Neurosarcoidosis

Definition

Neurosarcoidosis refers to an autoimmune disorder of unknown cause, which causes deposition of inflammatory lesions called granulomas in the central nervous system.

Description

Sarcoidosis is a multisystem disease of unknown cause. It is thought that the disorder is caused by an inflammatory reaction in the body which forms a lesion called a granuloma. Neurosarcoidosis is characterized by formation of granulomas in the central nervous system. The granulomas consist of inflammatory cells (lymphocytes, mononuclear phagocytes) which function during inflammatory reactions. The disorder is often unrecognized since most patients do not exhibit symptoms. Typically the disease is diagnosed by routine chest x ray. If symptoms are present they usually include respiratory problems (shortness of breath, cough) since the lungs are affected most frequently.

Neurological description

Patients can have a broad range of clinical signs and symptoms that typically could involve mononeuropathy, peripheral neuropathy, or central nervous system involvement. Mononeuropathy problems can include facial nerve palsy, impaired taste and smell, blindness (or other eye problems such as double vision, visual field defects, blurry vision, dry/sore eyes), or speech problems (impaired swollowing or hoarseness). Patients can also develop vertigo, weakness of neck muscles and tongue deviation and atrophy.

Peripheral nerve involvement

Neurosarcoidosis can cause damage to peripheral nerves that can affect motor nerves (responsible for movement of muscles) and sensory nerves (responsible for sensation). Symptoms of sensory loss include loss of sensation and abnormal sensation (numb, painful, tingling sensations) over the thorax (chest) and the areas where stockings and gloves are usually worn. Motor neurosarcoidosis is characterized by weakness that can progress to immobility and joint stiffness.

Central nervous system (CNS) involvement can affect the pituitary gland, cerebellum, or cerebral cortex. The spinal cord is rarely involved. Signs and symptoms of CNS involvement can include polyuria, polydipsia, obesity, impotence, amenorrhea, confusion/amnesia (short and long term memory), meningitis, and seizures (focal seizures).

Demographics

Sarcoid disorders are more prevalent in African Americans, and in the United States there seems to be a variable prevalence within different states. The prevalence is much higher in the southeastern United States among both Caucasian and African Americans. The prevalence is high in Puerto Rico, reaching approximately 175 cases per 100,000 persons. The frequency for neurological involvement for all cases of sarcoid disease is 5%. However, neurological involvement has been reported to occur in up to 5% to 16% of cases. Internationally the incidence of sarcoid varies widely. In Spain the incidence is low (0.04 per 100,000) whereas in Sweden the incidence is high, representing 64 cases per 100,000 persons. Studies reveal the prevalence in London is 27 per 100,000 and 97 per 100,000 among Irish men. In the Caribbean, studies indicate that the prevalence is as high as 200 per 100,000 in men from the West Indies and 13% of individuals from Martinique.

There does not seem to be a racial predilection for the development of sarcoid neuropathy. Sarcoid disease is uncommon in Chinese, Inuits, Southeast Asians, Canadian Indians, New Zealand Maoris and native Japanese. Death from neurosarcoidosis is unusual. About 66% of patients with neurosarcoidosis have self-limited monophasic illness. Approximately 33% have a chronic remitting and relapsing course. Neurosarcoidosis commonly occurs in adults aged 25-50 years. Neurosarcoidosis is not common in children, but if it does occur, it affects children age 9-15 years. The clinical signs in children are different than in adults. When neurosarcoidosis is present in children over the age of eight, there is usually a triad of signs which include arthritis, uveitis, and cutaneous nodules. In children ocular (eye) problems occur in approximately 100% of cases, which typically manifest as iritis and/or anterior vitreitis. For all cases, if the nervous system is involved it usually occurs within two years of disease onset.

Causes and symptoms

The causes of sarcoid disease are not clear. Current evidence suggests that sarcoidosis is due to the abnormal proliferation of a certain cell called a T-helper cell, which functions to help immune cells attack a foreign substance. The abnormal proliferation of T-helper cells is thought to result from an exaggerated response to a foreign substance or to self cells (a condition referred to as autoimmunity, in which for unknown reasons, the body's natural defense cells attack normal cells in organs).

During physical examination patients may exhibit weakness, absence of tendon reflexes, lack of sensation in a stocking and glove distribution, atrophy of muscles, and focal mononueropathies that may affect the cranial nerves (causing problem with hearing, vision, smell, balance, or paralysis of facial muscles). Some patients may develop Heerfordt syndrome characterized by fever, uveitis, swelling of the parotid gland, and facial palsy.

Diagnosis

Blood analysis is essential since patients may have increased erythrocyte sedimentation rate (ESR) or anemia (hypochromic microcytic type). Blood analysis can provide information concerning multiple organs (kidney, liver, blood) and this is important since sarcoidosis is a multisystem disease (affects many different organs in the body). CT and MRI scans are important in assessing neurosarcoidosis. MRI is the imaging tool of choice in cases of neurosarcoidosis, because of the high quality superior images obtained. The presence of a mass or lesion in the CNS can be visualized by MRI images. To confirm the diagnosis it is necessary to take a biopsy of either muscle or nerve tissue. Examination of the tissue specimen with a microscope reveals the characteristic granuloma within tissues.

Treatment team

The effects of neurosarcoidosis can involve several symptoms from different organ systems. The treatment team consists of a neurologist, neurosurgeon, endocrinologist, rheumatologist, and pulmonologist.

Treatment

There is no definitive treatment, but corticosteroids remain the standard treatment. The most commonly used oral corticosteroid is prednisone, which works to decrease inflammatory actions in the body that are responsible for granuloma formation. Doses are usually tapered down. Additionally, patients can be given immunosuppressant agents (e.g., cyclosporine) which can suppress autoimmune responses (which are responsible for granuloma formation). Surgery is rare and reserved for cases that require removal of a mass (space-occupying lesion) in the brain.

Recovery and rehabilitation

Neurosarcoidosis is a slowly chronic disease with a progressive course, which is fatal in about 50% of patients. Follow-up visits with a neurologist every three to six months are advisable. During visits the neurologist will monitor progress and make recommendations.

Clinical trials

There are several studies currently active concerning sarcoidosis. The National Heart, Lung and Blood Institute Drug study are conducting clinical research trials with patients who have lung involvement (pulmonary sarcoidosis). Contact Pauline Barnes, RN (1-877-644-5864) or visit their website: .

Prognosis

Spontaneous resolution of neurosarcoidosis can occur but it is not common. Many patients with neurosarcoidosis have a slow chronic and progressive course with intermittent exacerbations. Neurosarcoidosis responds to steroid therapy, but long-term outcome of neurologic impairment is unknown.

Special concerns

Sarcoidosis is difficult to diagnose, and sometimes a delay can cause patients to get sicker before proper treatment is initiated. On rare occasions a patient may even die because the diagnosis was not suspected. Caution must be taken to exclude other diseases before a final diagnosis is made. Additionally, before corticosteroid therapy is initiated, the clinician must rule out an infectious cause.

Resources

BOOKS

Goldman, Lee et al. Cecil's Textbook of Medicine 21st ed. Philadelphia: WB. Saunders Company, 2000.

Noble, John., et al eds. Textbook of Primary Care Medicine 3rd ed. St. Louis: Mosby, Inc., 2001.

PERIODICALS

Nikhar, N.K. Sarcoidosis and Neuropathy.

Suleman, Amer. Neurosarcoidosis.

WEBSITES

National Organization for Rare Disorders (NORD).http://www.rarediseases.org.

ORGANIZATIONS

Sarcoidosis Research Institute. 3475 Central Avenue, Memphis, TN 38111. (901) 766-6951; Fax: (901) 744-7294. paula@sarcoidosisresearch.org. http://www.sarcoidosisresearch.org.

Laith Farid Gulli, M.D.

Nicole Mallory, M.S., PA-C

A granulomatous disease of unknown cause involving the central nervous system, usually with concomitant systemic involvement.

Neurosarcoidosis
Classification and external resources
eMedicine	neuro/649

Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, involving the central nervous system (brain and spinal cord). It can have many manifestations, but abnormalities of the cranial nerves (a group of twelve nerves supplying the head and neck area) are the most common. It may develop acutely, subacutely, and chronically. Approximately 5-10% of people with sarcoidosis of other organs (e.g. lung) develop central nervous system involvement. Only 1% of people with sarcoidosis will have neurosarcoidosis alone without involvement of any other organs. Diagnosis can be difficult, with no test apart from biopsy being completely reliable. Treatment is with immunosuppression.^[1] The first case of sarcoidosis involving the nervous system was reported in 1948.^[2][3]

Contents 1 Signs and symptoms 1.1 Neurological 1.2 Endocrine 1.3 Mental and other 2 Diagnosis 3 Criteria 4 Pathophysiology 5 Treatment 6 Prognosis 7 Epidemiology 8 Notable cases 9 References

Signs and symptoms

Neurological

Abnormalities of the cranial nerves are present 50-70% of cases. The most common abnormality is involvement of the facial nerve, which may lead to reduced power on one or both sides of the face (65% resp 35% of all cranial nerve cases), followed by reduction in visual perception due to optic nerve involvement. Rarer symptoms are double vision (oculomotor nerve, trochlear nerve or abducens nerve), decreased sensation of the face (trigeminal nerve), hearing loss or vertigo (vestibulocochlear nerve), swallowing problems (glossopharyngeal nerve) and weakness of the shoulder muscles (accessory nerve) or the tongue (hypoglossal nerve). Visual problems may also be the result of papilledema (swelling of the optic disc) due to obstruction by granulomas of the normal cerebrospinal fluid (CSF) circulation.^[1]

Seizures (mostly of the tonic-clonic/"grand mal" type) are present in about 15%, and may be the presenting phenomenon in 10%.^[1]

Meningitis (inflammation of the lining of the brain) occurs in 3-26% of cases. Symptoms may include headache and nuchal rigidity (being unable to bend the head forward). It may be acute or chronic.^[1]

Accumulation of granulomas in particular areas of the brain can lead to abnormalities in the function of that area. For instance, involvement of the internal capsule would lead to weakness in one or two limbs on one side of the body. If the granulomas are large, they can exert a mass effect and cause headache and increase the risk of seizures. Obstruction of the flow of cerebrospinal fluid, too, can cause headaches, visual symptoms (as mentioned above) and other features of raised intracranial pressure and hydrocephalus^[1]

Involvement of the spinal cord is rare, but can lead to abnormal sensation or weakness in one or more limbs, or cauda equina symptoms (incontinence to urine or stool, decreased sensation in the buttocks).^[1]

Endocrine

Granulomas in the pituitary gland, which produces numerous hormones, is rare but leads to any of the symptoms of hypopituitarism: amenorrhoea (cessation of the menstrual cycle), diabetes insipidus (dehydration due to inability to concentrate the urine), hypothyroidism (decreased activity of the thyroid) or hypocortisolism (deficiency of cortisol).^[1]

Mental and other

Psychiatric problems occur in 20% of cases; many different disorders have been reported, e.g. depression and psychosis. Peripheral neuropathy has been reported in up to 15% of cases of neurosarcoidosis.^[1]

Other symptoms due to sarcoidosis of other organs may be uveitis (inflammation of the uveal layer in the eye), dyspnoea (shortness of breath), arthralgia (joint pains), lupus pernio (a red skin rash, usually of the face), erythema nodosum (red skin lumps, usually on the shins), and symptoms of liver involvement (jaundice) or heart involvement (heart failure).^[1]

Diagnosis

Left image: MRI findings (T1-weighted images) in a patient with neurosacoidosis showing thickening of infundibulum and both optic nerves (white signal marked with yellow arrows; width 6 mm).
Right image: MRI brain with contrast showing near resolution of enhancement after treatment.

The diagnosis of neurosarcoidosis often is difficult. Definitive diagnosis can only be made by biopsy (surgically removing a tissue sample). Because of the risks associated with brain biopsies, they are avoided as much as possible. Other investigations that may be performed in any of the symptoms mentioned above are computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, lumbar puncture, electroencephalography (EEG) and evoked potential (EP) studies. If the diagnosis of sarcoidosis is suspected, typical X-ray or CT appearances of the chest may make the diagnosis more likely; elevations in angiotensin-converting enzyme and calcium in the blood, too, make sarcoidosis more likely. In the past, the Kveim test was used to diagnose sarcoidosis. This now obsolete test had a high (85%) sensitivity, but required spleen tissue of a known sarcoidosis patient, an extract of which was injected into the skin of a suspected case.^[1]

Only biopsy of suspicious lesions in the brain or elsewhere is considered useful for a definitive diagnosis of neurosarcoid. This would demonstrate granulomas (collections of inflammatory cells) rich in epithelioid cells and surrounded by other immune system cells (e.g plasma cells, mast cells). Biopsy may be performed to distinguish mass lesions from tumours (e.g. gliomas).^[1]

MRI with gadolinium enhancement is the most useful neuroimaging test. This may show enhancement of the pia mater or white matter lesions that may resemble the lesions seen in multiple sclerosis.^[1]

Lumbar puncture may demonstrate raised protein level, pleiocytosis (i.e. increased presence of both lymphocytes and neutrophil granulocytes) and oligoclonal bands. Various other tests (e.g. ACE level in CSF) have little added value.^[1]

Criteria

Some recent papers propose to classify neurosarcoidosis by likelihood:^[1]

• Definite neurosarcoidosis can only be diagnosed by plausible symptoms, a positive biopsy and no other possible causes for the symptoms
• Probable neurosarcoidosis can be diagnosed if the symptoms are suggestive, there is evidence of central nervous system inflammation (e.g. CSF and MRI), and other diagnoses have been excluded. A diagnosis of systemic sarcoidosis is not essential.
• Possible neurosarcoidosis may be diagnosed if there are symptoms not due to other conditions but other criteria are not fulfilled.

Pathophysiology

Main article: Causes and pathophysiology of sarcoidosis

Sarcoidosis is a disease of unknown cause that leads to the development of granulomas in various organs. While the lungs are typically involved, other organs may equally be affected. Some subforms of sarcoidosis, such as Löfgren syndrome, may have a particular precipitant and have a specific course. It is unknown which characteristics predispose sarcoidosis patients to brain or spinal cord involvement.^[1]

Treatment

Neurosarcoidosis, once confirmed, is generally treated with glucocorticoids such as prednisolone. If this is effective, the dose may gradually be reduced (although many patients need to remain on steroids long-term, frequently leading to side-effects such as diabetes or osteoporosis). Methotrexate, hydroxychloroquine, cyclophosphamide, pentoxifylline, thalidomide and infliximab have been reported to be effective in small studies. In patients unresponsive to medical treatment, radiotherapy may be required. If the granulomatous tissue causes obstruction or mass effect, neurosurgical intervention is sometimes necessary. Seizures can be prevented with anticonvulsants, and psychiatric phenomena may be treated with medication usually employed in these situations.^[1]

Prognosis

Of the phenomena occurring in neurosarcoid, only facial nerve involvement is known to have a good prognosis and good response to treatment. Long-term treatment is usually necessary for all other phenomena.^[1]

Epidemiology

Sarcoidosis has a prevalence of 40 per 100,000. Given that less than 10% of these will have neurological involvement, and possibly later on in their disease course, neurosarcoidosis has a prevalence of less than 4 per 100,000.^[1]

Notable cases

The American television personality and actress Karen Duffy wrote "Model Patient: My Life As an Incurable Wise-Ass" on her experiences with neurosarcoidosis.^[4]

References

1. ^ ^{a b c d e f g h i j k l m n o p q r} Joseph FG, Scolding NJ (2007). "Sarcoidosis of the nervous system". Practical neurology 7 (4): 234–44. doi:10.1136/jnnp.2007.124263. PMID 17636138. 
2. ^ Colover J (1948). "Sarcoidosis with involvement of the nervous system". Brain 71 (Pt. 4): 451–75. doi:10.1093/brain/71.4.451. PMID 18124739. 
3. ^ Burns TM (August 2003). "Neurosarcoidosis". Archives of neurology 60 (8): 1166–8. doi:10.1001/archneur.60.8.1166. PMID 12925378. 
4. ^ Duffy, Karen Grover (2001). Model Patient : My Life As an Incurable Wise-Ass. New York, NY: Perennial. ISBN 0-06-095727-1. 

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