> I have had mild to moderate Parkinson's for approx.10 years which has been
> well controlled with Sinemet CR and Pergalide.
> I recently begun a course of chemotherapy for carcinoma of the breast.
> After my second lot of chemotherapy my Parkinson's seems to have become
> much worse. Most of the time I can't walk. Increasing my medication doesn't
> seem to help. I will have my last lot of chemotherapy in 4 weeks time.
> Has anyone else had this experience?
> Veronica Levin

Veronica, I don't have an answer; but I did notice a report re
chemotherapy-induced PD on the NPF forum recently, and I re-post it here
for you, in case you would like to print it and discuss it with your
doctor. Best, Kathrynne
================================================

Chemotherapy Induced Parkinsonism Responsive to Levodopa: An
under-recognized Entity

Cathy Chuang MD and others

Movement Disorders 2003 volume 18, page 329

CASE 1

A 49-year-old woman was admitted with a 3-week course of progressive
parkinsonism. Her past medical history was significant for breast cancer
diagnosed 8 years previously and treated with a mastectomy and adjuvant
chemotherapy. Cancer recurred 1 year before admission and she was
treated unsuccessfully with multiple agents, including capecitabine,
docetaxel, vinorelbine and tamoxifen. Six weeks before admission she
began a regimen of weekly infusions of the antimetabolite gemacitabine.
In addition to the above chemotherapeutic agents that were given over
the past several months the only other medication she had taken was
furosemide for upper extremity edema. She had no exposure to
neuroleptics or any other dopamine receptor blocking agents, including
anti-emetics. Three weeks later, she began to complain of generalized
slowness drooling, softness of speech, and restlessness, and required
increasing assistance with most daily activities.

Examination revealed severe parkinsonism with 4+ bradykinesia and 3+
rigidity bilaterally, 3+ right, leg rest tremor, severe facial masking,
hypophonia, and a shuffling gait with absent arm swing. Restlessness in
the legs prompted her to pace frequently. Routine laboratory studies
including blood counts and serum chemistries were normal, as was a
magnetic resonance imaging (MRl) scan of the brain. A
fluro-deoxyglucose-positron emission tomography (FDG-PET) scan showed
globally reduced uptake, with focal reductions in the frontal and
lateral temporal cortex and basal ganglia. A fluorodopa PET scan was
recommended, but. the patient refused further testing


Gemcitabine, which was last administered I week before admission, was
immediately discontinued, and she was treated with Sinemet
(carbidopa-levodopa), with dose increases up to 1,500 mg of levodopa per
day. Within 2 to 3 days of levodopa treatment, her akathisia and
parkinsonism began to improve; .she experienced wearing-off 'phenomena but
no dyskinesias, she was also treated with lorazepam and temazepam for
sleep difficulty and ondansetron for intermittent nausea. On follow-up
evaluation 2 months later (on 1000 mg of levodopa/day). her parkinsonism
had completely resolved, Levodopa was then discontinued 1 month later
without any recurrence of parkinsonism.


CASE 2

A 75-year-old woman with a history of chronic lymphocytic leukemia
hypertension idiopathic pulmonary fibrosis, and metastatic squamous cell
carcinoma of unknown primary received a course of treatment with
carboplatin and paclitaxel 2 weeks before onset of parkinsonism. Two weeks
later, she was hospitalized with acute respiratory distress and
diagnosed with a deep vein thrombosis and pulmonary embolus. At the same
time she developed severe slowing, tremor, and hypophonia. Her last dose
of carboplatin and paclitaxel was 1 month before admission. The only
other medication she had been taking was nifedipine. She had no exposure
to neuroleptics or any other dopamine-rcceptor-blocking agents including
antieimetics. A head computed tomography scan; blood counts and serum
chemistries: and anti-Hu, antithyroglobulin, and antimicrosomal
antibodies were normal. A brain MRI scan was only significant for mild
atrophy and white matter ischemic disease.

On examination, she had severe hypophonia and marked facial masking,
bilateral cogwheel rigidity and bradykinesia. and resting and action
tremor and myoclonic jerks and was unable to sit or stand without
assistance. A modified barium swallow revealed severe oropharyngeal
dysphagia and she was scheduled for placement of a feeding tube. In the
interim, she was treated with levodopa increasing up to 1000 mg per day.
Within 2 to 3 days, her parkinsonism and swallowing improved rapidly and
dramatically, averting the need for enteral feeding. Ten days after
admission, she was switched from carboplatin and paclitaxel to
docetaxel. After 2 weeks of levodopa therapy, she was able to walk
independently and feed herself. Parkinsonism although present, was
markedly improved. Two months later, levodopa was discontinued and she
remained free of any parkinsonian symptoms or signs when followed up 1
year later.

CASE 3

A 60-year-old woman with a 2-year history of chronic myelogenous
leukemia presented with a rest tremor of the face,tongue, and legs,
Eight months before evaluation. she underwent a bone marrow
transplantation for which she received high-dose cyclophosphamide,
hydroxyurea and a-interferon. Three, months later, she developed an
acute lymphoblastic leukemic transformation and was treated with
high-dose busulfan, cyclophosphamide, and stem cell rescue. Her
posttransplant course was complicated by acute renal failure, from which
she recovered; pneumonia, which was treated with intravenous
trimethoprim sulfamethoxozole and prednisone; and pansinusitis. which
was treated with levonfloxacin. She did not have any exposure to
neuroleptics or any other dopamine-receptor-blocking agents,
including antiemetics.

Approximately 4 months after her last course of chemotherapy, she
developed a rest tremor of her chin and both legs, which decreased with
action. Her medications at that time only included prednisone,
ciprofloxacin, and hydroxyurea. Examination showed dysarthric speech,
mild bradykinesia, minimal rigidity, stooped posture, and a shuffling
gait with en bloc turns. She was treated with levodopa (600 mg/day), and
tremor, speech, and gait difficulty improved within days. Two months
later, levodopa was discontinued without recurrence of parkinsonism.

DISCUSSION

We describe 3 patients who developed acute or subacute parkinsonism
after receiving chemotherapy. Signs of parkinsomsm included rest tremor,
cogwheel rigidity, bradykinesia, and in the first 2 cases, postural
impairment. Parkinsonism improved dramatically with levodopa, and
parkinsonian signs spontaneously improved over weeks to months despite
stable dosing of levodopa and eventual withdrawal of the drug.


Our first 2 cases were similar in the severity of their parkinsonism and
the rapid onset of symptoms after receiving chemotherapy. In the third
case, onset of parkinsonism was delayed by 4 months and symptoms were
less severe. There is precedent for such a delay in onset of
parkinsonism after chemotherapy. Howell reported a patient with
delayed-onset parkinsonism occurring 4-5 months after a course of CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisolone) A causal
relationship between the chemotherapy and the parkinsonism was not
proven, because the parkinsonism did not remit and, in fact, progressed
despite discontinuation of chemotherapy. In contrast, symptoms and signs
in our third patient were transient and resolved completely after
discontinuation of levodopa, consistent with chemotherapy induced
parkinsonism rather than idiopathic Parkinson's disease.


The response to levodopa was dramatic in all 3 cases, and improvement in
parkinsonism persisted even after levodopa was discontinued. The initial
improvement was rapid and occurred within a few days after levodopa was
started. We believe that this response was not solely secondary to
withdrawal of the offending chemotherapeutic agent. In Cases 2 and 3,
the, chemo therapeutic agents had been discontinued for 1 month and 4
months, respectively, but neither had any improvement of symptoms until
levodopa therapy was begun. Therefore, we assert that the improvement in
parkinsonism occurred as a result of a combination of levodopa therapy
and the withdrawal of the offending agent.

Our cases of chemotherapy-induced parkinsonism occurred after exposure
to gemcitabine, carboplatin and paclitaxel, and cyclophosphamide and
busulfan, agents that possess different mechanisms of action.
Gemcitabine is a novel deoxycytidine analog similar to cytosine
arabinose (ara-C) in the way it inhibits DNA polymerase. Carboplatin
cross-links DNA, and paclitaxel stabilizes microtubules inhibiting
mitosis. Both cyclophosphamide and busulfan act by alkylating and
cross-linking DNA. Many other agents have been reported to cause a
similar syndrome in single or multiple case reports (Table I).
Cyclophosphamide and ara-C are the most commonly implicated agents,
especially in combination with other chemotherapeutic agents before bone
marrow transplantation. Other agents reported to cause parkinsonism
include etoposide fluorouracil, vincristine and Adriamycin, doxorubicin,
mitoxantrone, and methotrexate.


The mechanism by which these drugs produce parkinsonism is unknown.
Features suggesting a presynaptic nigrostriatal insult in our patients
include the dramatic response to levodopa and the spontaneous remission of
symptoms with time. That die deficits were reversible suggests the
possibility that these agents cause parkinsonism by affecting the
synthesis, packaging, or release of dopamine, rather than causing direct
and irreversible degeneration of nigral neurons. In an analogous manner,
the vinca alkaloids vincristine and vinblastine have been reported to
decrease the plasma activity of dopamine b-hydroxylase, an enzyme that
catalyzes norepinephrine synthesis. If this were true, one would expect to
see decreased flurodopa uptake on a fluorodopa-PET scan obtained during
the peak period of parkinsonism unfortunately, we were not able to
obtain these scans. An FDG-PET scan in the first patient showed both
cortical and subcortical impairment of glucose uptake consistent with
diffuse cerebral injury (possibly related to her extensive history of
prior treatment for cancer). However, despite this diffuse
hypometabolism including the basal ganglia, this patient still had a
response to levodopa, which suggests that there was a preservation of
striatal dopamine receptors in the setting of a global toxic-metabolic
insult. In summary, we present 3 patients with reversible,
levodopa-responsive parkinsonism after treatment with chemotherapy.
Prompt recognition and treatment of this condition may profoundly affect
patients' quality of life. Parkinsonism, although uncommon, may be an
underrecognized complication of cancer chemotherapy.


--
Kathrynne Holden, MS, RD < [log in to unmask] >
"Ask the Parkinson Dietitian"  http://www.parkinson.org/
"Eat well, stay well with Parkinson's disease"
"Parkinson's disease: Guidelines for Medical Nutrition Therapy"
http://www.nutritionucanlivewith.com/

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