Francesca Brindani

Restless legs syndrome and polyneuropathy.

Restless legs syndrome (RLS), diagnosed according to the International RLS Study Group criteria, was investigated in 97 consecutive patients with polyneuropathy and found in 29 patients. RLS patients were more often women (22 of 29 vs. 33 of 68; P = 0.015), mainly with sensory neuropathy of small fiber type (15 of 29 vs. 16 of 68; P = 0.009). Changes of sensory action potentials were significantly less severe in RLS patients. In the RLS group, acquired neuropathies, and in particular dysimmune neuropathies, were significantly more frequent (27/29 vs. 46/68; P = 0.009). Thus, RLS is frequent in acquired polyneuropathy of sensory type and mild entity, mainly in women.

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

Abstract  As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A‐delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.

Clinical spectrum of cryoglobulinaemic neuropathy

Background and objective: Cryoglobulinaemic neuropathy (CN) is probably common, as it is usually related to HCV infection. The aim of this study was to delineate the clinical spectrum of CN in a large series and to investigate the factors influencing its expression. Methods: Seventy one consecutive patients (12 men, 59 women), diagnosed as having CN on the basis of clinical features of neuropathy, clinical and serological findings of mixed cryoglobulinaemia, and exclusion criteria, were identified during a six year period. All patients underwent clinical examination, and electrophysiological and laboratory investigations. Results: Results of the patients with “pure” CN (n = 54) and those with comorbidities (n = 17) were evaluated separately. Of the former 76% had sensory neuropathy (including selective small fibre sensory neuropathy (SFSN) in 14 patients), 15% had sensorimotor polyneuropathy, and 9% had mononeuritis multiplex. The pattern of distribution was similar in the patients with comorbidities. In 30/54 patients, CN was the first manifestation of cryoglobulinaemia. Patients with mild cryoglobulinaemic syndrome had sensory neuropathy more frequently than patients with active syndrome (p<0.001), in particular SFSN (p<0.001). The latter group had more severe features, with significantly more cases of reduced or absent motor (p = 0.028) and sensory action potentials (p<0.001), and a tendency towards higher Rankin scores (p = 0.06). Conclusions: Sensory neuropathy, often in the form of SFSN, is by far the commonest form of CN. Cryoglobulinaemia should be vigorously investigated in the diagnosis of sensory neuropathy, especially in older women. Activity of the cryoglobulinaemic syndrome is a major factor influencing the clinical expression and severity of CN.

Non-length dependent small fiber neuropathy. a prospective case series.

We report the features of non‐length dependent small fiber neuropathy (SFN) and compare them to those with distal length‐dependent SFN. In a series of 224 consecutive neuropathy patients, we evaluated 44 patients with SFN diagnosed in the presence of both symptoms and signs. Eleven were classified as non‐length dependent SFN. Disease associations were Sjögrens syndrome (two patients), impaired glucose tolerance, rheumatoid arthritis, hepatitis C virus, Crohns disease, and idiopathic (five patients). In the 33 patients with distal SFN, the age of onset was significantly older and more had impaired glucose metabolism (16/33). In both groups, pain was mainly characterized as burning, but patients with non‐length dependent SFN more often reported an “itchy” quality and allodynia to light touch.

Painful polyneuropathy associated with restless legs syndrome. Clinical features and sensory profile.

BACKGROUND The association of restless legs syndrome (RLS) with polyneuropathy, and its prevalence, have been evaluated differently throughout various studies. As subtypes of polyneuropathy characterized by neuropathic pain seem to be preferentially associated with RLS, we intended to investigate the prevalence and the features of RLS occurring with painful neuropathy, and to define whether there is a specific sensory phenotype. METHODS We prospectively investigated 58 consecutive patients with distal symmetric polyneuropathy and neuropathic pain or dysesthesia, using a bedside protocol for sensory assessment. RLS was diagnosed with an interview assessing the International RLS Study Group diagnostic criteria. RESULTS Overall, RLS was reported by 21 patients (36.2%), but it was occurring at the time of the evaluation in 12 patients (20.7%), significantly more than in controls. RLS was chronic in nine patients and remitting-intermittent in 12 patients. No difference was demonstrated between patients with or without RLS. Comparing patients with chronic RLS and remitting-intermittent RLS, the latter had more severe electrophysiological changes, whereas hyperalgesia, suggesting central sensitization, was significantly more frequent in chronic RLS patients. CONCLUSIONS RLS is frequently associated with painful polyneuropathy, in keeping with the hypothesis that its occurrence is favored by small fiber involvement. It represents a heterogeneous entity, differentiated in chronic and remitting-intermittent subtypes, possibly conditioned by indolent or aggressive neuropathy course and phenomena of central sensitisation.

Restless legs syndrome: differential diagnosis and management with pramipexole

Restless legs syndrome (RLS) is a condition characterized by discomfort at rest and urge to move focused on the legs. RLS may occur as an idiopathic, often hereditary condition (primary RLS), or in association with medical conditions (secondary RLS) including iron deficiency, uremia, and polyneuropathy. Current understanding of the pathophysiology of RLS points to the involvement of three interrelated components: dopaminergic dysfunction, impaired iron homeostasis, and genetic mechanisms. The diagnosis of RLS is made according to the consensus criteria by a National Institutes of Health panel: 1) an urge to move the legs, usually accompanied by uncomfortable sensations; 2) beginning or worsening during rest; 3) relieved by movement; and 4) worse, or only occurring, in the evening or at night. The differential diagnosis of RLS aims to: 1) distinguish RLS from other disorders with RLS-like symptoms and 2) identify secondary forms, with investigation of underlying diseases. The treatment of RLS demands a clinical evaluation to rule out and cure causes of secondary RLS, including iron supplementation when deficient, and to eliminate the triggering factors. The presence of neuropathy should be especially investigated in nonhereditary, late-onset RLS, in view of a possible treatment of the underlying disease. The first line treatment for idiopathic RLS is represented by dopamine agonists, in particular nonergot-derived ropinirole and pramipexole, whereas ergot dopamine agonists (cabergoline and pergolide) are no longer in first-line use given the risks of cardiac valvulopathy. Although no comparative trials have been published, a meta-analysis of pramipexole versus ropinirole suggests differences in efficacy and tolerability favoring pramipexole.

Reply: More on the relationship between restless legs syndrome and neuropathy

We thank Drs. Ramchandren and Chervin for their important comments on our study of polyneuropathy in restless legs syndrome (RLS).1 We agree that RLS may have a relevant impact on the quality of life of patients with peripheral neuropathy, although this point has not been formally investigated.2 Thus, neuropathic patients should be questioned for symptoms of RLS, which may represent in some cases the main target of symptomatic treatment. We are confident that our data are representative of the prevalence of RLS in polyneuropathy, as we evaluated a large series of nonselected consecutive outpatients. A reason for lower prevalence in other series3 may be that severe cases were overrepresented, as RLS, similarly to positive sensory symptoms, is mainly related to the early phases of the disease, disappearing with worsening of neuropathy. We used quite restrictive exclusion criteria in the aim of avoiding a misdiagnosis of polyneuropathy in primary RLS, and of excluding a casual association of polyneuropathy with primary RLS. However, patients with idiopathic neuropathy were not excluded (see our study on page 1255, last but one line1). Family history of RLS suggests a diagnosis of primary/genetic RLS, although the possibility of a genetic neuropathy manifesting with RLS should also be considered4 in the presence of other signs of polyneuropathy. It is unclear which share of RLS in the general population is provided by neuropathic patients,5 but this component could be greater than expected, as RLS is frequent in highly prevalent forms, such as diabetic neuropathy6,7 and HCV-related cryoglobulinemic neuropathy.8 We found a 33% prevalence of RLS in neuropathy associated with diabetes or impaired glucose tolerance, often as onset manifestation.7 The hypothesis of a role of ferritin in axon maintenance is stimulating, but our preliminary data9 are not in this direction, so we are prone to think that RLS associated with neuropathy belongs to an RLS phenotype not related to ferritin deficiency.10

262 RESTLESS LEGS SYNDROME IN PAINFUL NEUROPATHY IS RELATED TO NOCICEPTIVE DEAFFERENTATION

260 PREVALENCE OF POLYNEUROPATHY WITH OR WITHOUT NEUROPATHIC PAIN IN TYPE 1 AND 2 DIABETIC PATIENTS D. Bouhassira *, K. Van Acker , S. Weiss , K. Matthys , C. Mathieu , I. Colin e a INSERM U-792, Hopital Ambroise Paré, BoulogneBillancourt, France b Department of Diabetology, Sint Jozefkliniek, Bornem, Belgium c Pfizer Medical Department, Bruxelles, Belgium d Department of Endocrinology, KUL Leuven, Belgium e Department of Endocrinology and Diabetology, CHR Mons-Warquignies, Mons, Belgium

Frequency of clinically diagnosed small fiber neuropathy in a neuropathy population

We reviewed the files of outpatients with polyneuropathy or multiple mononeuropathy over a two‐year period (2002–2003), to assess the relative incidence of small fiber sensory neuropathy (SFSN), diagnosed with clinical criteria. The cohort included a total of 97 patients (41 men, 56 women), age 11–85 years (median 64), 91 with polyneuropathy and 6 with multiple mononeuropathy. Twenty‐seven patients with SFSN (27.8%) were identified (7 men, 20 women), age 11–76 years (median 62). SFSN was idiopathic in 8 cases, and secondary to other diseases in 19 cases, mainly diabetes or glucose intolerance (8 cases) and mixed cryoglobulinemia (6 cases). The most frequent manifestations of SFSN were burning feet (12 cases) and restless legs syndrome (12 cases). Duration of neuropathy was 2.2 + 2.06 years, whereas in the other patients with polyneuropathy was 9.02 + 13.6 (p = 0.011). Treatment with drugs for neuropathic pain was effective in 9 out of 16 cases (56.2%). In this series, SFSN diagnosed by minimal clinical criteria showed an unexpectedly high relative incidence among miscellaneous peripheral neuropathies. This can be due to overdiagnosis of SFSN, as we included patients diagnosed using minimal clinical criteria; on the other hand, the diagnostic sensitivity of additional tests (quantitative sensory examination and skin biopsy) is not definitive, thus diagnosis of SFSN is actually a frequent diagnostic challenge. The efficacy of treatment with drugs for neuropathic pain in many patients may provide further support for diagnosis.

Aquadynia. a manifestation of small fiber sensory neuropathy

Aquadynia is a rare phenomenon of water‐induced pain through presumed neural mechanisms. We describe two women in whom bathing was regularly followed by pain in the lower limbs, as a unique symptom (case 1) and, respectively, in the clinical context of an axonal polyneuropathy (case 2). Case 1: A 71‐year‐old woman complained, by age 69, of pruritus and pinprick‐like pain in the extremities that lasted about 20 minutes following bathing. Neurological examination and electroneurography were negative, as well as investigations for systemic diseases. Quantitative sensory testing (QST) showed abnormal cold‐pain sensation. Treatment with gabapentin was not effective. Case 2: A 69‐year‐old woman affected with HCV‐related cryoglobulinemia had numbness and aquadynia in the distal lower limbs and restless legs syndrome, in the last few months. Neurological examination showed absent ankle jerks, and decreased touch and vibration sense in the feet. Electroneurography demonstrated an axonal neuropathy. Aquadynia likely represents a manifestation of small fiber neuropathy. It is unclear whether it has to be viewed as a primary sensory phenomenon similar to allodynia, or a type of noradrenergic pain primarily due to autonomic dysfunction. Alteration of QST in case 1, and the association with obvious features of sensory neuropathy in case 2, may favour the sensory hypothesis.