Sarcoidosis is a systemic inflammatory disease characterized by the formation of microscopic clumps of inflammatory cells, called non-caseating granulomas, in various organs. Neuropathy is damage to the peripheral nerves, which are outside the brain and spinal cord. Sarcoidosis can definitively cause neuropathy, a manifestation known as neurosarcoidosis. Neurological involvement occurs in an estimated 5% to 15% of sarcoidosis patients, and peripheral neuropathy is a significant aspect of this presentation.
The Pathophysiology of Nerve Damage
Sarcoidosis causes nerve damage primarily through direct infiltration and secondary inflammatory processes. The hallmark non-caseating granulomas can directly invade the peripheral nervous system, particularly the protective sheaths around nerves (epineurium and perineurium). The physical presence of granulomas causes compression and destruction of nerve fibers, leading to axonal damage and loss of nerve function.
This direct involvement results in “granulomatous neuropathy.” Nerve damage is also driven by the intense systemic inflammation characteristic of sarcoidosis. Inflammation can lead to vasculitis, which is the inflammation of the small blood vessels supplying the nerves.
Narrowing or occlusion of these epineurial blood vessels reduces blood flow to the nerve tissue, causing ischemia, which damages the nerve fibers. This secondary damage from reduced blood supply can affect the nerves in a diffuse pattern. The cytokine-mediated inflammatory environment, separate from the granulomas, also plays a role, particularly in damaging the smallest nerve fibers.
Classification of Peripheral Neuropathy in Sarcoidosis
The clinical presentation of peripheral neuropathy in sarcoidosis is highly variable. One form is mononeuropathy or mononeuritis multiplex, where one or multiple isolated, non-contiguous nerves are affected. The most common example is facial nerve palsy, causing sudden weakness or drooping on one side of the face, which occurs in up to half of all neurosarcoidosis cases.
A more generalized presentation is symmetric sensorimotor polyneuropathy, which involves both sensory and motor nerves. This often starts in the feet and progresses upward, causing symmetric weakness and numbness. This type may present with features similar to chronic inflammatory demyelinating polyneuropathy (CIDP) or, less commonly, an acute form resembling Guillain-Barré syndrome (GBS).
Small fiber neuropathy (SFN) is a common manifestation, often considered a non-granulomatous or “parasarcoidosis” phenomenon. This type affects the unmyelinated and thinly myelinated sensory and autonomic nerve fibers. Patients with SFN often experience severe, non-length-dependent burning pain, tingling, and autonomic symptoms like orthostatic hypotension (a drop in blood pressure upon standing), palpitations, or gastrointestinal motility issues.
Identifying Symptoms and Diagnostic Confirmation
Symptoms depend on the type and location of the nerve damage. Large fiber damage, such as in polyneuropathy or mononeuritis multiplex, can cause muscle weakness leading to difficulty lifting the foot (foot drop) or loss of movement. Patients may also report sensory symptoms like numbness, tingling, or loss of sensation in a “stocking-glove” distribution.
Diagnosis of sarcoidosis-associated neuropathy is challenging because symptoms overlap with many other common conditions like diabetes or vitamin B12 deficiency. Electromyography (EMG) and Nerve Conduction Studies (NCS) are the initial specialized tests used to assess the function of large, myelinated nerve fibers, revealing the extent of axonal damage or demyelination. These studies are normal in cases of pure small fiber neuropathy, requiring different diagnostic methods.
To confirm small fiber neuropathy, a skin biopsy is performed to measure the intraepidermal nerve fiber density (IENFD). A reduced density of nerve fibers in the skin sample provides objective evidence of SFN. In cases of suspected granulomatous neuropathy, a nerve or muscle biopsy may be necessary to microscopically confirm the presence of non-caseating granulomas, which offers definitive evidence that sarcoidosis is the cause. Imaging, such as an MRI of the spine or nerve plexus, may be used to identify areas of nerve root inflammation or mass lesions causing compression.
Management and Treatment Strategies
The goal of managing sarcoidosis-related neuropathy is to reduce inflammation and halt the progression of nerve damage. Treatment strategies focus on immune modulation, as the nerve damage is fundamentally an inflammatory process. High-dose corticosteroids, such as prednisone, are the first-line treatment for large-fiber and cranial neuropathies, as they suppress the underlying inflammation.
If the neuropathy is severe, rapidly progressive, or fails to respond adequately to corticosteroids, second-line immunosuppressive agents are introduced. These steroid-sparing medications include agents like methotrexate, azathioprine, or mycophenolate mofetil. These agents help maintain disease control while allowing for a reduction in the corticosteroid dose, minimizing long-term side effects.
For refractory cases, particularly severe small fiber neuropathy or demyelinating forms, biological agents like TNF-alpha inhibitors (e.g., infliximab) or intravenous immunoglobulin (IVIg) may be used. Symptomatic management is also a core part of treatment, often involving medications like gabapentin or pregabalin to control the neuropathic pain that frequently accompanies nerve damage. Treatment choice is tailored to the type of neuropathy, its severity, and the patient’s overall systemic sarcoidosis activity.