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1543-2165(2003)127%3C1204:LPANCS%3E2.0.CO%3B2

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Archives of Pathology and Laboratory Medicine: Vol. 127, No. 9, pp.
1204-1206.

Lyme-Associated Parkinsonism: A Neuropathologic Case Study and Review of the
Literature

David S. Cassarino, MD, PhD,a Martha M. Quezado, MD,a Nitya R. Ghatak, MD,a
and Paul H. Duray, MDa

      aFrom the Laboratory of Pathology, National Cancer Institute, National
Institutes of Health, Bethesda, Md (Drs Cassarino, Quezado, and Duray); and
the Departments of Pathology and Neuropathology, {*filter*}ia Commonwealth
University, Richmond (Dr Ghatak)

Accepted April 11, 2003

     Neurological complications of Lyme disease include meningitis,
encephalitis, dementia, and, rarely, parkinsonism. We present a case of
striatonigral degeneration, a form of multiple system atrophy, in
Lyme-associated parkinsonism. A 63-year-old man presented with erythema
migrans rash, joint pains, and tremors. Serum and cerebrospinal fluid
antibodies and polymerase chain reaction for Borrelia burgdorferi were
positive. Clinical parkinsonism was diagnosed by several neurologists.
Despite treatment, the patient continued to decline, with progressive
disability, cognitive dysfunction, rigidity, and pulmonary failure. At
autopsy, the brain showed mild basal ganglia atrophy and substantia nigra
depigmentation, with extensive striatal and substantia nigral neuronal loss
and astrogliosis. No Lewy bodies were identified; however,
ubiquitin-positive glial cytoplasmic inclusions were identified in striatal
and nigral oligodendroglia. There were no perivascular or meningeal
infiltrates, the classic findings of neuroborreliosis. To our knowledge,
this is the first report of striatonigral degeneration in a patient with B
burgdorferi infection of the central nervous system and clinical
Lyme-associated parkinsonism.

Lyme disease is an infection caused by Borrelia burgdorferi, a spirochete
transmitted by Ixodes ticks in the United States. Patients often initially
present with the classic erythema migrans rash, a macular, erythematous,
circular area with central clearing that expands around the site of the tick
bite. The rash usually begins within 3 to 30 days after the bite, but is
only found in about 60% of patients.1 Patients with long-standing Lyme
disease may develop myocarditis, oligoarthritis of large joints, and central
nervous system involvement (typically meningitis, encephalitis, and cranial
neuropathy, and, rarely, basal ganglia and cognitive dysfunction) in the
tertiary phase of the disease. There have also been reported cases of
patients with Lyme disease developing clinical parkinsonism.2-6 We describe
what to our knowledge is the first such case with autopsy follow-up.

Patients with Lyme meningitis usually show increased numbers of lymphocytes
and plasma cells in the pia and arachnoid, with some atypical lymphocytes.1
In Lyme encephalitis, there is edema, microglial activation, and
intraparenchymal lymphoplasmacytic infiltrates in a pre{*filter*}ly
perivascular distribution.1 These findings were lacking in the current case.
Instead, the brain showed neuronal loss, gliosis, and glial cytoplasmic
inclusions in the striatum and substantia nigra, leading to the diagnosis of
striatonigral degeneration (SND).

Striatonigral degeneration is now recognized to be a subtype of multiple
system atrophy (MSA), a relatively uncommon neurodegenerative disease
characterized by neuronal loss and astrocytosis of the basal ganglia and
substantia nigra, with characteristic ubiquitin-positive glial cytoplasmic
inclusions.7 These inclusions contain -synuclein, which can be identified
immunohistochemically in glial cells. To our knowledge, the presence of
glial cytoplasmic inclusions and -synuclein has not been previously reported
in the brains of patients with Lyme disease.

REPORT OF A CASE

The patient was a previously healthy, 63-year-old white man who presented
with an erythema migrans rash on his left inner thigh in June 1995. He
developed diffuse musculoskeletal pain, swelling of the left knee, tremor of
the left hand, and pain in the left shoulder and arm during the subsequent
year. In June 1996, the diagnosis of Lyme disease was made based on a serum
Western blot showing B burgdorferi-specific immunoglobulin (Ig) G bands. The
patient's musculoskeletal pains and hand tremor worsened during the next few
months, with loss of function. He was treated with 3 weeks of intravenous
(IV) ceftriaxone without improvement in August 1996. A magnetic resonance
imaging scan of the head and neck was reportedly normal in February 1997. He
resumed antibiotic therapy with 2 weeks of IV ceftriaxone and then 42 days
of IV cefotaxime sodium, with little improvement in his condition. In May
1997, a neurology consult was obtained, at which time a spinal tap
cerebrospinal fluid (CSF) was found to be positive by enzyme-linked
immunosorbent assay (ELISA) for B burgdorferi-specific IgG. Neurological
examination documented parkinsonism, which was attributed to Lyme
neuroborreliosis. Pharmacological treatment was initiated, without apparent
benefit.

By July 1998, the patient had lost 20 kg and had developed symptoms,
including chronic fatigue, tremors, and neck and bilateral hand pain; his
movements were stiff and painful. He also developed cogwheel rigidity in
August 1998. Due to continued clinical deterioration, he was started on {*filter*}
antibiotics, including clarithromycin, ciprofloxacin, and
hydroxychloroquine. His tremors seemed to improve after treatment; however,
his other symptoms continued unabated. Western blots for B
burgdorferi-specific IgM (30, 34, 41, and 93 kd) and IgG (30, 39, 41, 58,
66, and 93 kd) antibodies were positive in November 1999. Despite continued
antibiotic treatments, the patient's movement disorder continued to
progress. By May 2000, he exhibited decreased memory, incontinence,
drooling, and inability to ambulate independently or to care for himself.
Cerebrospinal fluid and {*filter*} polymerase chain reaction (PCR) tests at that
time for Borrelia species were positive, and PCR for Babesia species was
negative. A red {*filter*} cell culture showed classic spirochetes in his red
cells. {*filter*}multiagent antibiotic therapy was continued.

In December 2000, the patient was admitted to the hospital for aspiration
pneumonia and was treated with antibiotics and parenteral nutrition. He was
readmitted in January 2001 for another episode of aspiration pneumonia. He
had a sputum culture that was positive for Staphylococcus aureus, and he was
treated with IV vancomycin. In February 2001, a sputum culture was
reportedly positive for B burgdorferi. A repeat serum Western blot for
Borrelia IgM and IgG was positive, and PCR for Babesia organisms was also
positive. Despite continued antibiotic treatments (IV vancomycin,
azithromycin, and atovaquone), the patient's neurological status continued
to decline, and he finally succumbed to infection and respiratory failure in
April 2001. A full autopsy was performed.

PATHOLOGIC FINDINGS

Gross examination revealed few significant findings. Externally, there were
multiple bruises and IV marks, and decubital ulcers over the sacrum. The
chest cavities contained fluid and there were bilateral pleural effusions.
The brain and spinal cord were externally unremarkable; on sectioning, the
basal ganglia showed mild atrophy bilaterally (Figure 1 ), with greater
changes on the left, and the substantia nigra showed depigmentation. The
cerebellum also appeared to show mild atrophy.

Microscopic examination of the heart showed scattered lymphocytes and plasma
cells, with areas of mild fibrosis, suggesting possible remote myocarditis.
No significant inflammation was identified in any other organs. The brain
showed extensive neuronal loss and severe astrogliosis in the striatum
(Figure 2 ) and substantia nigra (Figure 3 ). Other brain regions were
unaffected. No Lewy bodies were identified; however, there were
ubiquitin-positive glial cytoplasmic inclusions in scattered oligodendroglia
in the striatum (Figure 4 ) and substantia nigra, but not in the pons
(including the olivary nuclei) or cerebellum. These glial cytoplasmic
inclusions also stained positively with -synuclein immunohistochemistry
(Figure 5 ). Premortem Western blot and ELISA studies showed positive
reactions for Borrelia-specific IgM and IgG antibodies in both serum and CSF
samples (Tables 1  and 2 ). Polymerase chain reaction analysis for
Borrelia-specific sequences in the substantia nigra and basal ganglia was
performed; however, the results were not able to be confirmed on the
postmortem tissue.

COMMENT

To the best of our knowledge, this report describes the first case of
parkinsonism arising in association with Lyme disease to come to autopsy.
Histological study of the brain displayed characteristic morphologic changes
of SND, a variant of MSA. The patient's diagnosis of Lyme disease was well
documented, confirmed by both serum and CSF ELISA, Western blots, and
premortem PCR studies. The patient developed signs and symptoms of MSA after
his presentation with the erythema migrans rash, and there was no prior
history of neurologic dysfunction. Although it cannot be excluded that the
SND could have developed independent of his Lyme disease, the temp{*filter*}
association with tertiary Lyme disease, the high titer of Borrelia
antibodies in his CSF, and premortem PCR for B burgdorferi-specific
sequences in the CSF favor an association. The fact that the classic
inflammatory changes associated with Lyme disease were absent may indicate
an atypical central nervous system infection in this patient, or merely that
the infection and inflammation had resolved by the time of death (which
occurred 5 years after infection and after multiple courses of antibiotics).
In most cases, the organisms cannot be identified in histologic sections.1,6

Regardless of whether the infection had resolved by the time of death, we
hypothesize that it was sufficient to cause ongoing neuronal loss and
astrogliosis leading to SND. Therefore, the negative studies for organisms
in the postmortem tissue may reflect either the absence of organisms or the
persistence of low numbers of spirochetes and false-negative findings.
Overall, we believe that the SND and resulting parkinsonism in this case
might be related to direct infection by Borrelia organisms, or to the immune
response against the organisms, and these findings are therefore of
particular interest because the etiology of SND and MSA is unknown.

Clinical diagnosis of MSA is based on diagnostic criteria, including
parkinsonism with poor or transient response to L-dopa therapy. Patients
often develop progressive bulbar dysfunction leading to dysphagia and
laryngeal stridor, eventually predisposing to aspiration pneumonia.7 Our
patient's parkinsonism was resistant to traditional medications, and he
developed classic signs of parkinsonism as well as dysphagia, consistent
with the clinical course of MSA. In a previous report of Lyme-associated
extrapyramidal features in 5 patients,5 all of the patients exhibited
akinesia, pains, and rigidity, similar to our patient, although only 2
developed tremors. Four of the 5 patients also developed bulbar dysfunction,
a characteristic finding in MSA. Although none of these patients came to
autopsy, and therefore could not be definitively diagnosed with MSA, the
clinical findings were consistent with this conclusion and were generally
similar to findings in our case. One significant difference was that their
patients responded to anti-Parkinson's medications, which is unusual in MSA,
and they also improved on antibiotics. This dissimilarity may indicate a
different underlying pathology compared to the present case, in which there
was little or no improvement with anti-Parkinson's {*filter*} and antibiotics.
Alternatively, as our patient did not receive antibiotics until 14 months
after initial infection, he may have suffered irreversible neuronal damage
by the time treatment was initiated.

Autopsy brain studies on patients with Lyme disease are limited to single
case reports or small case series. In addition to meningoencephalitis,
multiple other neuropathologic findings have been reported. One patient was
found to have rhomboencephalitis on autopsy, with microgliosis and
obliterative inflammatory vasculopathy associated with ischemic infarcts.2
Another case showed multifocal inflammation, neuronal cell loss,
demyelination, and astrocytosis in the cortex, thalamus, cerebellum, and
spinal cord.3 Bertrand et al4 reported 3 cases, 1 of which showed cortical
involvement, and all 3 of which showed cerebral and cerebellar white matter
changes, with associated lymphocytic infiltrates, microglial activation,
spongiform changes, diffuse astrogliosis, and demyelination. To date,
however, no neuropathologic findings have been reported in the substantia
nigra or basal ganglia. Clinically, Kohlhepp et al5 described 5 patients
with Lyme disease with extrapyramidal symptoms and documented CSF infection
by B burgdorferi. Interestingly, treatment of the patients with high-dose
penicillin led to both normalization of their CSF and improvement in their
extrapyramidal symptoms.5

In primates infected with B burgdorferi, brain autopsy and PCR analysis
showed organisms in the leptomeninges, nerve roots, and dorsal root ganglia,
but not in the brainstem, cerebellum, or basal ganglia.6 Histologic and
immunohistochemical studies with polyclonal anti-B burgdorferi antibodies
confirmed the PCR results in this study.6

In summary, this is the first published report of SND or MSA, with
characteristic ubiquitin and -synuclein-positive inclusions, in a patient
with documented B burgdorferi infection of the central nervous system and
clinically diagnosed Lyme-associated parkinsonism. Therefore, this case
raises the possibility of a causal link between B burgdorferi infection of
the central nervous system and SND.

Acknowledgments

We thank Robert G. Beitman, MD, and Gregory P. Bach, DO, for submitting this
fascinating case to us.

References

1. Duray PH, Chandler FW. Lyme disease. In: Connor DH, Chandler FW, Schwartz
DA, Manz HJ, Lack EE, eds. Pathology of Infectious Diseases. Stamford, Conn:
Appleton and Lange; 1997:635-646.

2. Kuntzer T, Bogousslavsky J, Miklossy J. et al. Borrelia
rhombencephalomyelopathy. Arch Neurol 1991;48:832-836. [PubMed Citation]

3. Kobayashi K, Mizukoshi C, Aoki T. et al. Borrelia
burgdorferi-seropositive chronic encephalomyelopathy: Lyme
neuroborreliosis?. An autopsied report. Dement Geriatr Cogn Disord
1997;8:384-390.

4. Bertrand E, Szpak GM, Pilkowska E. et al. Central nervous system
infection caused by Borrelia burgdorferi: clinico-pathological correlation
of three post-mortem cases. Folia Neuropathol 1999;37:43-51.

5. Kohlhepp W, Kuhn W, Kruger H. Extrapyramidal features in Lyme
borreliosis. Eur Neurol 1989;29:150-155. [PubMed Citation]

6. Cadavid D, O'Neill T, Schaefer H, Pachner AR. Localization of Borrelia
burgdorferi in the nervous system and other organs in a nonhuman primate
model of Lyme disease. Lab Invest 2000;80:1043-1054. [PubMed Citation]

7. Lowe JS, Leigh N. In: Graham DI, Lantos PL, eds. Greenfield's
Neuropathology. New York, NY: Oxford University Press; 2002:343-346.

Presented as an abstract at the annual meeting of the American Association
of Neuropathologists, Denver, Colo, June 22, 2002.

Reprints: Paul H. Duray, MD, Laboratory of Pathology, National Cancer
Institute, National Institutes of Health, Bldg 10, Room 2N212, 10 Center Dr,
Bethesda, MD 20892)

? Copyright by College of American Pathologists 2004

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