Subacute Cerebellar Degeneration

Resumen

Summary

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.

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Signos y Síntomas

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.

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Causas y Herencia

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.

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Frecuencia

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.

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Enfermedades con síntomas similares

Symptoms of the following disorders can be similar to those of SCD. Comparisons may be useful for a differential diagnosis:

Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term «paraneoplastic» means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. PNS are categorized by the area of the nervous system that is principally affected, the type of symptoms or the type of immunological response. (For more information on these disorders, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)

Multiple sclerosis (MS) is a chronic disease of the central nervous system, which may be progressive, relapsing and remitting, or stable. MS is characterized by small lesions called plaques that form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nervous system signals and thus result in a variety of neurological symptoms including visual difficulties (blind spots, double vision, nystagmus), impairment of speech, abnormal skin sensations (paresthesia) or numbness, walking disturbance and difficulties with bladder or bowel function. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)

Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early. (For more information, on this disorder, choose “Korsakoff” or “Wernicke” as your search term in the Rare Disease Database.)

Hodgkin’s disease and several other types of cancers, such as lung, ovarian, breast, stomach, and uterine cancers may be associated with paraneoplastic cerebellar degeneration. Hodgkin’s disease is a form of cancer of the lymphatic system, especially the lymph nodes. Tumors occur in the lymph nodes (places where lymphatic vessels unite) and/or the area around the nodes. Fever, night sweats, and weight loss may occur along with swollen lymph nodes. (For more information on this disorder, choose “Hodgkin’s disease” as your search term in the Rare Disease Database.)

Spinocerebellar ataxia is a rare, hereditary disease that occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Spinocerebellar ataxia mainly affects the cerebellum and causes symptoms such as ataxia, abnormal speech, and vision problems. There are about 40 different types of spinocerebellar ataxia. Each type of spinocerebellar ataxia is associated with a different altered gene. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)

Episodic ataxia is a rare, neurologic condition that affects nerve cell signaling that controls body movement. There are currently 8 types of episodic ataxia. It is a disorder caused by altered genes and occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Each episode can last a few seconds up to a few hours, and can cause muscle weakness, seizures, or paralysis. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)

Spinocerebellar ataxia with axonal neuropathy is a rare, hereditary, disease that occurs when a non-working gene has been inherited by each parent. Spinocerebellar ataxia with axonal neuropathy is characterized by the onset of cerebellar ataxia during the late childhood years. The disease progresses slowly and can cause symptoms such as ataxia, dysarthria (abnormal speech), gaze nystagmus (uncontrolled movement of the eyes), and peripheral neuropathy. (For more information on this disorder, choose “spinocerebellar ataxia with axonal neuropathy” as your search term in the Rare Disease Database.)

Behcet’s disease is a disorder characterized by inflammation, skin lesions, and ulcers affecting mucous membranes around the mouth and genitals. Behcet’s disease can also cause symptoms affecting the central nervous system and can lead to headaches, impaired muscle movements of the throat and face, ataxia, stroke, or seizures. The exact cause of this disorder is unknown. (For more information on this disorder, choose “Behcet’s” as your search term in the Rare Disease Database.)

Creutzfeldt-Jakob disease (CJD) is a rare disorder characterized by the deterioration of the brain and a sudden onset of symptoms, such as confusion, behavior changes, impaired vision, impaired coordination, and muscle weakness. Creutzfeldt-Jakob disease occurs randomly in about 90 percent of cases and the other 10 percent of cases may be associated with a family history of the disease. It may also result from an abnormal prion protein, which is a protein that can cause other normal proteins in the brain to misfold. (For more information on this disorder, choose “Creutzfeldt Jakob disease” as your search term in the Rare Disease Database.)

Progressive multifocal leukoencephalopathy is a disorder caused by an infection of the JC virus, a virus named after the initials of its first known patient. The JC virus attacks cells that make myelin, a substance that forms a protective layer around nerve cells in the spinal cord and brain. Symptoms of progressive multifocal leukoencephalopathy may include difficulty speaking, sensory loss, impaired vision, weakness, and ataxia. (For more information on this disorder, choose “progressive multifocal leukoencephalopathy” as your search term in the Rare Disease Database.)

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Diagnóstico

The diagnostic criteria for paraneoplastic cerebellar degeneration are:

Severe cerebellar symptoms that have occurred for less than 12 weeks, along with no abnormal sign of cerebellar size reduction
Rankin scale score of at least a 3, indicating that symptoms interfere with daily life significantly
Clinical evidence of cerebellar dysfunction, specifically within the trunk or hemispheres, and established diagnosis of cancer within 5 years from the onset of symptoms
Cerebellar symptoms and cancer-related antibodies

The diagnostic criteria for alcoholic/ nutritional cerebellar degeneration are:

Magnetic resonance imaging showing significant size reduction of the cerebellum, specifically of the cerebellar vermis, a cerebellar region responsible for posture and locomotion
Magnetic resonance spectroscopy detecting metabolic deficits in the cerebellar vermis associated with chronic alcohol use

Clinical Testing and Work-Up

Paraneoplastic Cerebellar Degeneration –

Imaging Studies:
- Magnetic resonance imaging (MRI) scans
  - MRI scans can show cerebellar atrophy that can occur in paraneoplastic cerebellar degeneration as the disease progresses
- Computed tomography (CT) and MRI scans to rule out strokes and tumors
- Fluorodeoxyglucose-positron emission tomography scans (FDG-PET) to detect cerebellar metabolic activity. Paraneoplastic cerebellar degeneration may be associated with increased cerebellar metabolism.
Cerebrospinal fluid (CSF) Analysis:
- CSF examined in paraneoplastic cerebellar degeneration can show mild pleocytosis (white blood cells within the CSF), higher than normal amounts of protein, and/or the presence of oligoclonal bands, which are a class of proteins that function as antibodies.
Paraneoplastic Antibody Assays:
- Anti-Yo (PCA-1):
  - Commonly associated with breast cancer and ovarian cancer
- Anti-Tr (Anti-DNER) and/or Anti-mGluR1:
  - Associated Hodgkin’s lymphoma
- Anti-Zic and/or Anti-Hu:
  - Associated with small-cell lung cancer (SCLC)
- Anti-VGCC:
  - Associated with SCLC and lymphoma
- Anti-CRMP5 (Anti-CV2):
  - Associated with SCLC and thymoma
- Anti-Ri:
  - Associated with SCLC, breast cancer and ovarian cancer
- Anti-Ma2:
  - Associated with SCLC and testicular cancer

Alcoholic/ Nutritional Cerebellar Degeneration –

Imaging Studies:
- MRI scans to detect cerebellar vermian atrophy
Magnetic resonance spectroscopy to monitor cerebellar function

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Tratamiento

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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Investigaciones

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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Referencias

JOURNAL ARTICLES

Brown AM, White JJ, van der Heijden ME, Zhou J, Lin T, Sillitoe RV. Purkinje cell misfiring generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation. Elife. 2020;9:e51928. Published 2020 Mar 17. doi:10.7554/eLife.51928

Mitoma H, Manto M, Gandini J. Recent Advances in the Treatment of Cerebellar Disorders. Brain Sci. 2019;10(1):11. Published 2019 Dec 23. doi:10.3390/brainsci10010011

Zeigelboim BS, dos Santos Junior CA, Teive H, et al. Alcoholic cerebellar degeneration: A case report. Neurophysiologie Clinique. 2019;49(6):448. doi:https://doi.org/10.1016/j.neucli.2019.10.113

Proudfoot M, Wilkins A. Treatment of Cerebellar Ataxia in the Context of Systemic Diseases. Curr Treat Options Neurol. 2017;19(12). https://doi:10.1007/s11940-017-0485-y.

Shanmugarajah PD, Hoggard N, Currie S, et al. Alcohol-related cerebellar degeneration: not all down to toxicity?. Cerebellum Ataxias. 2016;3:17. Published 2016 Oct 3. doi:10.1186/s40673-016-0055-1

Lee JH, Heo SH, Chang DI. Early-stage Alcoholic Cerebellar Degeneration: Diagnostic Imaging Clues. J Korean Med Sci. 2015;30(11):1539. doi:10.3346/jkms.2015.30.11.1539

Phillips JR, Hewedi DH, Eissa AM, Moustafa AA. The cerebellum and psychiatric disorders. Front Public Health. 2015;3:66. Published 2015 May 5. doi:10.3389/fpubh.2015.00066

Ilg W, Synofzik M, Brötz D, Burkard S, Giese MA, Schöls L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73(22):1823-1830. doi:10.1212/WNL.0b013e3181c33adf

de Andrés C, Esquivel A, de Villoria JG, Graus F, Sánchez-Ramón S. Unusual magnetic resonance imaging and cerebrospinal fluid findings in paraneoplastic cerebellar degeneration: a sequential study. J Neurol Neurosurg Psychiatry. 2006;77(4):562-563. doi:10.1136/jnnp.2005.073379

Martin PR, Hiller-Sturmhöfel S, Singleton CK. The Role of Thiamine Deficiency in Alcoholic Brain Disease. Alcohol Research & Health. 2003;27(2): 134-42.

Leonovicz BM, Gordon EA, Wass CT. Paraneoplastic syndromes associated with lung cancer: a unique case of concomitant subacute cerebellar degeneration and Lambert-Eaton myasthenic syndrome. Anesth Analg. 2001;93(6): 1557-9. doi:10.1097/00000539-200112000-00047

Levite R, Fishman A, Kesler A, Altaras M, Gadoth N. Paraneoplastic cerebellar degeneration heralding fallopian tube adenocarcinoma. Int J Gynecol Cancer. 2001;11(2):169-171. doi:10.1046/j.1525-1438.2001.011002169.x

Mowzoon N, Bradley WG. Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report. J Neurol Sci. 2000;178(1):63-65. doi:10.1016/s0022-510x(00)00353-1

INTERNET

Aly R, Emmady PD. Paraneoplastic Cerebellar Degeneration. StatPearls. Updated December 12, 2020. https://www.ncbi.nlm.nih.gov/books/NBK560638/ Accessed March 9, 2021.

Dalmau J, Rosenfeld MR. Paraneoplastic cerebellar degeneration. UpToDate. Updated April 7, 2020. https://www.uptodate.com/contents/paraneoplastic-cerebellar-degeneration Accessed March 9, 2021.

Lan, E. Paraneoplastic Cerebellar Degeneration. Medscape. Updated July 1, 2020. www.emedicine.com/neuro/topic299.htm Accessed March 9, 2021

Paraneoplastic Syndromes Information Page. National Institute of Neurological Disorders and Stroke website. Updated March 27, 2019. https://www.ninds.nih.gov/Disorders/All-Disorders/Paraneoplastic-Syndromes-Information-Page Accessed March 9, 2021.

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