to antibiotic therapy supports
the role of spirochetal infection in the pathogenesis of each of the
syndromes described here. However, our results were not as good as
those in previous reports.6 , 7 Six months after treatment, more than
one third of the patients either had relapsed or were no better. In
addition, more than half had previously received antibiotic therapy
thought to be appropriate for their stage of disease and still had
progression of the illness. The likely reason for relapse is failure
to eradicate the spirochete completely with a two-week course of
intravenous ceftriaxone therapy. On the other hand, the patients whose
conditions did not improve may have had irreversible damage to the
nervous system, particularly since the response to therapy tended to
be worse in patients with longer durations of disease.
@@@@@@@@@@@@@@@@@@@@
This is reminiscent of far-advanced neurosyphilis, in which the
response to penicillin may be minimal.36
Supported by a grant (AM-20358) from the National Institutes of
Health.
We are indebted to Mr. Bruce Reinhardt, Ms. Karen Weeks, and Ms.
Jennifer Whalen for laboratory assistance; to Ms. Linda Vincent and
Ms. Mary-Ellen Meadows for assistance with neuropsychological testing;
to the neurology residents for their help with patient care; and to
Drs. John Halperin and Louis Caplan for their helpful advice.
Source Information
From the Departments of Neurology and Medicine, Tufts University
School of Medicine, New England Medical Center, #406, 750 Washington
St., Boston, MA 02111, where reprint requests should be addressed to
Dr. Steere.
References
1
Steere achéal. Lyme disease . N Engl J Med 1989; 321:586–96.
Full Text | Web of Science | Medline
2
Reik L, Steere achéal, Bartenhagen NH, Shope RE, Malawista SE.
Neurologic abnormalities of Lyme disease . Medicine (Baltimore) 1979;
58:281–94.
CrossRef | Web of Science | Medline
3
Pachner AR, Steere achéal. The triad of neurologic manifestations of
Lyme disease: meningitis, cranial neuritis, and radiculoneuritis .
Neurology 1985; 35:47–53.
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Chronic Neurologic Manifestations of Lyme Disease
N Engl J Med 1991; 324:1137April 18, 1991
Article
To the Editor:
In our opinion, the data provided by Logigian and coworkers (Nov. 22
issue)* are not sufficient to prove that chronic disease of the
central nervous system was caused by Borrelia burgdorferi. Our main
criticism concerns the interpretation of the cerebrospinal fluid
(CSF):serum ratio of specific antibodies. If total IgG and specific
antibodies could be measured with absolute accuracy, the ratio should
have a value of 1 in all patients without a Central-nervous-system
immune response. If the accuracy is lower, as in practice it always
will be, a logarithmic gaussian distribution with a mean value of 1
has to be expected. In the absence of normal values, the cut-off
values should be defined on the basis of statistical considerations.
Because values below 1 can only be interpreted by statistical
dispersion, the cut-off for positivity should be drawn at the
reciprocal of the lowest value measured. Since Logigian et al. found
values as low as 0.5, only ratios higher than 2.0 can be considered
definitely positive.
Because the study lacks case controls or a population-based estimate
of incidence, the possibility cannot be excluded that the neurologic
disease represented the accidental coincidence of a history of Lyme
disease with another disease. Even if the neurologic disease was
caused by B. burgdorferi, a partial recovery from the acute disease
seems more probable than progressive disease. In two of our patients
reporting similar symptoms after Lyme disease, antibiotic therapy
seemed to improve some of the symptoms, even though objective
improvement could not be documented. During a follow-up period of one
year, the patients presented with the same symptoms again, although
the clinical findings did not change at all. We believe that the
importance of chronic neuroborreliosis is overestimated.
This summary of the neurosurgical procedures available for the
treatment of pain, written by two specialists in the field, is well
organized, detailed, critical, and presented fairly. It is a book that
neurosurgeons should read. Every specialist in the management of pain
should be familiar with its contents. It will be an important
reference for anyone who wishes to understand specific surgical
procedures or the diseases in which they are used for pain control.
The book itself is timely. There have been great advances in our
understanding of the pathophysiology of pain in the past 10 years.
Much emphasis has been placed on the complexities of clinical problems
in pain, stressing medical, social, psychological, and even economic
mediators of chronic pain. The authors have carried out an extensive
review of the literature and have reassessed traditional and newer
procedures for pain control in the light of this new information.
The introduction is an outstanding philosophical and practical review
of the complexities of the problem of pain. The definitions of somatic
pain and neurogenic pain, with a subgroup called "central pain"
denoting pain from primary lesions in brain or spinal cord, is a
practical simplification of the problem of pain semantics. The
arguments concerning the long-term control of pain through the use of
narcotics in patients with nonlethal diseases are summarized
succinctly. The purpose of the book is to define the current role of
neurosurgical procedures in the management of persistent pain —
procedures based on our new understanding of the anatomical,
physiologic, and pharmacologic features of the pain pathways.
The book is organized on an anatomical and procedural basis. The first
topic details the experience of surgical interruption of nociceptive
pathways and is divided in the traditional way into operations on
cranial and peripheral nerves or their roots and ganglia. Interruption
of spinal-cord pathways, brain-stem lesions, and more central pain-
pathway interruptions follow. There is a major section reviewing the
neurosurgical approaches to the sympathetic nervous system. The newer
techniques of electrical stimulation for pain perception and the
administration of pharmacologic agents for pain in the spinal or
cranial compartments are also described in detail.
Individual sections begin with a useful historical note, discuss the
pathophysiology of the pain state involved, and then describe the
treatments available. The actual techniques are presented in some
detail. The authors then finish with a summary statement of their own
philosophy on the use of each procedure. When the data are
insufficient for a conclusion, they say so. Most important, they
present all the information, so the reader can agree, disagree, or
modify the authors' conclusions after a comprehensive review of the
available material.
Not surprisingly, the book begins with an exhaustive review of the
question of trigeminal neuralgia and procedures performed on the
trigeminal nerve. This reflects both the historical importance of
trigeminal neuralgia in neurosurgery and the great expertise of the
authors. Thermal coagulation of the trigeminal ganglion was introduced
into the United States by Sweet. His leadership in this field is well
recognized. The comparative data concerning radiofrequency thermal
coagulation, glycerol injection, and posterior fossa microvascular
decompression can be made against the background of an excellent
historical review. The arguments presented are not likely to sway the
proponents of these three techniques from their current practice, but
the information is available for all neurosurgeons who read the book
to make decisions concerning their own philosophy on the treatment of
this recurring neurosurgical problem.
In several areas the authors describe a technique and the sparse
supporting literature in enough detail to conclude that there are
insufficient data for any conclusive statement. The treatment of
cluster headache, medial-branch neurotomy for chronic back pain, and
dorsal-root ganglionectomy are examples of this balanced presentation.
Their review should serve as a spur for those who have been using
these procedures to examine the existing data and present information
rigorously.
There are other less well known procedures that the authors present as
worthy of wider use. Selective posterior rhizotomy is one such
operation. In other procedures, such as destruction of the dorsal-root
entry zone, the review serves to illustrate the usefulness of the
operation in some situations, principally in the treatment of pain of
brachial plexus avulsion, while reemphasizing its lack of utility in
others. The authors remind us that the success of a pain procedure in
one disease does not change its investigative status in others in
which it remains unproved.
The usefulness of cordotomy has diminished greatly in the recent past.
Improved oral narcotics and the use of intrathecal narcotic
medications for patients with terminal cancer have eliminated the use
of cordotomy in most centers. It is good to be reminded periodically
of how effective the operation can be, so that appropriate candidates
are not deprived of an excellent procedure for relieving pain.
The extensive review of lesions in the pain pathways in the brain
stem, hypothalamus, and thalamus are of historical and anatomical
value. They serve to remind us that this is a business for a limited
number of experts. The data remain sparse in spite of many years of
application.
By contrast, the review of the field of sympathectomy for pain
reemphasizes that this is an excellent operation for specific
indications. On the other hand, sympatholytic drugs have the potential
of accomplishing the same results, and the number of surgical
sympathectomies continues to decline. The new percutaneous techniques
are described, but as the authors tell us, their long-term denervation
potential remains to be assessed.
There is an excellent review of the stimulation techniques in
peripheral nerve, spinal cord, and brain for pain control. The data
are comprehensive and the conclusions balanced. The review of so-
called deep-brain stimulation is particularly useful. In the past five
years there has been an even greater interest in this field. The
detailed maps of the thalamus being presented by Tasker and Lenz have
the potential to make brain stimulation even more useful in its
current position as the last resort.
The book concludes with a review of the intraspinal and
intraventricular infusion of opioids for pain control. This has become
the standard technique for the treatment of patients with chronic pain
of cancer, and it is now being explored for its usefulness in pain
that complicates nonlethal disease.
The authors did not plan this book to be a comprehensive review of the
treatment of pain. It is a detailed account of the usefulness of
specific procedures. The assessment includes the historical data that
are so important in understanding the outcome of the application of
these procedures. The pathophysiology is described in modern terms,
and a balanced appraisal of the outcome of each procedure is
presented. This book should be required reading for all neurosurgeons
in training and any neurosurgeon who deals with problems of pain. It
is of equal value to pain specialists who need to know the potential
for these procedures to benefit their patients. If specialists do not
have this knowledge, patients can be both deprived of valuable help
and subjected to operations that have little chance of benefit. While
the authors make their own philosophy quite clear throughout the book,
they do so in a balanced fashion presenting all the data and allowing
the reader to come to individual conclusions concerning each
procedure. The reference list is extensive and well chosen. This book
is an invaluable resource to all those committed to the care of
patients with persistent pain.
E. Stark, M.D.
U. Wurster, Ph.D.
Hannover Medical School, 3000 Hannover 61, Germany
1 Reference
*
Logigian EL, Kaplan RF, Steere achéal. Chronic neurologic
manifestations of Lyme disease . N Engl J Med 1990; 323:1438–44.
The above letter was referred to the authors of the article in
question, who offer the following reply:
To the Editor: In diagnosing infection of the central nervous system
in Lyme borreliosis, Drs. Stark and Wurster question the validity of a
cut-off value of 1 for the CSF:serum ratio of antibody to B.
burgdorferi. We have published a separate study on the evaluation of
the intrathecal antibody response to B. burgdorferi in 37 American and
30 German patients with Lyme borreliosis and in 12 control subjects.1
The antibody responses were determined by capture enzyme immunoassay,
which measures directly the proportion of specific to total antibody.
Unlike the indirect systems commonly used, this method does not
require the adjustment of serum and CSF concentrations in order to
compare specific antibody titers.
In that study, American patients with neuroborreliosis had
significantly lower CSF:serum ratios of antibody to B. burgdorferi
than German patients. Even among the patients with meningitis, which
is known to be caused by intrathecal infection with the spirochete,
the mean CSF:serum ratio of specific IgG antibody to the spirochete
was 17 in the European patients as compared with 2 in the American
patients (P<0.05). Of 12 American patients with chronic
encephalopathy, only 5 (42 percent) had CSF:serum ratios above 1 but
not usually more than 2. In comparison, 6 seropositive patients with
peripheral neuropathy due to Lyme disease and 6 seropositive patients
with chronic fatigue after Lyme disease had a mean ratio of 0.7
(range, 0.3 to 1), and none of the 12 patients with other inflammatory
neurologic diseases had a ratio above 1. Thus, the mean values among
patients with Lyme disease who did not have central nervous system
abnormalities were not normally distributed around 1, as hypothesized
by Drs. Stark and Wurster.
For a number of reasons, only one of which concerns the central
nervous system immune response, we believe that the 27 patients
described in our recent article in the Journal had chronic neurologic
manifestations due to Lyme disease.2 Most of the patients had symptoms
of both an encephalopathy and a polyneuropathy, manifested primarily
by memory impairment, distal paresthesias, or radicular pain. In most
instances, memory impairment could be demonstrated on
neuropsychological tests, total protein levels in CSF were elevated,
and electromyograms showed evidence of an axonal polyneuropathy.
Although all the patients had current evidence of immunity to B.
burgdorferi, only about half of those with encephalopathy had
CSF:serum ratios of IgG antibody to the spirochete between 1 and 2.
Determination of the intrathecal antibody response to B. burgdorferi
has limitations as a diagnostic test. First, demonstration of an
intrathecal antibody response is an inconsistent finding among our
patients with central nervous system abnormalities. Perhaps in some
patients with this systemic illness, more antibody is produced in
peripheral lymph nodes than in the central nervous system, and
therefore selective concentration of specific antibody cannot be
demonstrated in CSF. Second, we agree that a positive test does not
prove the presence of a live spirochete; selective concentration of
specific antibody in CSF may still be found for at least months,
albeit at lower levels, in patients who have apparently been treated
successfully for neuroborreliosis.2 We do not think, however, that
this is the explanation for the elevated CSF:serum ratios in our
patients with encephalopathy, since elevated ratios were not found
more frequently in the subgroup of these patients who had previously
had early neurologic manifestations of the illness.
In their introduction, the authors state clearly that this second
edition bears little similarity to the first. The focus and format
have been both improved and amplified, with the result being a very
good small, functional manual for interpreting renal biopsies.
Throughout the book the diagrams are excellent, and they provide a
helpful guide to the photographs. While most of the pictures are very
good, several appear to lack appropriate contrast and are a bit out of
focus. The text is clear, concise, and well written, and it relates
well to the diagrams and photographs. The selected readings after the
discussion of each disease category are particularly well chosen and
very convenient for the reader. It is important to emphasize that The
Renal Biopsy is not a primer or an introduction to nephrology. A basic
understanding of normal and pathologic anatomy is required to maximize
its use.
As an aid to the interpretation of renal biopsies, this small book
succeeds admirably, and it should be useful to any knowledgeable
physician interested in understanding the morphologic and clinical
correlations of renal diseases. The authors' preface provides an up-to-
date list of comprehensive references for those desiring a more
detailed description.
Allen C. Steere, M.D.
New England Medical Center, Boston, MA 02111
Eric L. Logigian, M.D.
Brigham and Women's Hospital, Boston, MA 02115
2 References
1
Steere achéal, Berardi VP, Weeks KE, Logigian EL, Ackerman R.
Evaluation of the intrathecal antibody response to Borrelia
burgdorferi as a diagnostic test for Lyme neuroborreliosis . J Infect
Dis 1990; 161:1203–9.
2
Logigian EL, Kaplan RF, Steere achéal. Chronic neurologic
manifestations of Lyme disease . N Engl J Med 1990; 323:1438–44.