Figure 50-1 Selected microscopic fields from sural biopsy from the patient presented. The upper frame is a paraffin section stained with hematoxylin and eosin that demonstrates a giant cell (arrow) situated in the perineurium of a fascicle. The perineurium is markedly thickened and infiltrated by macrophages. Noncaseating granuloma formation is evident in the right lower corner of this frame. In the lower frame, CD 68 reactivity (for macrophages) demonstrates the granulomatous involvement of the endoneurium, perineurium, and epineurium. This section was taken from the same region and block of nerve as the upper frame. These views provide evidence of the typical pathologic alteration, and marked infiltration and scarring induced by the process, which changes that may account for the poor recovery in some cases, such as this one.
(Reprinted from Burns TM, Dyck PJB, Askamit A, Dyck PJ. The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J Neurol Sci 2006;244:77–87. Copyright 2006, with permission from Elsevier.)
He was treated with prednisone, with doses ranging from 30 mg every other day to 60 mg every other day over the next 15 years. Prednisone doses were changed according to his varying degrees of pain and disability. Attempts to titrate the patient to lower doses of prednisone over the years were unsuccessful. NCS/EMG studies were repeated at various time points, but results remained essentially unchanged. NIS scores ranged from 91 to 118 throughout his illness, thus demonstrating significant impairment throughout the course of his illness. He died 15 years after symptom onset. A postmortem study was not obtained.
Our patient presented with the abrupt onset of back, hip, and left lower extremity pain, followed by asymmetric lower extremity numbness 1 week later. The abrupt onset is typical of limb sarcoid neuropathy, occurring in 89% of cases in one series.1 The distribution of symptoms is usually multifocal, asymmetric, and nonlength dependent.1 Our patient’s manifestations of back, hip, and leg neuropathic pain, associated with proximal and distal weakness with reflex impairment, is typical of sarcoid polyradiculoneuropathy.1 Although the pattern of neuropathy is most frequently polyradiculoneuropathy or polyradiculopathy, polyneuropathy and small fiber neuropathy are also common presentations.1 Symptoms of limb sarcoid neuropathy manifest as positive neuropathic sensory symptoms (PNSS) (burning pain, pins and needles and aching) more so than weakness or sensory loss.1 Patients with sarcoidosis suffering from sensory symptoms may demonstrate selective small fiber involvement, as evidenced by reduced intraepidermal fiber density on skin biopsies.6,7
Constitutional symptoms such as malaise, fatigue, fever, or unexplained weight loss are reported in approximately 50% of patients with biopsy proven limb sarcoid neuropathy.1 Eye involvement, which occurred in our patient, is reported in approximately 15% of limb sarcoid neuropathy patients.1
Cranial neuropathies and thoracic radiculopathies can occur in cases of limb sarcoid neuropathy. In one case series, transient cranial neuropathies or thoracic radiculopathies, preceding or concurrent with limb symptoms, occurred in approximately 35% and 17% of patients respectively.1
There are no pathognomonic radiologic or laboratory results in patients with limb sarcoid neuropathy. Pulmonary involvement on CXR, defined as hilar or mediastinal lymphadenopathy, is reported in approximately 50% of the patients with biopsy proven limb sarcoid neuropathy.1,5 Our patient’s CXR was remarkable only for a pulmonary nodule many years before his presentation.
CSF from our patient revealed an elevated protein and a mild pleocytosis. CSF pleocytosis (range of 1-471 white blood cells [WBCs]/μL) occurs in about one third of patients with limb sarcoid neuropathy.1 CSF pleocytosis occurs in about three quarters of patients with neurosarcoidosis (that is, sarcoidosis affecting the peripheral and/or central nervous system) (range of 0 to 455 cells/μL and a mean of 53 cells/μL).8
The most sensitive and least specific spinal fluid test for central nervous system involvement by sarcoidosis is elevated CSF protein. Aksamit and Norona found that in patients with neurosarcoidosis, CSF protein was elevated in 80% of patients (range of 18–2882 mg/dL and mean of 174 mg/dL).8 By comparison, patients with limb sarcoid neuropathy had elevated spinal fluid protein approximately 50% of the time (range of 13–510 mg/dL).1
Our patient’s electrodiagnostic studies, demonstrating predominant axonal loss, are typical.1,3,5 However, in one series, 3 of 57 patients presented with a primarily demyelinating neuropathy.1 Electrophysiologic features of demyelination in limb sarcoid neuropathy include partial conduction blocks.1,5
Histopathologic specimens from patients with limb sarcoid neuropathy reveal noncaseating granulomas in the epineurium2,3,5 and endoneurium.2,4 Granulomas consist of epithelioid cells and mononuclear infiltrates that stain positively for macrophage markers.1,2 Multinucleated giant cells can be present on tissue biopsy.1,4,9 Angiopathic changes in small- to medium-sized vessels are present.1–3,5 In our case, sural nerve biopsy revealed lymphocytic infiltration of epineurial vessels, along with macrophage infiltration of the epineurium, perineurium, and endoneurium (see Fig. 50-1).
Treatment for limb sarcoid neuropathy usually consists of high-dose corticosteroids. In the largest series of limb sarcoid neuropathy, 19 of 47 patients treated with corticosteroids improvement based on NIS scores.1 At follow-up, 9 of 13 patients who were treated with corticosteroids reported improvement of pain.1 Improvement in symptoms of pain and disability was associated with short duration between symptom onset and treatment. This suggests that earlier diagnosis and treatment are associated with better outcomes. Five of six patients followed for more than 3 years were treated with corticosteroids. Disability based on a disability score at diagnosis versus at last follow up was no worse in four of six patients followed for more than 3 years.1 Another study reported two patients with improved motor and sensory disturbances after 8 to 10 weeks of treatment with corticosteroids.3
Corticosteroids are not the only treatment for limb sarcoid neuropathy. One case report describes successful treatment of a 38-year-old woman diagnosed with sarcoid polyneuropathy using intravenous immunoglobulin (IVIg) at a dose of 0.4 g/kg for 4 days.9 Before use of IVIg, oral prednisolone at 40 mg/day for 4 months did little to alter the patient’s sensory disturbances or strength.9 The authors report improvement lasted 10 weeks before pretreatment symptoms (pains in hands and legs, ambulation with a cane) returned.9
Infliximab, a tumor necrosis-α (TNFα) inhibitor, has also been used with success in the treatment of sarcoid small fiber neuropathy.6 In one series from the Mayo Clinic, 15 patients with biopsy proven neurosarcoidosis showed evidence of response to infliximab.10 Each of those patients had either steroid unresponsiveness or steroid intolerance. Fourteen of the fifteen patients had measurable responses at least for 1 year. The dose was a bolus of 5 mg/kg given intravenously at initiation, 2 weeks, 4 weeks, and then monthly for a target duration of 3 to 6 months on therapy. The conclusions from this open-label prospective study were that infliximab is a useful therapy for neurosarcoidosis patients who are intolerant or refractory to corticosteroid therapy. Expense is a major issue limiting widespread use. Neurosarcoidosis is an off-label use of this drug.
Our case illustrates how sarcoidosis should be considered in patients who present with the abrupt onset of multifocal, asymmetric, painful neuropathies (or polyradiculopathies or polyradiculoneuropathies), especially if accompanied by fatigue or weight loss, history of cranial neuropathy or thoracic radiculopathy. Chest imaging should be performed because 50% of these patients will have an abnormality. CSF analysis may show pleocytosis or elevated protein, but these abnormalities are not specific for neurosarcoidosis. Earlier identification, by means of biopsy, and aggressive treatment may result in better outcomes. Unfortunately, our patient was treated with corticosteroids for more than 10 years with little change in symptoms, impairments, or degree of disability. However, in most cases of limb sarcoid neuropathy, treatment with corticosteroids appears to be of some benefit, particularly for painful symptoms and disability related to pain. Treatment with infliximab or IVIg holds promise as potential treatments and should be considered in patients who do not respond to corticosteroids.