Brian A. Fallon, Mori Schwartzberg, Robert Bransfield, Barry Zimmerman,
Angelo Scotti, Charles, Webber, Michael Liebowitz

Lyme borreliosis (Lyme disease) is a multisystem illness caused by the
spirochete Borrelia burgdorferi. Although dermatologic, articular,
cardiac, opthalmologic, and neurologic manifestations are well known, it is
less well known that psychiatric disorders may also arise as a result of
borrelial infection (1). Depression (2), panic attacks (3), schizophrenia-like
psychotic state (4), bipolar disorder (3), and dementia (5) have been atributed to Lyme borreliosis. In this report, we present
two patients in whom psychiatric symptoms represented the primary manifestations of their late-stage Lyme borreliosis. Specific dilemmas of diagnosis and treatment will be discussed.

CASE REPORTS

CASE 1. Mrs. A. was a 34-year-old, previously healthy married woman who
presented with frontal headaches, slurred speech, distal paresthesias,
fatigue, memory loss, and intermittent visual blurring and diplopia. A
neurologic exam was normal. Brain magnetic resonance imaging (MRI)
revealed multiple whilte matter lesions on T2-weighted scanning. The
differential diagnosis included multiple sclerosis (MS), multi-infarct
syndrome, or Lyme encephalitis. Blood tests were unremarkable except for a
reactive antibody test for Lyme borreliosis. Because of the prominent
headaches (uncommon in MS), treatment for presumed Lyme borreliosis was
begun using intravenous ceftriaxone. Within 2 weeks, Mrs. A's speech
became pressured and her mood became irritable. She refused further
treatment.

Over the following months, Mrs. A's mood fluctuated from marked agitation
to severe depression accompanied by suicidal threats. Auditory
hallucinations and paranoid delusions emerged along with a full manic
syndrome. She also became violent - slapping her son repeatedly and
breaking furniture.

At this time, a spinal tap reevealed 11 white blood cells (86% lymphocytes
and 14% monocytes) with an elevated cerebrospinal fluid (CSF)
immunoglobulin G (IgG) index of 1.17. There were no oligoclonal bands. A
lyme Ab test was negative in the CSF but positive in the serum. Other labs
were all normal (including TFT's, RPR, ANA, ESR). A neurologist diagnosed
probable MS, although Lyme borreliosis as a cause of these symptoms could
not be ruled out. She was then promptly admitted to a psychiatric
hospital. A sleep-deprived EEG was normal. She was treated with lithium,
perphenazine, and valproic acid. Her thoughts became less paranoid and her
behavior less impulsive, but intermittent illogical thinking and poor
insight remained. After 2 months, she was discharged with the diagnoses of
"bipolar disorder, manic, and psychosis - improved" and "MS".

During the following 8 months, Mrs. A's poor insight, illogical thinking,
irritability, and headaches continued. In addition, she developed diffuse
paresthesias, migratory large-joint arthralgias, a stiff neck, lancinating
spine pain, and persistent severe fatigue. At this point, a rheumatologist
elicited a history 2 years earlier of a circular red rash with central
clearing followed by flu-like symproms and a stiff neck. Repeat serologic
tests again revealed a positive Lyme antibody test. Repeat CSF tests,
other than a mildly elevated protein, were normal [including cell count,
Lyme Ab by enzyme-linked immunosorbent assay (ELISA), oligoclonal bands,
and myelin basic protein]. Despite apparently normal CSF, Mrs. A. was
re-diagnosed as having persistent Lyme borreliosis (not MS) because of
symptoms suggestive of peripheral and cranial neuropathies, large joint
articular symptoms, past lymphocytosis in CSF (meniogoencephalitis),
continued positive Lyme serologies, and a history of probable erythema
migrans rash. Mrs, A, was given 15 weeks of IV ceftriaxone. Her physical
and psychiatric symptoms improved markedly by the 5th week of therapy, and
she was asymptomatic by the 12th week. All medications, including the
psychiatric ones, were discontinued. This remission was sustained for 1.5
years.

Four years after the initial rash, Mrs. A. had another episode of manic
psychosis that required hospitalization. A repeat MRI showed one new white
matter lesion. There were no physical symptoms suggestive of active Lyme
borreliosis. A spinal tap revealed 10 lymphocytes. Although conventional
indirect antibody tests for CNS Lyme disease were unremarkable (CSF Lyme
ELISA at the upper limits of normal), more sensitive ELISA tests using
immune complex dissociation methods (6) (Stony Brook University) revealed
Borrelia-specific IgG complexes in the CSF at a level of 0.120 (cutoff =
0.067). The serum Lyme IgG was also reactive. Under the assumption that
this manic episode was related to active CNS Lyme disease, Mrs. A. was
given psychiatirc medication (lithium, valproic acid, and perphenazine) and
12 weeks of IV antibiotics followed by maintenance of oral antibiotics.
She improved rapidly. her psychiatric medications were tapered at 10
months. Twelve months after the second manic episode, Mrs. A. remains
completely well.

The illness imposed a marked strain upon Mrs. A's family. After her
husband and children left her, she lived in a homeless shelter. Once the
infectious cause of the manic episode was explained, the family reunited.
Mrs. A. had no prior psychiatric problems and no family history of mania.
When she developed the presumed erythema migrans rash, she was living in a
Lyme-endemic rural area heavily inhabited by deer. Shortly thereafter, she
moved to a suburban area. Between recurrences of Lyme disease, there was
no known tick bite or reexposure to a wooded area.

CASE 2. Mrs. B. was a 22-year-old, previously healthy woman who in late
summer developed a flu-like illness and headaches, followed months later by
swollen glands and painful joints, low-grade fevers, severe fatigue,
stuttering, and more severe occipital headaches. At times, she had
hyperacusis and photophobia. Physical and neurologic exams were normal.
Blood tests revealed an "indeterminate" Western blot for Lyme borreliosis
(41 kDa, 83 kDa bands), a positive cytomegalovirus (CMV) IgG titer (1:16),
and a positive Herpes IgG titer (2.60). Brain MRI was normal on two
occasions.

there was no history of a tick bite or rash. She did however live in a
Lyme-endemic area and 4 months prior to the onset of symptoms she worked in
a veterinarian's office.

Nine months after onset of illness, a diagnosis of probable Lyme
borreliosis was made based on the physical symptoms and the two reactive
bands on the Western blot. Four weeks of oral antibiotics were of no help.
A subsequent 8-week course of IV ceftriaxone led to marked improvement in
her headaches and joint pain. Several months later, because of extreme
fatigue and the possibility of a systemic CMV infection (IgG titer 1:64),
Ms. B. was treated with acyclovir. The fatigue persisted, and the
headaches and painful joints resumed. Fifteen months after illness onset,
given the possibility of persistent Lyme borreliosis, Ms. B. was treated
with a second course of IV ceftriaxone (7 weeks). This led to a resolution
of the fatigue and physical symptoms.

Twenty-one months after illness onset, Ms. B developed irritability, a
spontaneous panic attack, intrusive obsessional thoughts with checking, and
depression. She was treated with clomipramine. This syndrome then
developed into mania with rapid mood swings ( from grandiosity to sudden
tearfulness), suicial thoughts, paranoid delusions, and auditory
hallucinations. Serologic and routine CSF tests for Lyme borreliosis were
negative. She was hospitalized and diagnosed as having atypical bipolar
disorder and possible obessive compulsive disorder. Her manic state was
partially controlled with lithium. After discharge, she continued to be
severly depressed, and she had evidence of cognitive dysfunction - trouble
in spelling, writing, and verbal fluency.

Over the course of the following year, Ms. B's depression worsened and
culminated in a life-threatening suicide attempt for which she was
hospitalized. Mania and panic attacks emerged, along with paranoia, verbal
aggressiveness, violent impulses, irritability, and auditory
hallucinations. Other symptoms returned: stuttering, hip and knee pain,
blurred vision, concentration and memory problems, and occipital headaches.
Serologic studies for Lyme borreliosis were negative. An EEG was normal.
Additional courses of antidepressants were tried without success.
Electroshock theraoy was considered. Because case reports have linked Lyme
borreliosis with psychiatric disorders, an empiric trial of IV ceftriaxone
was initiated. During the first 2 weeks, Ms. B's psychiatric symptoms
worsened with a marked increase in agitation. Obsessive-compulsive
symptoms, such as horrific images of killing others and excessive bathing,
returned. After 2 week, Mrs. B's symptoms markedly diminished and she was
discharged shortly thereafter. After 12 weeks of IV antibiotics, Ms. B's
psychiatric and cognitive symptoms were nearly completely resolved. The
arthralgias and headaches were less severe. On 5 month follow-up, Ms. B.
remains stable. She continues on lithium and oral antibiotic. Although
tests for Lyme borreliosis were negative throughout the hospitalization (2
Western blots and 1 ELISA), Lyme tests after the hospitalization revealed
a Western blot that was equivocal for IgG (41 kDa band) but positive for
IgM (25, 41, and 83 kDa bands).

Mrs. B's past psychiatric history is unreemarkable. Her family history is
positive for migraines. A maternal aunt was hospitalized twice for
"nervous breakdowns".

DISCUSSION
Mrs. A. and Ms B. were diagnosed as having disseminated, late-stage Lyme
borreliosis. In both cases, psychiatric presentations were prominant and
profoundly disruptive. In both cases, initially no relationship was
thought to exist between the history of Lyme borreliosis and the
psychiatric disorders. In both cases, treatment for Lyme borreliosis led
to a marked improvement in both the psychiatric and systemic symptoms. In
both cases, a return of symptoms occurred despite prior antibiotic
treatment. In this discussion, different aspects of the diagnosis and
management of Lyme borreliosis will be presented with illustrations fromt
these two patients.

DIAGNOSIS. the Centers for Disease Control and Prevention (CDC)
epidemiologic surveillance criteria for the diagnosis of Lyme disease
require a history of exposure to a Lyme-endemic area and either 1) a
physician-diagnosed erythema migrans rash, or 2) serologic evidence of
exposure to B. burgdorferi and one of the following: arthritis, neurologic
symptoms (peripheral neuropathy, meningitis, encephalitis,
meningoencephalitis), or cardiac conduction defects. These criteria are
unduly restrictive for clinical purposes because about one-third of
patients do not recall an erythema migrans rash and because serologic
testing may be unreliable (7), with both false positive and false negative
results. The serologic tests most commonly used are the ELISA and the
Western blot, but newer methods are being standardized such as the
polymerase chain reaction (8) and the antigen capture assays (9). Further
complicating diagnosis is that some patients with CNS Lyme borreliosis may
have apparently normal EEG, MRI, and CSF Lyme studies (10). In these
situations, physicians must rely on the patient's full clinical
presentation in making the diagnosis.

Lyme borreliosis is known to have protean manifestations, some of which do
not include any of the typical features outlined by the CDC. Some of the
presentations are listed in TABLE 1.

----------------------------------------------
TABLE 1
DISORDERS ASSOCIATED WITH
NEUROLOGIC LYME BORRELIOSIS
-----------
COMMON OR TYPICAL

"Aseptic meningitis
Encephalopathy
Meningoencephalomyelitis
Cranial nerve palsies (e.g., Bell's palsy, optic neuritis)
Radiculoneuropathy
Chronic fatigue-like syndrome
Depression
Insomina
Mood lability and behavioral disorders in children

LESS COMMON

Spastic paresis or hemiparesis
Transverse myelitis
Cerebellar syndromes
Extrapyramidal syndromes
Seizure disorders
Dementia
Pseudo-tumor-like syndromes in children
Tulio phenomenon
Cerebrovascular disease
Demylinating-like disorders (e.g., multiple sclerosis-like)
Anterior horn cell-like disease (e.g., ALS-like, diffuse motor neuropathy)
Guillain-Barre-like syndrome
Psychotic or anxiety disorders
--------------------------------------

Because of lyme borreliosis's ability to mimic other known disease, it has
been dubbed the "new great imitator" (11). As was true for syphilis - the
former "great imitator" - late-stage Lyme borreliosis psychiatric disorders
may appear as the predominant symptom. When Lyme borreliosis is suspected
but not proven, either because the clinical profile is not typical or
because the diagnostic tests are negative, some physicians opt to use a
trial of antibiotics as both a diagnostic and therapeutic tool. If the
patient improves, the diagnosis is supported.

With the exception of AIDS, infectious causes of psychopathology are not
commonly recognized in this country. TABLE 2 lists a variey of medical
disorders, including infectious diseases, that should be considered in the
differential diagnosis of any new psychotic disorder.

-------------------------------------
TABLE 2
-------------------------------------
SELECTED INFECTIOUS CAUSES OF PSYCHIATRIC DISORDERS
___________________________________________
BACTERIAL INFECTIONS

ACUTE: Group A Beta Hemolytic streptococcus,
Pneumococcus, Haemophilus,
Meningococcus

SUBACUTE: Leptospira, Borrelia burgdorferi,
Treponema pallidum,
Mycobacterium tuberculosis,
Whipple's disease

VIRAL
INFECTIONS: Coxsackievirus, Cytomegalovirus,
Enterovirus, Epstein-Barr virus,
Herpes simplex virus, Human
immunodeficiency virus,
Influenza virus, Measles virus,
Papovavirus, Poliovirus, Rabies
virus, Toga virus

PROTOZOAL
INFECTION: Toxoplasmosis

FUNGAL
INFECTIONS: Cryptococcosis, Coccidiomycosis,
Histoplasmosis

PARASITIC
INFECTION: Cysticercosis

__________________________________________

Different diagnostic issues are raised by the two cases presented here.

In the case of Mrs. A., doctors were initially uncertain whether the
correct diagnosis was Lyme borreliosis or MS. These disorders share
similiar features: fluctuating neurologic symptoms, demyelinating-like
lesions or MRI scans, and CSF lymphocytosis. The diagnosis was made more
difficult by the fact that routine CSF testing for Lyme antibody was
negative. The rheumatologist linked this patient's mania, psychosis, and
aggressive behavior to infection with B burgdorferi because of the clinical
and laboratory constellation: a probable erythema migrans rash prior to the
onset of illness, positive Lyme serologies, MRI lesions, central and
peripheral neurologic symptoms, prominent headaches, migratory arthralgias,
repeated CSF lymphocytosis, and the remission of articular and psychiatric
symptoms after an extended course of antibiotics. Confirmation of B.
burgdorferi's involvement in the CNS came when more sensitive techniques
were used to isolate Borrelia-specific antibodies. Although there is
significant overlap in the clinical phenomenology between Lyme borreliosis
and MS, Lyme borreliosis is the most parsimonious diagnosis when
extraneural disease is present (e.g., dermatologic, articular), when there
is a history of an erythema migrans rash and/or positive serologic tests,
and when CSF oligoclonal bands and/or myelin basic protein are absent.

The diagnosis of Lyme borreliosis in Ms. B. was made based on the presence
of a multisystem illness that included severe headaches, fatigue, joint
swelling and pain, insomnia, and memory problems. Ms. B's initial Lyme
tests were negative except for a Western blot IgG that had two positive
bands. A more recent Lyme test was positive; this may represent a
late-appearing IgM response as has been described (12) or, possibly,
reinfection. Ms. B.'s psychiatric symptoms started 21 months after the
presumed onset of infection. These symptoms included depression, paranoid
delusions, bipolar disorder, panic attacks, and obsessive-compulsive
disorder. Worth noting is that the influenza epidemic of the 1920's was
also associated with obsessive-compulsive disorder in some patients (13).
More recently, a theory has been proposed that links new-onset
obsessive-compulsive disorder in children to neuroimmunological
dysfunction; cross-reactive antineuronal antibodies in some children with
obsessive-compulsive disorder are thought to have been triggered by
infection with Group A Beta Hemolytic Streptococcus (14). Ms. B's
psychiatric disorder was unresponsive to psychiatric medications. When IV
antibiotics were instituted, the psychiatric disorders resolved rapidly.
The presence of typical Lyme symptoms, suggestive serologies, excellent
response to IV antibiotic treatment, and the exposure to a Lyme-endemic
area all support the diagnosis of Lyme borreliosis.

TREATMENT. Guidelines for the treatment of Lyme borreliosis have been
changing rapidly. Until recently, a 4-week course of IV antibiotics was
considered curative for patients with symptoms of CNS Lyme borreliosis.
Now it is recognized that some patients relapse after an initial good
response and require additional courses of IV antibiotics (15). Patients
who are not treated until later in the course of illness are thought to be
more likely to develop a chronic, relapsing disorder. Such was the case
with these two patients. Mrs. A.'s first antibiotic course was begun 1
year after the presumed onset of infection (rash), and Ms. B.'s first
course was begun 9 months after the onset of symptoms. Despite extensive
courses of oral and IV antibiotics (17 weeks), Mrs. A. experienced a second
manic episode with evidence of persistent CNS infection. Similarly, Ms.
B.'s first signs of psychiatric illness began after having received 15
weeks of IV antibiotics and 4 weeks of oral antibiotics.

The persistence of symptoms despite antibiotic treatment suggests several
possibilities: Lyme borreliosis has nothing to do with the psychiatric
disorder; Lyme borreliosis triggered a psychiatric disorder that is now
unrelated to ongoing infection; the spirochete has an unusual ability to
resist antibiotic treatment; much longer courses of antibiotic treatment
are needed; or the patient was reinfected. As already discussed, in both
cases we believe Lyme borreliosis was related to the psychiatric disorder.
In the case of Mrs. A., it is unlikely that Lyme borreliosis triggered a
psychiatric disorder that is now autonomously occurring. Mrs. A. had
borrelial antibodies in her CSF, thus suggesting ongoing infection.
However, because psychiatric medications and IV antibiotics were
administered simultaneously to treat her second manic episode, we cannot be
certain that the psychiatric medications alone would not have been
sufficient to treat the psychiatric disorder. In the case of Ms. B., the
psychiatric disorder was refractory to all psychiatric treatments.
Although she was maintained on lithium throughout her hospital stay, the
dramatic response to the IV antibiotic treatment supports the assumption of
ongoing infection. Could these patients have been reinfected? Mrs A. had
moved out of the Lyme-endemic area where she contracted her initial
infection, making reinfection unlikely. Ms. B. continued to reside in an
endemic area and therefore may have been reinfected.

That B. burgdorferi is capable of resisting routine courses of antibiotic
treatment has long been suspected on clinical grounds. Preclinical and
clinical evidence is now emerging to support the need for long-term
treatment in some patients (15). How does B. burgdorferi evade both the
patient's immune system and antibiotics? Recent studies have identified B
burgdorferi intracellularly in human fibroblasts (16) and endothelial cells
(17). Because organisms with intracellular localizations are difficult to
cure, these in vitro observations may explain how B. burgdorferi can
persist in the human host. Patients' symptoms, including psychiatric
oones, may worsen during the first few weeks of antibiotic treatment (1).
This phenomenon has been compared to the Jarisch-Herxheimer reaction that
occurs when antibiotic treatment for syphilis is initiated. Mrs. A.'s
first manic episode actually may have been precipitated or hastened by the
IV antibiotic treatment. Ms. B.'s clinical condition deteriorated
dramatically during the first 2 weeks of IV antibiotic treatment only to
improve thereafter. It is worth noting that, in the treatment of tertiary
syphilis, the Jarisch-Herxheimer reaction has included new-onset psychosis
(18).

CONCLUSIONS. The psychiatric presentations of Lyme borreliosis may be as
diverse and as debilitating as occur with neurosyphilis. Primary
prevention and early treatment are keys to the control of this epidemic.
However, because neurologic symptoms may emerge months to years after the
initial infection (2), Lyme borreliosis may not be considered in the
diagnosis - especially if the patient has moved out of the Lyme-endemic
area. Failure to recognize active Lyme borreliosis can allow the infection
to progress, perhaps allowing a treatable acute infection to become a
relapsing chronic one that is ultimately less reponsive to antibiotics.
Therefore, psychiatrists need to keep in mind the diagnosis of Lyme
borreliosis when evaluating a patient with a new onset of
treatment-refractory psychiatric illness.
----------------------------------------
REFERENCES:
1. Fallon, BA et al: The neuropsychiatric manifestations of Lyme
borreliosis. Psychiatr Q. 1992; 63:95-117.

2. Logigian, EL et al.: Chronic neurologic manifestations of Lyme
disease. New Engl J Med 1990; 323:1438-1444.

3. Fallon, BA et al.: Psychiatric manifestations of Lyme borreliosis. J.
Clin Psychiatry 1993; 54:263-268.

4. Pfister HW, et al.: Catatonic syndrome in acute severe encephalitis
due to Borrelia burgdorferi infection. Neurology 1993; 43:433-435.

5. Ackerman R, et al.: Chronic neurologic manifestations of Erythema
migrans borreliosis. Ann NY Acad Sci 1998; 539:16-23.

6. Schutzer SE, et al.: Sequestration of antibody to Borrelia
burgodorferi in immune complexes in seronegative Lyme disease. Lancet 1990;
1:312-315.

7. Bakken, LL, et al.L Performance of 45 laboratories participating in a
profeciency testing program for Lyme disease serology. JAMA 1992; 268:
891-895.

8. Rosa PA, Schwan TG: A specific and sensitive assay for the Lyme
disease spirochete B. burgdorferi, using the polymerase chain reaction. J
Infect Dis 1989;160:1018-1029.

9. Hyde, FW et al.: Detection of antigens in urine of mice and humans
infected with B. burgdorferi, etiologic agent of Lyme disease. j Clin
Microbiol 1989; 12:58-61.

10. Coyle, PK: Neuroloic Lyme disease. Semin Neurol 1992; 12:200-208.

11. Pachner, AR: Neurologic manifestations of Lyme disease, the new "Great
Imitator". Reviews of Infectious Diseases 1989;11(suppl 6):S1482-S1486.

12. Craft, JE et al.: Antigens of B burgdorferi recognized during Lyme
disease: appearance of a new immunoglobulin M response and expansion of the
immunoglobulin G response late in the illness. J Clin Invest 1986;
78:934-939.

13. von Economo C: Encephalitis lethargica: its sequelae and treatment.
London, Oxford University Press, 1931, pp 118-131.

14. Swedo SE, Leonard HL, Kiessling LS: Speculations on antineuronal
antibody-mediated neuropsychiatric disorders of childhood. Pediatrics 1994;
93:323-326.

15. Liegner KB: Lyme diseaseL the sensible pursuit of answers. J. Clin
Microbiol 1993; 31:1961-1963.

16. Georgilis K, Peacocke M, Klempner, KS: Fibroblasts protect the Lyme
disease spirochete, B burgdorferi, from ceftriaxone in vitro. J. Infect Dis
1992; 166:440-444.

17. Ma Y, Sturrock A, Weis JJ: Intracellular Localization of B.
burgdorferi within human endothelial cells. Infect Immun 1991; 59:671-678.

18. Thomas, EW: Syphilis: Its course and Management. New York, Macmillan,
1949, pp 112-113.

Address reprint request:
Dr. Fallon, New York Psychiatric Institute, 722 West 168th Street, New
York, New York 10032.

Unfortunately we lost a lot with the expiry of Donna Herrell's website a few months back.

Glad to see Paula posted complete articles!

Cheryl

quote:

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Originally posted by Tincup:
Up for Cheryl and to be saved from the axe.

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