NORD gratefully acknowledges Catherine Ho and Dominique Miller, Doctor of Pharmacy Candidates, NORD Editorial Interns from the Keck Graduate Institute School of Pharmacy and Health Sciences and Rachita K. Sumbria, PhD, Associate Professor of Biopharmaceutical Sciences for assistance in the preparation of this report.
Subacute cerebellar degeneration (SCD) is characterized by the deterioration of the area of the brain concerned with muscle coordination and balance (the cerebellum). Less frequently, the area involved may include the region connecting the spinal cord to the brain (the medulla oblongata, the cerebral cortex, and the brain stem). There are two types of SCD: 1) paraneoplastic cerebellar degeneration, which sometimes precedes the diagnosis of cancer, and 2) alcoholic or nutritional cerebellar degeneration, caused by a lack of the vitamin B-1 (thiamine). These two types share symptoms but not the same cause. Hallmark symptoms include weakened muscle coordination (ataxia), difficulty speaking (dysarthria), difficulty swallowing (dysphagia), abnormal walking patterns and dementia.
Paraneoplastic cerebellar degeneration may be an autoimmune disorder (diseases where the immune system mistakenly attacks one own body) that affects more females than males and has an average age of onset of 50 years old. It has been associated with certain cancers and production of certain autoimmune antibodies, proteins released by immune cells that mistakenly recognizes and attack proteins in one’s own body instead of foreign substances like bacteria and viruses. Cancers associated with paraneoplastic cerebellar degeneration are Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers. The cancers may trigger production of autoimmune antibodies that attack brain cells in the cerebellum called Purkinje cells, leading to cerebellar degeneration. In alcoholic cerebellar degeneration, symptoms usually begin to occur in middle-aged individuals with a history of chronic alcohol abuse. These symptoms are caused by thiamine deficiency, which also occurs in nutritional cerebellar degeneration.
If SCD is suspected, magnetic resonance spectroscopy, cerebrospinal fluid analyses, paraneoplastic antibody assays, and imaging studies such as magnetic resonance imaging (MRI) scans and computed tomography (CT) scans, may be performed for a definitive diagnosis. If diagnosed with paraneoplastic cerebellar degeneration, available therapies include treatment of the underlying cancer and associated antibodies. If diagnosed with alcoholic or nutritional cerebellar degeneration, treatment includes receiving thiamine, along with either decreasing alcohol consumption or resuming a normal diet.
Common symptoms of SCD include:
1) Weakened muscle coordination (ataxia) of the limbs (especially of the arms in paraneoplastic cerebellar degeneration, and of the legs in alcoholic or nutritional cerebellar degeneration);
(2) Problems in articulation of speech (dysarthria), which are especially noticeable in paraneoplastic cerebellar degeneration;
(3) Difficulty in swallowing (dysphagia);
(4) Loss of reason (dementia); this occurs in approximately half the patients with paraneoplastic cerebellar degeneration;
(5) Involuntary rapid movements of the eyeball in a horizontal or vertical direction (nystagmus); as well as double-vision (diplopia), vertigo (dizziness), and paralysis of the eye muscles (ophthalmoplegia) if the patient has alcoholic/nutritional cerebellar degeneration;
(6) Cell loss localized to the midline structures of the cerebellum contributes to poor motor coordination of the head, such as head bobbing and loss of limb movements
(7) Tremors (shaking) related to complex motor tasks or purposeful movements due to abnormal Purkinje cells (a particular kind of nerve cell) throughout the cerebellum;
(8) Repetitive behaviors in children (hand clapping, rhythmic rocking, twirling of objects) associated with cerebellar vermis damage;
(9) Problems with cognitive and emotional regulation (autism, schizophrenia, attention deficit-hyperactivity disorder)
In addition, patients with SCD lose many Purkinje cells throughout the cerebellum. Computerized axial tomography (CAT) scans may show enlargement of the area of the brain between the spinal cord and the rest of the brain (fourth ventricle) as well as areas of the cerebellum. Examination of cerebrospinal fluid may show a high volume of lymph cells (white blood cells formed in lymphoid tissue) and an elevated protein level.
Paraneoplastic cerebellar degeneration may potentially be an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against invading organisms mistakenly attack healthy tissue for unknown reasons. It may also be an abnormal response to cancer. In cases where there is an underlying cancer, the individual’s immune system may react to the cancer by stimulating the body’s natural defense mechanisms. These natural defense mechanisms include producing antibodies, which are proteins that help the immune system detect harmful substances, and increase the number of T-cells, which are white blood cells that destroy infected cells and tumors. These antibodies and T-cells normally target only the cancerous tumors; however, in paraneoplastic cerebellar degeneration, these antibodies bind to and attack normal cells in the nervous systems, such as Purkinje cells in the cerebellum, leading to their death and loss of function. Purkinje cells are cells specifically found in the cerebellum that gather multiple signals throughout the brain to control motor movements.
Some antibodies and cancers appear to have a direct role in causing paraneoplastic cerebellar degeneration. Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers are strongly linked to paraneoplastic cerebellar degeneration. In the absence of a detected tumor, some of these antibodies may still be produced in individuals with paraneoplastic cerebellar degeneration. These antibodies react with Purkinje cells, causing inflammation in the brain and cell death.
Alcoholic/nutritional cerebellar degeneration is associated with thiamine deficiency. The human body needs thiamine, also known as vitamin B1, to function properly. Humans need to consume thiamine in their diet because they are unable to produce it within the body. Once consumed, thiamine becomes absorbed in the small intestine and is stored in the liver. Thiamine is an essential vitamin for the brain and other tissues and is important for many cellular processes. This includes glucose metabolism and energy production, which are required for normal brain function. A reduction in thiamine will impair cellular energy production and, therefore, disrupt brain function. In addition, heavy alcohol use and thiamine deficiency will cause inflammation in the brain, leading to brain damage. Secondary thiamine deficiency results from impaired absorption or utilization or from increased requirements for thiamine. Individuals with a history of chronic alcohol abuse tend to eat poorly and may not get enough thiamine-containing foods. They also absorb or utilize the vitamin less efficiently, due to the effect of alcohol on the liver, and therefore, may require larger than normal amounts of thiamine.
In paraneoplastic cerebellar degeneration, the average age of onset is 50 years, with females affected more often than males. This form of cerebellar degeneration may precede cancer, however <1% of patients with cancer have paraneoplastic cerebellar degeneration. Alcoholic or nutritional cerebellar degeneration affects alcoholics and people with thiamine deficiency. In alcoholic cerebellar degeneration, symptoms usually occur in middle aged individuals who have a history of chronic alcohol abuse.
The diagnostic criteria for paraneoplastic cerebellar degeneration are:
The diagnostic criteria for alcoholic/ nutritional cerebellar degeneration are:
Clinical Testing and Work-Up
Paraneoplastic Cerebellar Degeneration –
Alcoholic/ Nutritional Cerebellar Degeneration –
Standard therapeutic options for paraneoplastic cerebellar degeneration include diagnosing and treating the underlying cancer. Prompt tumor removal, chemotherapy and/or radiation may be beneficial and help reduce symptoms in patients. Adjuvant therapy with glucocorticoids such as methylprednisolone and immunotherapy with potent T cell inhibition, such as rituximab and tacrolimus may be elusive. However, small cases have shown both rituximab and tacrolimus may help to stabilize symptom progression in patients with paraneoplastic cerebellar degeneration only. For alcoholic/nutritional cerebellar degeneration, thiamine is given along with other B vitamins, usually relieving the condition if the patient stops drinking alcohol and resumes a normal diet. Physical therapy with focus areas on strengthening, balance and gait balance can help to restore function and prevent long term disability in patients with progressive symptoms. Occupational therapy may focus mainly on activities of daily living and dysphagia rehabilitation.
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