source:  www.canlyme.com/lymepark.html

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

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.