Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
The author reviews current concepts of sarcoidosis-associated neuropathies. Clinical features, diagnostic considerations, and management strategies are discussed. In particular, the recent literature on sarcoidosis-associated small fiber neuropathy and possible new target-directed treatment options are highlighted. Concepts regarding the use of immunomodulatory agents are also highlighted.
• Sarcoidosis can involve the peripheral nervous system in a variety of ways.
• Patients can have a motor, sensory, sensorimotor, and/or autonomic neuropathy; the neuropathy may be primarily axonal or demyelinating.
• Patients can have involvement of isolated peripheral nerves, such as an ulnar neuropathy, or generalized involvement.
• Sarcoidosis is associated with virtually all peripheral neuropathy subtypes, eg, large fiber sensorimotor, pure motor, etc.
• Small fiber sensory neuropathy is the most common peripheral nerve manifestation and is seen in up to a third of patients with systemic disease.
• Small fiber sensory neuropathy is commonly associated with autonomic dysfunction.
• Intraepidermal nerve fiber density analysis, autonomic testing, and more recently, corneal confocal microscopy, provide objective confirmation for the diagnosis of small fiber neuropathy.
• Sarcoidosis-associated neuropathy may respond to immunosuppressive medications.
Sarcoidosis was first described by Sir Jonathan Hutchinson more than a century ago (30; 12). The term "sarcoidosis" is derived from "sarkoid," used by Caesar Boeck at the turn of the twentieth century (10). Neurologic manifestations of sarcoidosis were reviewed as early as 1935 by Levin (38). Peripheral nerve involvement with sarcoidosis was first recorded by Winkler and Mazza (77; 42).
Sarcoidosis is best thought of as a multisystemic granulomatous disorder that typically involves the lungs, lymph nodes, skin, and eyes (32; 31). Neurologic manifestations of sarcoidosis occur in 5% to 10% of patients with sarcoidosis, although subclinical involvement may be found in up to 27% of sarcoidosis patients at autopsy (41; 66). Patterns of neurologic involvement include cranial neuropathies, meningeal disease, hydrocephalus, CNS parenchymal disease, neuropathy, and myopathy (64).
Neurologic disease can be the presenting feature of sarcoidosis or can develop during the course of known sarcoidosis. Neurosarcoidosis tends to occur within the first 2 years of illness onset. Patients can have several neurologic manifestations, but after presentation, it is relatively unlikely that new categories of neurologic disease will develop. Not uncommonly, patients with a sarcoidosis-associated peripheral neuropathy can present with their neurologic disease as the initial feature of sarcoidosis (54).
Neuropathies can take the form of entrapment syndromes, pure sensory (80) or motor (24) axonal disorders, sensorimotor axonopathy, mononeuropathy, and mononeuritis multiplex (57). Reports of an acute or subacute demyelinating motor neuropathy with a presentation similar to the Guillain-Barré syndrome have raised the question of the relationship between sarcoidosis and the Guillain-Barré syndrome (43; 80; 54; 19). Chronic demyelinating forms of sarcoidosis neuropathy mimicking chronic inflammatory demyelinating polyneuropathy have also been described (59). A polyradiculopathy associated with anti-neurofascin (NF)-155 and NF-140 antibodies has been reported in a patient with sarcoidosis who also demonstrated multiple cranial neuropathies, although the significance of the antibodies is unknown (11).
Sarcoidosis-associated neuropathies can be of acute or chronic onset. The clinical course may be monophasic, chronically progressive, or remitting-relapsing. Large fiber neuropathy is not always painful, but it can be (80). A patient with painful sensory mononeuropathies evolving to a symmetric sensory neuropathy has been described (17). Patients may also develop subclinical mononeuritis multiplex (14) or multifocal motor nerve conduction block (36).
The sensory or motor loss associated with a neuropathy is dependent on the specific nature of the disturbance. For instance, an intercostal neuropathy or radiculoneuropathy has been described with dermatomal sensory loss (51; 13; 71). Hypoventilation has been associated with phrenic neuropathy (52). A “neuromyopathy” characterized by fatigue, myalgia, and areflexia and associated with selective inflammation of intramuscular nerve fibers has been described (23). Clinically it may be difficult to distinguish a widespread mononeuritis multiplex from a generalized sensorimotor neuropathy.
A commonly recognized entity associated with sarcoidosis is small fiber neuropathy, which may present with somatic and autonomic symptoms (29). Somatic manifestations include painful paresthesias and dysesthesias that often occur in a non-length dependent manner in which the face, trunk, or arms are more affected than the distal lower extremities (63; 34). Autonomic dysfunction is common as well. In a series of 115 patients with sarcoidosis small fiber neuropathy, autonomic symptoms were reported by over half of the patients (65). Symptoms included gastrointestinal disturbances, bowel or bladder dysfunction, sweating abnormalities, palpitations, and orthostasis.
Patients with a sarcoidosis-associated neuropathy can have a monophasic course with symptom resolution (20). More commonly, however, patients have a protracted illness with progressive deterioration, a static deficit, or a remitting-relapsing course (13). Although immunosuppressive therapy can lead to improvement, it is unclear whether treatment alters the natural history of the disease.
Patients are at risk for any of the complications associated with a neuropathy. These include, for instance, contractures, anesthetic injuries, decubiti, and falls.
A 53-year-old woman with a known history of sarcoidosis presented with loss of sensation in her feet and paresthesias in all distal limbs. Pertinent medications consisted of prednisone 7.5 mg daily. Examination revealed a stocking glove decrease in pain and temperature sensation in the distal extremities with a band of hyperpathia about the ankles. Strength was normal. Muscle stretch reflexes were diminished at the ankles. Tests for thyroid function, vitamin B12 level, and diabetes were unremarkable. The patient’s prednisone dose was increased to 20 mg daily, and her symptoms improved. A mild pain and temperature gradient was detectable in her distal limbs. She had a sustained response to prednisone in the 10 to 15 mg per day range.
The cause of sarcoidosis is unknown. A hypothesis addresses the possibility of a genetically based immune activation directed against as yet unknown antigens. A genome-wide association study defined an association with the gene coding for annexin A11, which has a role in apoptosis and cellular proliferation (27).
The inciting event in the pathogenesis of sarcoidosis is unknown. Inflammatory cells, particularly Th1 helper cells, are activated (02; 31). CD4 cells congregate at sites of disease activity. The cells secrete various cytokines, including interleukin-2, interleukin-12, interferon-gamma, and tumor necrosis factor. Monocytes and macrophages form granulomas, and ultimately irreversible fibrosis can develop. Small foci of ischemic necrosis can be found, presumably a result of vascular compromise from perivascular inflammation. Polyclonal immunoglobulin synthesis occurs.
An entrapment neuropathy can develop at sites of nerve compression from neurogenic or nonneurogenic granulomatous infiltration. The classic example is at the carpal tunnel with compression of the median nerve. However, the cause of most neuropathic manifestations of sarcoidosis is not well defined. Granulomas can be seen in peripheral nerves, typically in an epineural and perineural distribution (57; 54; 75). There is increasing evidence that in some cases the presence of diffuse perineural granulomas may potentially be a cause of small fiber neuropathy in sarcoidosis due to local compression (45; 33). Inflammation can develop about and within blood vessels, with luminal compromise (22; 54). The major histologic feature is that of an axonopathy (57) with relative sparing of unmyelinated fibers (46). Vital and colleagues note that necrotizing vasculitis was observed in 8 of 38 cases of sarcoidosis-associated neuropathy and microvasculitis without associated necrosis in 2 additional cases (73). Demyelination can be seen but is not the predominant pathologic feature. Perhaps a combination of nerve ischemia (47; 74) and the actions of cytokines leads to damage to the peripheral nerves (22). Why an axonal or demyelinating process develops in a specific individual is unknown. With respect to small fiber neuropathy, a cytokine-mediated pathology rather than granulomatous inflammation is suspected; pro-inflammatory cytokine profiles are found to be increased in the affected skin of sarcoidosis patients with small fiber neuropathy (70). Additionally, in a report of patients with cutaneous sarcoidosis who had pain in the region of the skin manifestations, perineural granulomas were identified on skin biopsy and, thus, may also play a role in neuropathic pain symptoms (45).
Sarcoidosis occurs with an incidence of approximately 11 patients per 100,000 patients for whites and 35 patients per 100,000 patients for blacks (68). Neurologic disease develops in approximately 5% to 10% of these patients (66). Although large fiber nerve involvement is rare in sarcoidosis, accounting for only 1% of patients with systemic disease, small fiber neuropathy symptoms have been confirmed in up to a third of those with systemic disease (04). Higher prevalence rates have been suggested by a European web-based survey of over 1000 patients with sarcoidosis in which 81% reported symptoms that may be consistent with at least “probable small fiber neuropathy” as measured by the Sarcoidosis Small Fiber Neuropathy Screening List, a 21-item self-administered survey (76).
In contrast to the higher prevalence of systemic sarcoidosis noted in African Americans, sarcoidosis small fiber neuropathy is more commonly seen in Caucasians. In 1 series of sarcoidosis-associated small fiber neuropathy patients, 87% were white, whereas only 10% were African American (65). However, the incidence was still higher in women, with a nearly 2:1 ratio.
The sibling odds ratio for sarcoidosis is 5.8 (95% CI, 2.1 to 15.9), and the parental odds ratio is 3.8 (95% CI, 1.2 to 11.3). The adjusted familial relative risk is 4.7 (95% CI, 2.3 to 9.7). White patients have a higher familial relative risk (18.0) compared to African Americans (2.8) (53).
Although sarcoidosis is not thought of as a primarily genetic disease, there are family clusters of the disorder. No method is known for prevention of sarcoidosis.
There is nothing specific about the presentation of sarcoidosis neuropathy to alert the physician to the diagnosis. However, the development of a neuropathy in a patient with sarcoidosis should lead to a consideration of a sarcoidosis-associated problem.
Sarcoidosis should be considered as a possible diagnosis in patients with an otherwise undefined neuropathy especially if subacute or rapidly progressive in presentation. Therefore, in those individuals in whom the physician is considering an inflammatory or infiltrating neuropathy, sarcoidosis should be included among the diagnostic possibilities.
If granulomatous inflammation is found in a nerve specimen, selected diagnostic considerations besides sarcoidosis include leprosy, syphilis, Wegener granulomatosis, and lymphomatoid granulomatosis (18). It is especially important to evaluate the possibility of tuberculosis. Diagnostic tools employing DNA analysis, especially the polymerase chain reaction, can detect tuberculous infection even in patients with no apparent clinical exposure (21). In the appropriate setting, the AIDS-related diffuse infiltrative lymphocytosis syndrome should be considered.
The diagnosis of sarcoidosis is most secure if noncaseating granulomas can be demonstrated in multiple organ systems (31). If organ dysfunction is obvious, attention should be directed at this site in the hope of obtaining pathologic confirmation of the diagnosis. If there is no overt systemic disease, the inflammatory process is most likely to involve the lymph nodes, lungs, skin, and eyes. Therefore, particular attention should be directed at these sites in the hope of detecting an abnormality.
In patients in whom the diagnosis of sarcoidosis is being considered and in whom there is no overt organ dysfunction, several diagnostic approaches can be followed:
• A careful skin and lymph node examination may detect an abnormality that can be biopsied.
• Blood tests (including an angiotensin converting enzyme assay, calcium level, liver and renal function, and quantitative immunoglobulins) can yield abnormalities suggestive of a systemic illness. Although an elevated serum angiotensin-converting enzyme assay is suggestive of the diagnosis of sarcoidosis, it can be abnormal in other conditions such as Gaucher disease. The other laboratory tests are relatively nonspecific as to a diagnosis of sarcoidosis.
• An ophthalmological evaluation can find iritis, conjunctival nodules, uveitis, and retinal inflammation. The conjunctiva can be biopsied; this is best done if a nodule is detected.
• A chest x-ray can reveal pulmonary lesions or mediastinal or hilar adenopathy. If the chest x-ray is unremarkable, pulmonary function tests, including a diffusion capacity, can reveal occult disease, as can a CT scan of the chest. If the pulmonary function tests or CT scan are abnormal, bronchoscopic or mediastinal biopsy can yield a diagnosis.
• If there are any sinus or nasal symptoms, an endoscopic examination can reveal mucosal abnormalities that can be biopsied.
• A whole-body gallium scan can demonstrate lacrimal, parotid, and salivary gland inflammation, which, if bilateral, is suggestive of a diagnosis of sarcoidosis (62). The gallium scan can also detect intrathoracic or intra-abdominal inflammation.
• A whole-body PET scan with fluorine-18-fluorodeoxyglucose can detect increased metabolic activity suggestive of sarcoidosis (67). This is a nonspecific finding in that malignancy and infection can cause foci of increased metabolic activity. The demonstration of an abnormal focus of activity can guide a diagnostic biopsy.
• An increase in 24-hour urinary calcium excretion is suggestive of a diagnosis of sarcoidosis.
• A muscle magnetic resonance scan can detect foci of inflammation. A biopsy can be directed at these sites.
• A skin test or QuantiFERON analysis for tuberculosis should be considered to evaluate the possibility of infection.
If there are neurologic symptoms or signs, in addition to a neuropathy, attention should be directed to further evaluating these findings with appropriate CT or MRI scans or a CSF evaluation.
Large fiber neuropathy can be assessed with electromyography (57). However, there is nothing specific about the findings to suggest the diagnosis of sarcoidosis. In axon loss lesions, the sensory and motor nerve amplitudes may be reduced or absent depending on the severity of the neuropathy, whereas demyelinating lesions may result in prolonged latencies, slowed motor conduction velocities, and/or conduction block. Needle examination can demonstrate denervation in appropriate muscles and help characterize the problem as a mononeuritis multiplex, radiculopathy, or symmetric polyneuropathy (57).
The CSF may demonstrate a number of abnormalities in patients with sarcoidosis-associated neuropathy, including an elevated CSF protein level, a modest, predominately lymphocytic pleocytosis, a low CSF glucose, an elevated IgG, and the presence of oligoclonal bands (47; 57). The value of a CSF angiotensin converting enzyme assay in patients with a sarcoidosis-associated neuropathy is unknown but is likely of low yield.
If a patient with a neuropathy of unknown cause undergoes a nerve biopsy and noncaseating granulomas are found, an evaluation should be pursued to define the possible multisystem nature of the disorder. In addition to histologic examination and microbial cultures of the biopsy specimen, consideration should be given to employing DNA technology to search for subtle evidence of tuberculous infection. Consideration should also be given to obtaining a muscle biopsy, especially if there is evidence of muscle inflammation.
A skin biopsy with determination of the intraepidermal nerve fiber density can document a small fiber neuropathy (29). In a series of 72 patients with sarcoidosis on no immunosuppressive therapy, 58 patients had symptoms suggestive of small fiber neuropathy (04). One third of these 58 individuals had an abnormal intraepidermal nerve fiber density; 2 patients without neuropathic symptoms had an abnormal biopsy. A small fiber neuropathy screening questionnaire has been developed (28). In clinical trials, corneal confocal microscopy evaluating corneal nerve fiber parameters (eg, number and density) has been used to confirm the presence of small fiber neuropathy in patients with sarcoidosis (72; 15).
Autonomic testing can be used to assess the extent and severity of an autonomic neuropathy. In some cases, it may be used as a complementary test to confirm the diagnosis of a small fiber neuropathy, even if there are no autonomic manifestations (65).
The patient with known sarcoidosis in whom a neuropathy develops can be initially assumed to have a sarcoidosis-associated neuropathy, after other common causes of neuropathy are reasonably excluded. However, if the patient does not respond to treatment, consideration should be given to obtaining a nerve or skin biopsy to further evaluate the problem.
Studies have demonstrated the presence of paraneoplastic autoantibodies in patients with small fiber neuropathy, the most common of which was antiganglionic acetylcholine receptor antibodies (40; 48). Although in some cases this may represent false positive test results, 1 study found positive autoantibodies in 22% of sarcoidosis small fiber neuropathy patients compared to only 6.5% of those with similar symptoms but no diagnosis of sarcoidosis (40). Larger studies are needed to elucidate the significance of these findings but they may be suggestive of a possible antibody-mediated mechanism for some patients with sarcoidosis small fiber neuropathy.
Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.
The mainstay of treatment of sarcoidosis is corticosteroid therapy (68). Unfortunately, there has never been a rigorous prospective trial to define the efficacy of corticosteroids for the neurologic complications of sarcoidosis. Nevertheless, most authors advocate the use of corticosteroid therapy for patients with a functional deficit from a sarcoidosis-associated neuropathy (57).
Prednisone is usually begun at a dose of 40 to 60 mg daily; some physicians will prescribe 0.5 to 1.0 mg/kg per day. The higher dose range is reserved for patients with severe deficits. This dose is continued for 2 to 4 weeks as the clinical status is observed. As the patient's functional state is monitored, the dose can be adjusted by 5 mg decrements every 2 weeks or so. Once stabilized, patients can often tolerate a dose reduction to approximately 10 mg (or 0.1 mg/kg) daily. Near this level, patients are most likely to relapse. The patient can be observed for 4 weeks, and, if all is well, the dose can be further lowered in 1 mg decrements every 2 to 4 weeks as the clinical status is watched. If the patient deteriorates, often doubling the prednisone dose (unless the patient was at a small dose) can lead to improvement. Patients may require a prolonged treatment program, with constant attempts to slowly taper the prednisone to the lowest therapeutic level and upward adjustments as warranted by the clinical course.
If the patient is severely ill or if the question arises whether an increase in immunosuppression can help the patient, a 3- to 5-day course of intravenous methylprednisolone, 20 mg/kg per day or 1 gm per day, can be administered initially followed by an oral prednisolone taper. This may be helpful for acute presentations of large and/or small fiber neuropathy (55). The clinical status can be observed over the next 2 to 4 weeks while prednisolone 0.5 to 1.0 mg/kg daily is maintained. Another therapeutic option for severely ill patients is a trial of infliximab, a monoclonal antibody directed at tumor necrosis factor alpha (06; 78; 50; 16; 35).
If corticosteroid treatment is contraindicated, severe corticosteroid adverse effects have developed, or the patient has deteriorated in spite of "optimal" corticosteroid therapy, alternate immunosuppressive medications can be tried (08; 56). These include agents such as azathioprine, mycophenolate mofetil (37), methotrexate (01; 09), cyclosporine (61), cyclophosphamide (60), chlorambucil, and cladribine (69). Hydroxychloroquine (58), pentoxifylline (79), and thalidomide (05) have also been used as immunomodulatory drugs for the treatment of sarcoidosis. Periodic administration of infliximab or similar tumor necrosis factor antagonists (adalimumab, etanercept) may be another therapeutic strategy, although etanercept may not be as beneficial as infliximab (07). These drugs usually allow the dose of prednisone to be lowered gradually, but rarely is it possible to stop the prednisone. The decision as to which drug to employ depends, in part, on the potential adverse drug effects that need to be avoided. For instance, thalidomide and leflunomide can cause sensory neuropathy. Infliximab has also been reported to cause a demyelinating polyneuropathy (03).
Occasionally, a clinical response is obtained with polypharmacy that is better than that obtained with corticosteroid monotherapy. Moravan and Segal found a beneficial response to combination therapy with infliximab and mycophenolate mofetil in 7 patients with refractory CNS sarcoidosis (44). Although 1 reported case of sarcoidosis-associated peripheral neuropathy did not respond to intravenous immunoglobulin (IVIG) treatment (39), a subsequent report of 3 patients with small fiber neuropathy (49) and 1 case of large fiber neuropathy (25) noted anecdotal improvement with IVIG therapy. In addition, a case of multifocal motor nerve conduction block associated with sarcoidosis also responded to IVIG (36).
In a study evaluating the use of immune-modulating treatment for sarcoidosis-associated small fiber neuropathy, symptomatic improvement was seen in 47 of 62 patients who received IVIG, 8 of 12 patients who received anti-TNF, and 10 of 14 patients who received combination therapy (65). Cibenitide (previously known as ARA-290), an experimental erythropoietin agonist that targets specific receptors involved in pro-inflammatory cytokine production was shown to reduce autonomic and neuropathic pain symptoms in a small pilot trial of patients with sarcoidosis-associated small fiber neuropathy (26). Follow-up studies have shown improved quality of life measures and increased corneal fiber parameters in this population (72; 15).
Supportive therapy is key. Appropriate bracing and pain management can optimize patient function. Physical and occupational therapy may be beneficial as well. The patient should be cautioned about the risk for burns or otherwise unsuspected injuries. A skin inspection should be routine.
Pregnancy can alleviate systemic sarcoidosis. There is no information on the effect of pregnancy on sarcoidosis-associated neuropathies. Corticosteroid therapy can continue during pregnancy, but the lowest dose possible should be used. Treatment with alternate immunotherapy agents should be avoided if at all possible because of potential adverse effects on the fetus. Thalidomide should not be administered to a woman who is or could become pregnant.
There is no known effect of anesthesia on the degree of inflammation associated with sarcoidosis. If the patient is on low-dose corticosteroid therapy, supplemental corticosteroids may need to be administered during a surgical procedure.
Jinny O Tavee MD
Dr. Tavee of Northwestern University Feinberg School of Medicine received consulting fees from Argenx, a research grant from Kabafusion Infusion Services as an investigator, and a lecture fee from Alexion.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Jan. 18, 2022
Nerve ultrasound for neuropathy allows for the determination of peripheral nerve anatomical course, echogenicity, vascularity, and degree of mobility. Magnetic resonance neurography allows for visualization of higher soft-tissue contrast, which can depict milder abnormalities when there are subtle T2 signal abnormalities.
Jan. 13, 2022
The author reviews the clinical neurotoxicity of the antiarrhythmic agent amiodarone, an amphiphilic drug that forms intralysosomal lipid complexes in
Jan. 07, 2022
After carpal tunnel syndrome, the most common median nerve entrapment is the pronator teres syndrome. The most common features of the pronator teres syndrome are insidious proximal forearm fatigability, pain, and tenderness amplified by exercise and, at times, radiating to the shoulder. Other less common entrapment sites include the ligament of Struthers, lacertus fibrosus, and the tendinous origin of the flexor digitorum superficialis.
Jan. 02, 2022
Movement disorders are prominent in the clinical presentation of many autoimmune disorders. These abnormal motor phenomena include faciobrachial dystonic seizures, neuromyotonia, chorea, myorhythmia, stereotypies, dystonia, tremor, parkinsonism, ataxia, and stiff-person-like phenomena. Each type of autoimmune encephalitis presents with a different profile of abnormal movements, and a therapeutic response to immunomodulatory therapy suggests that these motor phenomena also have an autoimmune pathogenesis.
Dec. 30, 2021
Acquired sensory neuronopathies depend on a primary involvement of sensory neurons in dorsal root ganglia leading eventually to a definitive and irreversible degeneration of the cell body. They include toxic, infectious, and dysimmune mechanisms, although an important proportion remains idiopathic after an extensive workup. The loss of large sensory neurons results in ataxia that usually predominates in the lower limbs, resulting in ataxic gate and Romberg sign.
Dec. 02, 2021
Familial dysautonomia is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN) disorder characterized by both sensory and autonomic dysfunction, resulting in decreased pain and temperature perception as well as pervasive manifestations of autonomic dysregulation. Four unique features associated with this particular HSAN type are absence of overflow emotional tearing, afferent baroreflex failure, hyperadrenergic vomiting crises, and optic neuropathy.
Nov. 18, 2021
Neuroacanthocytosis is a neurologic syndrome characterized by a broad spectrum of movement disorders that often share acanthocytes on the blood smear. A variety of other neurologic symptoms may accompany neuroacanthocytosis, including seizures, motor neuron disease, and dementia. Chorea-acanthocytosis is an autosomal recessive disorder due to mutations in the VPS13A gene (chromosome 9q21), and is among the disorders known to cause neuroacanthocytosis.
Nov. 09, 2021