Sarcoidosis is a condition where the inflammatory cells of the body are active and grouping together as if is there is an infection despite the absence of any microbe. It is essentially a condition where the inflammatory response, that is intended to protect the body from injury, is active throughout the system for no apparent reason. When this condition affects the tissue of the nervous system – the brain, spinal cord and nerves – then it is known as neurosarcoidosis. Lesions known as granulomas form in the brain and nerves.
The cause of neurosarcoidosis is unknown. However, it is more likely to appear in individuals who had a recent infectious disease. Sarcoidosis affects 30 out of every 100,000 individuals every year but only 5 to 15% develops neurological manifestations. Although neurosarcoidosis is more likely in adults especially within the 40 to 50 year age group, it sometimes affects children as well. Occasionally it resolves spontaneously but typical neurosarcoidosis presents as a progressive disorder that may be fatal.
The Immune System
The body’s immune defense is a well coordinated system. Cells target and destroy foreign agents that enter the body. Chemicals trigger inflammation to protect the body against injury and recruit immune cells to the site of the threat. Certain protein tags known as antibodies allow the body cells to quickly target any invaders and destroy it. Once the threat is neutralized the body’s immune system shuts down the exacerbated response and remains at a state of readiness for the next threat. Even after the threat passes, the body’s antibodies which were developed against the specific antigen of the microbe, remains in the circulation for years or even throughout life. This is a form of protection against future attacks.
Sometimes the immune system does not “switch off” after the threat is neutralized or it starts up even without any threat. The exact reason why this may occur is not known. When the immune response is left unchecked, it can cause inflammation throughout the body. In sarcoidosis large amounts of immune cells start clumping together at a specific site to form a granuloma. These granulomas can be present anywhere in the body. It is more likely in the lymphatics of organs that are regularly exposed to the external environment like the lungs but may also appear in otherorgans like kidney, liver, spleen and bones. Neurosarcoidosis is the presence of these granulomas in the neural tissue like that of the brain, spinal cord and different peripheral nerves which run from the spinal cord to various parts of the body. The granulomas cause lesions or nerve compression that leads to disruption in the nerve function. Over time, however, the manifestations of neurosarcoidosis becomes more widespread.
Muscles and Nerves
Nerves transmit signals between the central nervous system (brain and spinal cord) and different parts of the body. Some of these nerves relay information about sensations – sensory nerves. Others send signals to control different muscles in the body – motor nerves. Although neuroscarcoidosis affects the nerves, granulomas can also affect the muscle tissue and therefore can present with a combination or muscle and nerve symptoms. This is known as myopathy (muscle dysfunction) and neuropathy (nerve disease). Sometimes it is the muscle itself that is affected but due to the inflammatory process, the nerves connecting to it or lying close to it are also affected.
Although the etiology of sarcoidosis remains unknown, an exaggerated immune response is usually considered to be the major cause. The heightened response is possibly a result of :
- Prolonged presence of antigen that triggers immune response
- Inability of immune response to shut down after the removal of foreign body
- Abnormality in genes regulating the immune response
Infected cells release chemicals that cause lymphocytes, a type of immune cell, to undergo maturation. During this maturation, the cells communicate with each other through cell-to-cell contact mechanisms, clump together and develop into granuloma.
When immune cells like phagocytes become overactive, it starts to damage tissue in the body. The damaged tissues then harbor lymphocytes leading to formation of sarcoid granuloma nodules.
Antibodies developed from past infections can become excessive in the system. Although these antibodies are not related to pathogenesis of neurosarcoidosis, it suggests a heightened immune responsive condition that favors development of granulomas.
Women are at slightly higher risk of developing neurosarcoidosis as compared to men.
A genetic predisposition for extreme sensitivity or exaggerated immunity is more likely to contribute to the development of neurosarcoidosis.
Neurosarcoidosis is easy to identify in a patient known to have sarcoidosis. However, when the symptoms appear suddenly, other conditions of the nerves are first suspected. The symptoms of neurosarcoidosis can be broadly discussed based on the number of nerves and types of nerves affected.
When the formation of granulomas affect functions of a single nerve, it is referred to as mononeuropathy. Neurosarcoidosis often affects the facial nerve causing weakness on one side of the face, which is known as Bell’s palsy. Sometimes there is an acute phase of fever, swelling of parotid glands and paralysis of facial nerve called Heerfordt syndrome.
- Weakness of jaw muscles and muscle twitch
- Loss of sight or defects in visual perception
- Impaired taste and smell
- Sensorineural deafness (“brain deaf”), tinnitus and vertigo
- Involuntary tongue movements causing speech abnormalities and problems with swallowing
Depending on the distribution of granulomas, nerves in different regions are simultaneously or sequentially affected. However, involvement of central nervous system causes interference with almost all major functions of brain and its cranial nerves. Some common effects include:
- Seizures (often the first symptom of NS)
- Changes in rhythmic cycles including sleep, eating habits, menstruation, cardiac functions and respiration
- Loss of memory (amnesia), both short and long-term; dementia (forgetfulness)
- Confusions and loss of judgement or decision-making abilities
- Meningitis, hydrocephalus or cerebral infarct (stroke)
- Several neuroendocrine diseases like diabetes and obesity
- Coma and sudden death
When the functioning of peripheral nerves are affected, it is known as peripheral neuropathy. It could be classified as sensory or motor neuropathy depending on whether it involves the nerves of sensation or muscle control respectively. While sensory neuropathy causes numbness, loss of sensation or abnormal sensations, motor neuropathy leads to immobility or reduced movements.
Sensory neuropathy symptoms include :
- Tingling sensation
- Excruciating pain in lower back and chest
Motor neuropathy symptoms include:
- General muscle weakness
- Immobile joints
The peripheral neuropathies develop progressively. Initially it affects distal areas of the body like the limbs and gradually progresses to proximal regions. Often presents as loss of myelin sheath from axons of peripheral nerves.
These symptoms may vary from acute to chronic depending on the stage of neurosarcoidosis progression.
Patients with pre-existing sarcoidosis are easier to diagnose for neurosarcoidosis, if they present with any neurologic symptoms. However, diagnosis becomes challenging in cases of previously active diseases where ruling out other possible reasons serve as the only hope of diagnosing neurosarcoidosis. Possible diagnostic features include:
- Weakness in the distal body parts (diffused polyneuropathy)
- Impaired fine sensory perception like vibrations along with immense pain (small-fiber neuropathy)
- Muscle tenderness, especially on the distal ends (myopathy)
- Paralysis of facial nerve showing unilateral or bilateral effect (focal neuropathies)
- Vision defects (Optic atrophy)
- Weakness and sensory loss in lower extremeties including anal region (polyradiculopathy)
Various blood tests are conducted including :
- Complete blood cell count (CBC) or erythrocyte sedimentation rate (ESR) to ensure the presence of infection
- Blood sugar levels to exclude diabetes mellitus
- Concentration of vitamin B-12
- Presence of toxins
- Urea and creatinine levels and liver function tests to rule out any defect in metabolism
Although the cerebrospinal fluid (CSF) usually remains unaffected, few neurosarcoidosis positive cases report presence of anti-Ma2 antibodies in the CSF. Functional evaluation of neuroendocrine hormones should be performed, to rule out any damage to hypothalamo-pituitary axis.
Radiography, MRI and PET scans are helpful in detecting locations of sarcoid granulomas. While nerve conduction and evoked potential studies provide an insight to the functional status of a nerve, electromyography helps in understanding muscles. Collectively, they help in assessing proper functioning of nervous system.
For definitive diagnosis of neurosarcoidosis, biopsy of nerves and muscles is the best approach. However, in non-symptomatics presence of granuloma does not vouch for the development of neurosarcoidosis. Histologically, presence of granuloma, axonal degeneration or loss of myelin indicates neurosarcoidosis.
Neurosarcoidosis Differential Diagnosis
The following disease may present with symptoms similar to neurosarcoidosis :
- Brain tumors
- All types of myopathies
- Toxic substances including drugs and alcohol
- Neuropathies associated with cancers
- Multiple sclerosis
- Meningitis and neurosyphilis
- Inflammatory brain disorders
- Vitamin B-12 deficiency
Although neurosarcoidosis rarely affects children, visual abnormalities may be the first symptoms in children. Involvement of the brainstem often makes neurosarcoidosis fatal.
Neurosarcoidosis presents a broad-spectrum of symptoms. It may either resolve spontaneously or require lon -term treatment. Since neurosarcoidosis develops due to uncontrolled immune responses, immunosuppressants are often the medication of choice.
- Immunosuppressants including methylprednisolone, cyclosporine, methotraxate or cyclophosphamide may be used depending on the duration of use, individual’s response and the severity of associated side-effects.
- Intravenous immunoglobulin therapy is reported to ease certain neuropathic symptoms. It is usually advised as a compensatory approach to the conventional immunosuppressant-therapy.
- Low-doses of radiation is also beneficial in cases of neurosarcoidosis.
- Removal of lesions in the brain does not often prove beneficial and is only considered in extreme conditions.
Additional medication may be required for the treatment and management of other symptoms and nerve dysfunction as a result of neurosarcoidosis. Severe or progressive neurosarcoidosis symptoms often require treatment for longer durations to subside completely.