Immunohistochemical stains are valuable tools to differentiate Schwann cells from other cell types. S-100 is a protein unique to neural crest-derived cells, so anti-S-100 antibodies can be used to stain for healthy Schwann cells or nervous tissue neoplasms, such as schwannomas.[9] Myelin basic protein (MBP) neutralizes phospholipid charges on the inner surface of the membrane and is present in Schwann cells but not satellite cells, the other major PNS glial cell. Anti-MBP can be used to differentiate Schwann cells or oligodendrocytes from other glial cells.[10] P0, a peripheral nerve myelin protein, is a transmembrane adhesion protein that promotes the extracellular lamellar apposition that forms the intraperiod lines.[1] Anti-P0 can be used to identify granular cell tumors, which derive from Schwann cells.[11]

Under light microscopy, Schwann cell nuclei and myelin sheath are visible, as well as their basal laminae and associated axons.[12] Both light and electron microscopy demonstrate myelin sheaths of various thicknesses according to neuregulin expression by the axon. More heavily myelinated axons may have more than 40 lamellae, as visualized by alternating intraperiod and dense lines. Intraperiod lines demonstrate the apposition of extracellular surfaces of compact lamellae of the Schwann cell plasma membrane. Dense lines demonstrate the close apposition of the cytoplasmic surfaces of the membrane in compact myelin.[1]

Under transmission electron microscopy, the lamellar structure and Schwann cell cytoplasmic content can be visualized clearly, including mitochondria, microtubules, and microfilaments. Osmium tetroxide is used to stain the myelin, allowing the dark (osmiophilic) myelin of myelinating Schwann cells to be clearly distinguished from the lighter membranes of the non-myelinating Schwann cells. Myelinating Schwann cells can be seen surrounding a single axon with a myelin sheath, though it may also have unmyelinated axons associated with its outer cytoplasm. Bundles of unmyelinated axons are visible, settled into the cytoplasm of a non-myelinating Schwann cell. Endoneurium, the loose connective tissue sheaths that surround individual nerve fibers, can also be visualized.[12]

The major diseases involving Schwann cells are demyelinating or neoplastic processes. Disorders that cause damage to the myelin sheath in the PNS, affecting the function of Schwann cells and axons, are called peripheral demyelinating diseases. Various insults, such as genetic mutations, infections, trauma, and autoimmune processes can trigger this demyelination and eventual neurodegeneration. Guillain-Barre Syndrome is a rare autoimmune peripheral demyelinating disease characterized by acute ascending flaccid paralysis, which can be life-threatening if the disease affects the muscles of respiration. It is often associated with a preceding infection of the gastrointestinal or respiratory tract, particularly C. jejuni and associated anti-GM1 and anti-GD1a antibodies. The association with infection and accumulation of anti-ganglioside antibodies suggests that ganglioside-like antigens found on C. jejuni lead to the production of antibodies that are cross-reactive with myelinating cells of the PNS. Guillain-Barre can also be caused by other pathogens, trauma, surgery, monoclonal antibody treatment, and rarely by vaccination. The patients usually present with proximal muscle weakness of lower extremity. The most common variant of Guillain-Barre is acute inflammatory demyelinating polyradiculopathy (AIDP), which presents histologically with segmental demyelination with lymphocytic and monocytic infiltration.[13][14]

Charcot-Marie-Tooth disease (CMT) is a rare hereditary peripheral demyelinating disorder, most commonly with autosomal dominant inheritance. Several subtypes affect different proteins and can affect both sensory and motor nerves, but all disrupt Schwann cell structure and function. PMP22 is the most commonly affected protein and causes CMT1A, leading to growth arrest in Schwann cells and abnormal Schwann cell number between nodes of Ranvier. CMT1 is characterized by segmental demyelination and remyelination, causing onion skin appearance on biopsy, and greatly reduced conduction velocity of nerves.[13][15] 

Diabetes mellitus is associated with hyperglycemia, hyperlipidemia, hypertension, and impaired insulin signaling, which can damage microvasculature, leading to the common complication of diabetic peripheral neuropathy. Diabetic neuropathy is due to damage to Schwann cells and axons in both sensory and motor nerves. Schwann cells appear to be more susceptible to direct damage caused by hyperglycemia. In contrast, neurons are highly metabolically active, and function better in a hyperglycemic environment but are at greater risk of degeneration caused by hypoxia and loss of trophic support from Schwann cells. Hyperglycemia causes Schwann cell dysfunction, production of reactive oxygen species, initiation of the inflammatory cascade, disruptions in axon conduction, and impaired regeneration after nerve damage.[2]

Schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs) are all neoplastic conditions that arise from Schwann cells. Schwannomas are typically solitary encapsulated lesions made exclusively of neoplastic Schwann cells. Schwannomas do not invade the associated nerve but may produce symptoms caused by mass effect. Neurofibromas and MPNSTs are made of multiple cell types, including Schwann cells, and commonly infiltrate the associated nerve. Neurofibromas commonly arise in patients with neurofibromatosis 1 (NF1), an autosomal dominant disorder caused by a mutation in the NF1 tumor suppressor gene, which may present with dermal and/or plexiform neurofibromas. Dermal neurofibromas are hormone-sensitive tumors that begin to appear as NF1 patients enter puberty, and these tumors have little to no malignant potential. Plexiform neurofibromas are often congenital, not hormone-responsive, and can undergo malignant transformation to MPNSTs.[16][17]

Guillain-Barre manifests clinically with symmetric ascending paralysis and paresthesia, which may progress to dyspnea and choking over hours to days. Management is supportive and, with ventilatory support and monitoring for cardiac arrhythmias and other complications, the prognosis is good with patients typically recovering function within 12 months.[13] The earlier the clinician identifies and treats the condition, the better the prognosis. In randomized controlled trials, there are two treatment options currently considered the standard of care in Guillain-Barre syndrome (GBS). These include either intravenous immunoglobulin (IVIG) or plasma exchange. IVIG is thought to act by its immune-modulating action; however, the exact mechanism remains unclear. IVIG dosing is 2 grams/kilogram divided over 5 days.[18] [Level I] Plasma exchange is thought to act by removing pathogenic antibodies, humoral mediators, and complement proteins involved in the pathogenesis of GBS. Similar to IVIG, its exact mechanism of action in the treatment of GBS remains unproven. The patient generally receives plasma exchange as a volume of an exchange over five sessions.

Patients with CMT may present with distal muscle weakness, foot drop, depressed or absent deep tendon reflexes, atrophy of muscles of below the knee, and atrophy of the muscles of the thenar eminence. CMT does not reduce the lifespan, and management is supportive.[13][15]

Diabetic neuropathy classically arises in patients with long-standing diabetes as a sensory neuropathy with loss of temperature, vibration, touch, and pain sensation. Patients may also have accompanying neuropathic pain. Nerve damage progresses from small sensory fibers to large sensory fibers, to large motor fibers, causing weakness, loss of function, and paralysis. Nerve damage also is more pronounced in distal extremities, a characteristic “stocking-glove” pattern. Treatment of diabetic neuropathy is limited to symptomatic treatment of neuropathic pain and maintenance of euglycemia to prevent the development of diabetic neuropathy or slow its progression.[2]

Schwann cell neoplasms can be identified by immunohistochemistry for Schwann cell markers such as S-100. Management varies from monitoring and supportive care for asymptomatic dermal neurofibromas to surgery, chemotherapy, and radiation for metastatic MPNSTs.[16][17][19][20]