Neurosarcoidosis: Granulomas in the Nervous System

What Is Neurosarcoidosis?

Neurosarcoidosis is a complication of long-term chronic sarcoidosis that causes abnormal microscopic cell clusters of inflammatory cells (also called granulomas) in the central (brain and spinal cord) and peripheral nervous system (both or just one system). The granulomas are characteristic of underlying sarcoidosis and can form in a single or multiple organ systems. The formation of multiple granulomas in an organ system can make the system go haywire, leading to the presentation of various pathologic outcomes. The neurological form of sarcoidosis, neurosarcoidosis, usually occurs in the cranial and facial nerves, hypothalamus, and pituitary gland.

Who Is Susceptible to Neurosarcoidosis?

The prevalence of sarcoidosis is higher in the African American population, much higher in New York at one in 100,000 population. Whatsoever may be the global distribution of sarcoidosis, neurological involvement is seen in about five percent of the cases. But in some studies, prevalence within the sarcoids was noted as high as 16 percent; 26 percent in one particular study. At an average of five percent prevalence, neurological deficits are seen in almost half of neurosarcoidosis cases.

A wide range of global prevalence has been reported with 175, 0.04, 64, 27, 97, 200, and 1 in 100,000 population of Puerto Ricans, Spaniards, Swedes, Englishmen, Irishmen, West Indies, and ones dwelling in south Wales and South West-England. Asians are barely touched by the prevalence, with just a few Japanese cases reported across Asia.

The racial predilection is quite distinct, with the ratio of affected blacks to whites in the United States ranging between 10:1 to 17:1. The condition is predominant in Whites in Europe. The most untouched populations belong to China, Southeast Asia, Inuits, Canadian aboriginals, and New Zealand Maoris. The sex ratio ranged between 55:45 to 63:37, mostly occurring between the ages of 25 to 50 years. Children are rarely affected, usually between the ages of 9 to 15, with almost a cent percent probability of ocular involvement.

What Are the Causes of Neurosarcoidosis?

The exact cause of sarcoidosis, and subsequently neurosarcoidosis, is still unknown. It is hypothesized that sarcoidosis occurs from an exaggerated cellular immune response to foreign or self-antigens, which means it can also be an autoimmune response. T-helper lymphocytes are responsible for the exaggerated response.

The T-helper cells undergo differentiation to form Th-1 cells with the help of interleukin-4 (IL4) and CD28. The Th-1 cells further induce interleukin-2 (IL2) and interferon-gamma (INF-gamma) over the macrophages, which induces a cascade of chemotactic factors that promotes the formation of granulomas. INF-gamma increases major histocompatibility class (MHC)-II receptors on macrophages. These activated macrophages carry immunoglobulin G (IgG) receptors that induce their phagocytosis functionality. The following tissue destruction and granuloma formation occur secondarily.

The immune response is thought to have been induced by:

• The persistent presence of foreign or self-antigen.

• Inadequate response to negative feedback of immunity.

• Genetic predisposition to exaggerated immune response.

Additionally, sarcoidosis patients with antibodies against several infections and IgM anti-T-cell-antibodies may also contribute to disease pathogenesis. However, there is no concrete evidence in favor of this.

Neuropathies have been hypothesized to occur through two mechanisms:

• Neural tissues may get directly involved causing myositis and neuropathies.

• Granulomas invade the perineurium and epineurium, causing localized symptoms and axonal damage.

What Are the Clinical Features of Neurosarcoidosis?

General sarcoid symptoms are primary manifestations, followed by secondary neurological manifestations (neurosarcoidosis).

Sarcoid Symptoms:

• Chest pain.

• Chronic dry cough.

• Fatigue.

• Fever.

• Pain and swelling in the joints.

• Shortness of breath.

• Swollen lymph nodes.

• Weight loss.

• Wheezing.

Neurological Symptoms:

Neurological symptoms can be categorized based on the affected anatomy.

Involvement of the pituitary gland can present as:

• Fluctuation of the menstrual cycle.

• Intense fatigue.

• Polydipsia (excessive thirst).

• An increased amount of urination.

• Weight discrepancies.

• Hair problems.

• Diabetes insipidus.

• SIADH (syndrome of inappropriate antidiuretic hormone secretion).

• Hyperprolactinemia (elevated prolactin levels).

• Hypothyroidism (decreased secretion of thyroid hormones).

• Hypoadrenalism (decreased secretion of adrenal hormones-cortisol and aldosterone).

Involvement of the cranial nerves or the brain shows symptoms like:

• Confusion.

• Disorientation

• Dementia.

• Dizziness.

• Vertigo.

• Abnormal movement sensation.

• Bell’s palsy or facial palsy.

• Headache.

• Loss of taste or abnormal tastes.

• Loss of smell.

• Mental disturbances.

• Seizures.

• Optic neuropathy.

• Total or peripheral vision loss.

• Uveitis (inflammation of the middle layer of the eye wall).

• Ptosis (drooping of upper eyelid).

• Diplopia (double vision).

• Speech impairments.

Involvement of the peripheral nervous system presents as follows:

• Abnormal sensations.

• Loss of movement in any part of the body.

• Loss of sensation in any part of the body.

• Weakness in any part of the body.

CNS (central nervous system) manifestations can be summarized as cranial neuropathies, myelopathies, sellar disease, parenchymal disease, encephalopathy, and neuropsychiatric illness. PNS (peripheral nervous system) sarcoidosis can be summarized as manifestations of small fiber neuropathies and muscle diseases.

How to Diagnose Neurosarcoidosis?

Diagnosis of neurosarcoidosis is based on excluding differentials and identifying the sarcoid granulomas by histological studies of nerve or muscle samples.

Other diagnosis tests include

1. Blood Tests: CBC (complete blood picture) may show normochromic normocytic anemia, megaloblastic changes, basophilic stripping, lymphopenia, and other dysfunctional hematopoietic changes. ESR (erythrocyte sedimentation rate) may be elevated. CK (creatinine kinase) and aldolase may be deviant from normal. Abnormal LFT (liver function tests) and C-ANCA (antineutrophil cytoplasmic antibody) titles may be required to differentiate neurosarcoidosis from other diseases.

2. Endocrine Studies: Since the condition affects the pituitary-hypothalamic axis, it is possible to have endocrine dysfunction in various glands. Tests for thyroid function, prolactin, testosterone, growth hormone, luteinizing hormone, FSH (follicle-stimulating hormone), corticotropin-releasing hormone, estradiol, urine osmolality, and insulin-like growth factor can be done to detect the severity of pituitary involvement.

3. Chest Radiograph: Chest radiograph images may be similar to ILD (interstitial lung disease), demonstrating perihilar lymphadenopathy. This is characteristic of the pulmonary manifestation of sarcoidosis. This is also seen in lymphoma and other systemic diseases.

4. Magnetic Resonance Imaging: MRI scans are indispensable tools for neurosarcoidosis diagnosis. The MRI scans can show

• Periventricular high-signal lesions.

• Multiple supratentorial.

• Multiple infratentorial brain lesions.

• Solitary intra-axial mass.

• Solitary extra-axial mass.

• Leptomeningeal enhancement.

• Optic nerve enhancement.

• Spinal cord intramedullary mass.

5. Positron Emission Tomography: PET scans may show areas of hyper or hypometabolism in the CNS. A combination of fluorodeoxyglucose-PET scan and F-18 fluorothymidine PET scan can help in differentiating neurosarcoidosis from other malignancies and also help in determining the biopsy site.

6. Electromyography: Also known as nerve conduction studies (NCS or EMG) are done to confirm the presence of neuropathies. The findings of EMG include slow motor nerve conduction, abnormal sensory nerve conduction, absent potentials, and reduced amplitudes, with mild slowing. These changes can be interpreted as mononeuropathy multiplex, showing axonal degeneration and segmental demyelination.

7. Biopsy: Biopsy of an enlarged lymph node may reveal noncaseating granulomas suggestive of sarcoidosis. The biopsy may reveal axonal injury and demyelination. The biopsy sample is sent to pathologists for differential staining and further microscopic analysis for histopathological evidence of sarcoidosis and neurosarcoidosis.

8. Other Tests: Other tests include evoked potential study, CSF (cerebrospinal fluid) analysis, and optical coherence tomography (OCT). OCT is especially useful in detecting retinal abnormalities prior to discovery by ophthalmologic examination. CSF findings can be non-specific in peripheral neurosarcoidosis but may show certain changes like elevated proteins, low glucose, leukocyte count aberrancy, ACE (angiotensin-converting enzyme), lysozyme, and beta-2-microglobulin; in case of CNS-neurosarcoidosis.

What Are the Histopathological Findings of Neurosarcoidosis?

Some of the histopathological findings of neurosarcoidosis include

• Non-caseating or solid, discrete, and naked granulomas.

• A paucity of lymphocytes and plasma cells.

• Secondary axonal degeneration (degradation of the axons of the nerve cells).

• Nerve fiber atrophy (wasting of the nerve fibers).

• Myelin ovoids (suggestive of demyelination).

• Necrotizing vasculitis (inflammation and death of blood vessel walls).

How to Treat Neurosarcoidosis?

Despite leaps of advancement in medical science, some conditions still evade any progression in the development of a cure. Some patients may undergo gradual remission without any intervention, while others need to be medicated to control the symptoms and prevent complications. The first line of pharmacotherapy includes corticosteroids like Prednisone, followed by the second line of immunosuppressants. Other drugs that have been recruited in medical therapy include Methotrexate, Cyclophosphamide, Azathioprine, Infliximab, Adalimumab, Leflunomide, Tocilizumab, Tofacitinib, and Baricitinib.

Surgery is usually not indicated for neurosarcoidosis except for biopsy purposes but may be implemented in fatal complications like hydrocephalus, increased intracranial pressure, or spinal cord compression.

What Is the Prognosis of Neurosarcoidosis?

The prognosis widely varies among individuals and is based on the severity of the condition and the location of the granulomas along the neural system. The patient may develop permanent blindness. Spinal cord involvement portrays a worse prognosis. Pituitary involvement often causes irreversible damage, and hormone replacement therapy can be continued for the entire lifespan. However, aggressive therapy (keeping in mind the extensive side effects of corticosteroids and immunosuppressants) in the initial stages can turn the outcomes favorable.

What Is the Differential Diagnosis of Neurosarcoidosis?

• Acute inflammatory demyelinating polyradiculoneuropathy (autoimmune neural inflammatory disease of the peripheral nervous system).

• Infectious myositis (infection of the skeletal muscles).

• Leptomeningeal carcinomatosis (cancers of the pia mater and arachnoid layers of the brain).

• Multiple sclerosis (autoimmune disorder affecting the nerve coverings).

• Neuromuscular and myopathic complications of HIV (neural and muscular disorders secondary to human immunodeficiency virus infection).

• Neurosyphilis (syphilis infection of the brain and spinal cord).

• Otolaryngologic manifestations of granulomatosis with polyangiitis (ear, nose, and throat manifestations of autoimmune vasculitis-GPA).

• Pediatric-Lyme disease (juvenile onset of a bacterial disease spread by ticks).

• Primary CNS lymphoma (cancers of the brain and spinal cord lymphatics).

• Systemic lupus erythematosus (autoimmune disorder against the connective tissues).

What Are the Complications of Neurosarcoidosis?

• Opportunistic infections.

• Permanent blindness.

• Bell’s palsy.

• Paralysis.

• Hydrocephalus (fluid buildup within the ventricles of the brain).

• Increased intracranial pressure (increasing pressure within the brain).

• Endocrine dysfunctions (abnormal secretions from endocrine glands).

• Neuropsychiatric disturbances (like seizures. attention deficit disorders, cognitive deficits, etc.).

Conclusion

Neurosarcoidosis is a secondary complication of sarcoidosis. Even with limited success in treatment, early and aggressive treatments have shown some success in improving the outcomes. It is of utmost importance for diagnosed sarcoid patients to follow up with specialists to catch the neurologic manifestations at incipient stages. Clinicians must rule out all possible differentials to avoid misdiagnosing and ensure the implementation of medical therapy.