40-Year-Old Woman with Patchy Painful Paresthesia


Fig. 40.1

PGP9.5 immunostaining of skin biopsy sections shows reduced intraepidermal nerve fiber densities at the left distal leg (a), distal thigh (b) and proximal thigh (c) with no distal-to-proximal gradient



Final Diagnosis


Non-length-dependent small fiber neuropathy associated with systemic sarcoidosis


Patient Follow-up


The patient was started on intravenous immunoglobulin (IVIG) infusion 2 grams/kg followed by 1 gram/kg every 1 month. The painful paresthesias and orthostatic intolerance markedly improved within 2 months, and she could function better. Prednisone was tapered off in 6 months. She continued to take Gabapentin 900 mg three times a day and Tramadol 50 mg twice a day as needed.


Discussion


Small fiber neuropathy (SFN) is a common neuromuscular disorder which predominantly affects small myelinated Aδ and unmyelinated C fibers. Small fibers mediate sensory and autonomic functions [1]. Patients with small somatic sensory fiber involvement commonly present with pain, burning, tingling, and/or numbness. When autonomic fibers are affected, patients may develop autonomic symptoms including dry eyes, dry mouth, palpitations, orthostatic dizziness, bowel constipation, urinary retention, sexual dysfunction, sweating abnormalities, and skin discoloration [13]. Autonomic symptoms are present in nearly half of the patients with SFN in one study population [4]. Our patient also has SFN with both somatic and autonomic involvement , which is frequently seen in association with amyloidosis, diabetes mellitus, sarcoidosis, and Sjogren’s syndrome. The SFN in our patient is associated with sarcoidosis.


SFN is mostly length-dependent (LD-SFN) with symptoms and signs in a stocking-glove pattern with a distal-to-proximal gradient [1]. Non-length-dependent SFN (NLD-SFN) is relatively rare, accounting for 20–25% of cases of pure SFN [5, 6]. The sensory symptoms and signs in NLD-SFN are usually patchy, asymmetrical, migrating or diffuse, which often involve trunk and face in addition to limbs [6]. There is no distal-to-proximal gradient of the sensory symptoms or signs in the affected limbs. The sensory symptoms and signs in our patient are typical for NLD-SFN . Chest pain is relatively common in SFN associated with sarcoidosis as seen in our patient. Many of these patients undergo cardiac evaluation due to the concern of cardiac ischemia, and the cardiac work-up is usually unrevealing as the symptom is caused by SFN. The symptoms of NLD-SFN are frequently suspected to be psychogenic as NLD-SFN is less well recognized than LD-SFN. By comparing 63 patients who had pure NLD-SFN with 175 patients who had pure LD-SFN, we found that the age at onset (Mean ± SD years) was younger in NLD-SFN (45.5 ± 13.1) than in LD-SFN (55.1 ± 11.4; p < 0.001), more women were affected in NLD-SFN (73.0%) than in LD-SFN (48.0%; p < 0.001), and the neuropathy was more likely to be association with immune-mediated conditions in NLD-SFN (14.3%) than in LD-SFN (3.4%; p = 0.012) [6]. The increased association of NLD-SFN with immune-mediated conditions such as sarcoidosis and Sjogren’s syndrome has also been reported by other studies [710].


Skin biopsy with IENDF evaluation is the gold standard diagnostic test for SFN, as routine NCS/EMG, a valuable test for evaluating large fiber neuropathy, is typically normal in SFN and cannot confirm or exclude SFN. Skin biopsy in NLD-SFN typically shows reduced IENFD with no distal-to-proximal gradient and with a high distal leg:proximal thigh IENFD ratio as compared with that in LD-SFN [6, 11]. The skin biopsy findings in our patient are typical for NLD-SFN. QSART and cardiovascular autonomic testing are valuable in evaluating autonomic symptoms when present. Combining these tests can increase the diagnostic yield [9, 12].


Our patient had systemic sarcoidosis before developing the SFN symptoms. We still ordered a battery of blood tests to search for other possible associated conditions. It has been shown that additional conditions can be identified in over 25% of SFN patients with known underlying associated conditions prior to the neuropathy etiology evaluation [13]. Therefore, a thorough evaluation of associated conditions should be done in every patient with SFN. Treating the underlying associated conditions is the key to prevent or slow down SFN progression. It can also improve SFN symptoms [3, 9, 10]. Our patient did not have an associated condition other than sarcoidosis. She had sarcoidosis-associated NLD-SFN.


SFN symptoms have been reported in up to 40% of patients with sarcoidosis [14]. A retrospective study of 115 patients with sarcoidosis-associated SFN without other causes showed that 63% were women and mean age at onset was 46 years. Over 50% of these patients presented with NLD-SFN affecting both somatic sensory and autonomic small fibers. Combining skin biopsy and QSART increased the diagnostic yield. The development of SFN in sarcoidosis is felt to be mediated by inflammatory cytokines rather than granulomatous inflammation [15]. The non-lesion skin biopsy for diagnosing SFN usually shows reduced IENFD in a non-length-dependent pattern but not granulomas.


Unlike other forms of neurosarcoidosis, sarcoidosis-associated SFN symptoms respond poorly to steroids or immunosuppressants such as methotrexate, but they may respond very well to IVIG and/or anti-TNF therapy infliximab [9, 10, 16, 17]. In a large cohort of sarcoidosis-associated SFN [9], 75.8% of patients responded to IVIG, 66.7% responded to infliximab, and 71.4% responded to IVIG and infliximab. The mechanism underlying this is not entirely clear. Large prospective controlled studies are needed to further determine the therapeutic effects of IVIG and infliximab to direct the long-term management.


Pearls


Apr 21, 2020 | Posted by in NEUROLOGY | Comments Off on 40-Year-Old Woman with Patchy Painful Paresthesia

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