Download Paraneoplastic Cerebellar Degeneration

Paraneoplastic Cerebellar Degeneration
Cynthia Curry
November 21, 2008
ALHE 4060 Research in Allied Health
East Tennessee State University
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Abstract
The purpose of this article is to take a close look at paraneoplastic syndromes, and
to mainly focus in on paraneoplastic cerebellar degeneration (PCD).This article will
explain the process of this disease, although uncommon, and how it produces
neurological disabilities. This article will recognize who will get it, and how it is
properly diagnosed and treated. PCD is characterized by the degeneration of the
cerebellum, which is responsible for muscle coordination, balance and many other
neurological functions needed to survive.
This type of disease can be very debilitating. It can cause inability to coordinate
muscle movement, disturbance of speech and loss of fine motor skills. Paraneoplastic
cerebellar degeneration’s are triggered by the patient’s immune system in association
with a malignant disease. Paraneoplastic cerebellar degeneration should be considered in
patients who experience these nervous disorders with no other obvious cause. To aid in
the diagnosis, imaging studies such as CT, MRI or PET scans would be useful and could
help find the primary cause in patients with this disorder, which is usually an underlying
malignancy.
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Introduction
Paraneoplastic cerebellum degeneration falls under a group of disorders called
Paraneoplastic syndromes; they are usually degenerative and are triggered by the
patient’s immune system in association with a malignant disease (Santacrose). These
conditions are not due to the direct impact of the tumors, yet rather due to the production
of chemical substances from the cancer cells (IPA). The chemical substances are
produced and released in the blood stream and their effect may present itself in various
ways. Not all cancers cause a Parneoplastic syndrome (Mason). The complete
understanding of how and why this happens is not fully understood. What is known is the
cancer cells in certain people produce a protein or chemical substance that is normally
produced by the brain or nerve cells. It is believed that the patients body then launches a
normal immunological attack against these antigens and foreign malignant cells, the
immune system responds with the production of white blood cells known at T-cells or
killer cells (Horacio). These cells then send messages to the entire immune system to
destroy this foreign antigen, but because this protein or chemical substance has been
recognized as foreign, this leads to the auto-antibodies attacking both the tumor as well as
the patient’s nervous system. In paraneoplastic cerebellar degeneration, the immune
system thinks the cerebellum is a foreign body and begins to attack it.
The cerebellum is located just above the brainstem, beneath the occipital lobes at
the base of the skull and is responsible for coordination and memory. It also receives
information from the visual pathways and determines where the body is and where it is
going and keeps the subconscious conscious. The cerebellum also assesses information
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on muscle movement, direction, force and extent of muscle contraction. When this part
of the body begins to be attacked many things can happen to the body.
Pareneoplastic cerebellar degeneration is one of the paraneoplastic syndromes and
is not directly related to the physical effects of the primary tumor, or neoplasm itself
(Rubin). All of these syndromes follow a course parallel to the tumor; they may resolve
or slow with successful treatment of the primary tumor and tend to recur with its relapse
or the onset of metastases. These disorders, especially paraneoplastic cerebellar
degeneration, are uncommon and rare and usually if not always, show up in the patient
long before their cancer is diagnosed (Rubin). These syndromes are typically relentless
and disabling. The destruction of the nervous system being destroyed by the immune
system gives rise to a host of diseases which constitutes the paraneoplastic syndromes.
These syndromes may occur in up to 10 – 15% of malignancies, and they are usually the
first to manifest, however this incidence could be underestimated.
The groups of paraneoplastic disorders are comprised of the following, along with
possible symptoms and/or side effects (Posner, Mason).
1. Cerebellar Degeneration, which can lead to the inability to coordinate muscle
movement, disturbance of speech, loss of fine motor skills.
2. Sensory neuropathy is the degeneration of the nerve cells specialized for the
body’s sensations. Therefore patients experience numbness and loss of feeling in
arms and legs, burning or tingling in extremities.
3. Lambert-Eaton’s syndrome, where the antibodies are directed against the
terminals of nerves and leads to limb weakness, fatigue, muscle stiffness,
drooping eyelids and double vision.
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4. Encephalomyelitis, the brain and spinal cord is affected and results in confusion,
agitation, memory disturbances, seizures, emotional issues and double vision.
Myelitis is a term used to describe inflammation of the spinal cord and leads to
weakness and twitches.
5. Motor neuron diseases are characterized by muscle weakness, twitching, body
jerking and muscle wasting.
These conditions are not due to the direct impact of the tumors, yet rather to the
production of the chemical substances from the cancer cells and the destruction of the
nerve cells. Once the attack has begun, the only way to subside the crisis is to discover
the primary tumor and treat the malignancy itself (Mason).
Diagnosis of parneoplastic cerebellar degeneration is usually delayed due to the
misdiagnosis of the patient’s symptoms, because these symptoms usually mimic some
sort of neurological disorder instead of a malignant disease (Mason). Symptoms usually
develop slowly over months then rapidly increase within days or weeks due to the
degeneration or destruction of the nervous system or cerebellum leaving the patient
generally disabled. Symptoms can affect any part of the central or peripheral nervous
system. Patients with a suspected paraneoplastic syndrome disorder should receive a
CBC, urine study and cerebral spinal fluid tap (Horacio). Tumor markers are very useful
for the diagnosis of certain kinds of cancer that can be silent or slow growing. One of the
most prominent markers for paraneoplastic syndromes is the demonstration of an autoantibody or serum that is produced with these disorders (Hain).
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The table below outlines the most well-known paraneoplastic auto-antibodies
verified by researchers in the serum of antigens against the tumor cells, the clinical
presentations associated with them, and their most commonly associated cancers (Hain).
Auto-antibody
Clinical presentation
Commonly Assoc. Cancer
Anti-HuAb
Cerebellar Degeneration, Encephalomylitis
Small cell lung cancer, Neuroblastoma
Anti- Yo
Sensory Neuronopathy
Small cell lung cancer, Gyn’s and Breast
Anti-Ma
Cerebella dysfunction, brainstem dysfunction
Breast, Lung, Colon
Anti-Ta
Limbic encephalitis, brainstem dysfunction
Testicular
Anti-Ri
Opsoclonu
Breast
Anti-Car
Photoreceptor degeneration
Small cell lung cancer
Anti-Vgcc
Lambert-Easton myasthenia syndrome
small cell lung cancer
To aid in the diagnosis, any possible imaging studies such as CT, MRI and PET
would be useful and could help find the primary tumor in patients with these disorders.
Histology of the patients found with paraneoplastic syndromes has not been determined.
No certain race or sex seems to be affected more than the other. People of all ages may
be affected by these syndromes and the incidence of death and complication related to
paraneoplastic syndromes are unknown (IPA).
There are no proven treatment options for paraneoplastic syndromes including
pareneoplastic cerebellum degeneration but emphasis on early detection of the patient’s
tumor are of importance (Santacrose). This may stabilize and/or decrease the immune
response that is damaging the nervous system or brain. All patients who have received
oncological treatments such as chemotherapy or radiation therapy showed partial
neurological improvement (Mason).
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Other efforts to decrease the auto immune response have been the use of drugs as
in Corto-steroids, such as cortisone or prednisone t alleviate some of the symptoms, and
the use of Cyclosporine type drugs are often used to suppress the immune reaction along
with Klonopin to control muscular problems and seizures (Horacio).
The research being done is aimed at better understanding and evaluating new
treatment interventions. Researchers are looking into why the auto-immune system
responds in the way to cause these disorders. Studies are being done to detect the
different types of antibodies causing these responses. Scientists are also hoping to
develop animal models for these diseases which may be used to determine effective
treatment strategies (Mason).
Researcher is also being done to find the gene involved with these disorders
(Shamsili). Discovering the gene, identifying their mutations and understanding how the
abnormal proteins they produce cause these disorders will hopefully help scientists find a
way to prevent, treat and even cure the damage that has been done (Posner).
Methods
I was able to find my research participants at the Memorial Sloan-Kettering
Cancer Center. All consent forms were obtained to allow medical information to be
released for this study after I had my research questions and study information needed
reviewed by the medical centers Institutional Review Board (IRB). I made sure all
Health Insurance Portability and Accountability (HIPPA) regulations were followed for
all patients’ protection and confidentiality. I also made sure this study was approved and
in compliance by the ETSU VA IRB. All participants being researched and analyzed for
this study and all medical personnel treating these patients completed the IRB and
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required CITI modules regarding the ethical conduct and research involving human
studies and agreed there was no danger to the patients being researched.
I have only included the study of patients with small-cell lung cancer (SCLC)
with/without PCD. Patients who have an acute onset of gait difficulty, and limb
weakness, memory loss and other symptoms associated with cerebella dysfunctions have
been followed for 18 months. Two separate studies showed that (1) 57 patients with PCD
and SCLC showed HuAb antibodies against neuronal proteins expressed by the tumor
while (2) 109 patients with SCLC without PCD, 19 had low HuAb and 90 were negative.
Age and sex has no discrimination for PCD. This study shows no significant differences
observed for survival rate, although patients with the HuAb positive PCD were more
likely to die from neurological diseases including respiratory muscle failure due to low
motor neuron dysfunction. What needs to be taken into consideration is the overall health
of the patient and stage of cancer at time of diagnosis, because the neurological
symptoms preceded the cancer diagnosis in 49 of the patients with PCD we don’t know
how long prior to diagnosis their malignancy had occurred.
Conclusion
In conclusion, Paraneoplastic cerebellum degeneration is a rare disorder and
research seems to be limited. The primary concern for the physicians is treatment of the
underlying cancer. Many physicians hold the belief that pareneoplastic syndromes are an
untreatable sign of imminent death and therefore find research a waste of time and
money. This is an unfortunate attitude since many of the patients live for years after their
diagnosis.
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It is equally important to support the family members and caregivers of these
patients with this horrific disabling disorder. The neurological symptoms can establish
themselves very quickly and often leave the patient needing 24 hour care (IPA). Advice
is needed for the family members and caregivers on how to deal with the neurological
deficits that will be placed upon the patient. Physicians should have readily available
information on insurance benefits, social security, physical therapy, medical equipment
along with the hospital beds and wheelchairs. Also needed, will be home health care and
visiting nurses, social workers and possible nursing home care.
Paraneoplastic cerebellar degeneration should be considered in patients who
experience the new onset of chorea (nervous disorder) with no other obvious cause,
particularly if other neurological abnormalities are present (Santacrose). Many patients
survive their cancer only to die or be permanently disabled by this disease. Finding the
reason for the autoimmune system to go astray might actually help us to better fight
cancer.
References
Dalmau J. Posner JB. Neurological paraneoplastic antibodies, the case for nomenclature
based on antibody and antigen specificity. Neurology 1994; 44
International Paraneoplastic Association – Paraneoplastic support and information.
http://www.paraneoplastic.org/2.html
Horacio Senties-Madrid, MD and Felipe Vega-Boada, MD (February, 2001).
Paraneoplastic Cerebellum Degeneration. JAMA, Vol. 3
Lieberman, Frank MD.Clifford S, MD. Associate professor of Neurology, University of
Pittsburgh Cancer Institute. (November 2002) Oncology, Volume 16
Mason WP, Graus F, Lang B, Department of Neurology Sloan Kettering Cancer Center,
Small cell lung cancer, Paraneoplastic Cerebeullum Degneration. Oxford Journal, Brain,
Bol. 120 Issue 8 1279-1300
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Santracrose, Luigi MD. (July 2005). Paraneoplastic Syndromes,
www.emedicine.com/MED
Hain, Timothy, MD. (November, 2001) Paraneoplastic Cerebellar Degeneration
www.tchain.com/otoneurology
Posner, Jerome MD.,Shapiro William MD., Forman, Arthur MD (November 2002)
Oncology Vol. 16, Number 11 Distant Effects of Cancer on the nervous system,
www.cancernetwork.com/oncology
Rubin, Michael MD, FRCP ©, (July/August 2005) Paraneoplastic Syndromes and the
nervous system, Volume 3 Number 4
Shamsili S. Grefkens, J. (June 2003) Oxford University Press, Paraneoplastic cerebellar
degeneration associated with antineuronal antibodies. Brain Volume 126, Number 6,
1409-1418
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