Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy.

BACKGROUND: The best treatment for polyneuropathy associated with IgM monoclonal gammopathy (MGUS) is unknown. Oral cyclophosphamide combined with prednisone showed limited efficacy in a previous open label pilot study. We therefore performed a double-blind, randomized, placebo-controlled study of combined oral cyclophosphamide and prednisone in IgM MGUS polyneuropathy. METHODS: Thirty-five patients with progressive IgM MGUS polyneuropathy were included. After stratification for anti-MAG antibodies patients were randomized to oral cyclophosphamide 500 mg once daily for 4 days combined with oral prednisone 60 mg once daily for 5 days (treatment) (n = 16), or placebo (n = 19), repeated every 28 days for six times. Primary outcome was improvement of the Rivermead Mobility Index (RMI). Secondary outcomes were improvement of the modified Rankin scale, Medical Research Council and sensory sum scores, levels of M protein, EMG, and Short Form-36 scale after treatment. Patients were examined at 0, 6, 12, 18, and 24 months. RESULTS: After 6 months of treatment and at later follow-up, no difference in change of the RMI between the two groups was observed. Change of the Rankin scale was similar in both groups. Other outcome parameters showed more improvement in the treatment group: the MRC sum score improved more from 6 to 24 months after treatment; the sensory sum score improved more at 6 months; the SF 36 mean health change score and physical role score improved more; and the median nerve distal conduction (abductor pollicis brevis muscle) improved more in the treatment group. The most common adverse event was nausea. CONCLUSIONS: Compared with placebo treatment, this first double-blind randomized trial with cyclophosphamide and prednisone in IgM MGUS polyneuropathy showed no beneficial effect on the functional scales, but a beneficial effect on muscle strength and sensation was observed.

Is cardiovascular disease a risk factor in the development of axonal polyneuropathy?

OBJECTIVES: To determine if cardiovascular disease may be a risk factor in the development of chronic idiopathic axonal polyneuropathy (CIAP). METHODS: In this incidence case-control study, the prevalence of cardiovascular disease and risk factors in 97 patients with CIAP (mean age 67.5 (SD 7.9) years) and the prevalence of neuropathic features in 97 patients with peripheral arterial disease (PAD) (mean age 67.1 (SD 7.3) years) were investigated. The results were compared with those for 96 age and sex matched controls without diagnosed PAD or polyneuropathy (mean age 67.5 (SD 9.1) years). In a randomly chosen subgroup of 23 patients with CIAP, 42 patients with PAD, and 48 controls, an electrodiagnostic investigation was performed. RESULTS: Patients with CIAP more often had manifest cardiovascular disease and cardiovascular risk factors than controls (stroke 18% v 6% of patients, odds ratio (OR) 3.2 (95% confidence interval (CI) 1.8 to 5.9); heart disease 29% v 15%, OR 2.4 (95% CI 1.2 to 4.9); family history of cardiovascular disease 42% v 21%, OR 2.8 (95% CI (1.5 to 5.2); hypertension 56% v 39%, OR 2.0 (95% CI 1.1 to 3.6); hypercholesterolaemia 46% v 21%, OR 3.3 (95% CI 1.5 to 7.3); current smoking 38% v 23%, OR 2.1 (95% CI 1.1 to 3.9)). The prevalence of cardiovascular disease and cardiovascular risk factors was lower than in patients with PAD. Patients with PAD more often had polyneuropathy than controls (15% v 5%, OR 3.3 (95% CI 1.1 to 10.0)). There was a trend towards lower nerve conduction velocities and lower amplitudes on electrodiagnostic investigation compared with controls. CONCLUSION: This study shows that cardiovascular disease and CIAP often coexist, and therefore cardiovascular disease may be a cofactor in the development of CIAP.

Quantitative assessment of the innervation of epineurial arteries in the peripheral nerve by immunofluorescence: differences between controls and patients with peripheral arterial disease.

The peripheral nerve is supplied by the vasa nervorum. The epi- and perineurial vessels are innervated by an autonomic plexus, which plays a role in regulation of the endoneurial blood flow. This innervation is decreased in diabetes and alcohol polyneuropathy and seems to precede the development of diabetic polyneuropathy. A decreased innervation may therefore play a role in the development of polyneuropathy. In peripheral arterial disease (PAD) clinical and morphological features are present, related to severity of ischemia. To investigate the innervation of the vasa nervorum in severe ischemia, we performed immunofluorescence staining with the general neural marker protein gene product (PGP) 9.5 in whole mount preparations of epineurial vessels of nine sural nerves taken from patients with legs amputated because of severe PAD (59+/-15 years, mean +/- SD) and ten age-matched controls (61+/-24 years). In patients with PAD the nerve density of the perivascular plexus was decreased in comparison with controls (mean intercept density/mm +/- SD) 26.0+/-6.9 in PAD and 39.9+/-10.7 in controls, area% 6.0+/-1.6 in PAD and 9.9+/-2.6 in controls, both P<0.01, t-test). A decreased perivascular plexus may result in a diminished regulation of the endoneurial blood flow in patients with severe PAD.

Thickness of endoneurial vessel basal lamina area in chronic idiopathic axonal polyneuropathy.

For chronic idiopathic axonal polyneuropathy (CIAP), even after extensive evaluation, no cause has yet been found. Considering the age and sex distribution of patients with this disease, it is possible that vascular disease plays a role in the development of this polyneuropathy. As endoneurial vessel abnormalities can be related to ischemia, we investigated endoneurial vessels in sural nerve biopsies of 18 patients with CIAP. As controls we used sural nerves of 4 patients with diabetes mellitus, 6 patients with hereditary motor and sensory neuropathy type II (HMSN type III) and 10 autopsy cases. Basal lamina area thickness, endothelial cell area, lumen area, and the number of basal laminae, endothelial cells and periendothelial cell nuclei were investigated. Basal lamina area thickness, endoneurial cell area and number of endothelial cell nuclei in CIAP were increased in comparison with HMSN type III, whereas the basal lamina area thickness of patients with CIAP and diabetes mellitus were in the same range. The structure of the basal lamina area in CIAP differed from diabetes mellitus; in diabetes mellitus there was a larger number of lamellae, whereas in CIAP there was an increase in collagen. There was no correlation between basal lamina area thickness and age. In CIAP patients with peripheral vascular disease of the legs, basal lamina area thickness was increased. The relation between basal lamina area thickening and peripheral vascular disease of the legs in CIAP may indicate a role for ischemia in the development of this polyneuropathy.

Relationship between ischemia and neuropathy.

To evaluate what at present is known about the relationship between vascular diseases and the development of chronic polyneuropathy, the literature on ischemia and peripheral nerve damage was reviewed with emphasis on chronic ischemia.

Quality of life in patients with axonal polyneuropathy.

"Quality of life" (QOL) measurement reflects the impact of a disease on the daily life of a patient, and this can be used as an outcome measure in clinical trials. QOL measurements are rarely used in patients with neuromuscular disease. The aim of this study was to determine whether QOL is reduced in chronic polyneuropathy, whether there is a relationship between QOL and objective measures of disease severity, and whether measuring QOL is a useful addition to the assessment of severity of polyneuropathy. We measured QOL in 90 patients with chronic axonal polyneuropathy (33 with hereditary motor and sensory neuropathy type II and 57 with chronic idiopathic axonal polyneuropathy) using the RAND 36-item Health Survey questionnaire (RAND-36). We compared the results with the QOL of a reference population, with summed motor and sensory scores, and with the Rankin scale for handicap. Patients had worse scores than the reference population on seven of eight areas of the RAND-36. Patients with both low motor and low sensory scores rated lower in physical and emotional areas than less impaired patients. A low Rankin score was related only to physical domains. We conclude that in patients with chronic axonal polyneuropathy the severity of disease can be assessed with a general QOL instrument, and that this provides additional information, particularly on areas related to emotional and social functioning.

Differences between hereditary motor and sensory neuropathy type 2 and chronic idiopathic axonal neuropathy. A clinical and electrophysiological study.

To evaluate whether chronic idiopathic axonal polyneuropathy (CIAP) should be considered as hereditary motor and sensory neuropathy type 2 (HMSN type 2), we compared the clinical features of 48 patients with CIAP with those of 47 patients with HMSN type 2. In addition, we studied electrophysiological data in 20 patients with CIAP and in 20 patients with HMSN type 2. We found, in patients with HMSN type 2, that the initial symptoms were predominantly motor and that weakness and handicap were more severe and skeletal deformities more frequent, compared with those of CIAP patients. Electrophysiologically, the tibialis anterior muscle showed more denervation in patients with HMSN type 2, consistent with the predominance of motor symptoms. There was no important effect of age of onset on clinical features in HMSN type 2 patients. We conclude that in an individual patient with a sensory or sensorimotor idiopathic axonal polyneuropathy and no family history of polyneuropathies, the diagnosis HMSN type 2 is unlikely. However, if motor symptoms predominate, the diagnosis of HMSN type 2 should be considered.

Intermittent cyclophosphamide and prednisone treatment of polyneuropathy associated with monoclonal gammopathy of undetermined significance.

In an open prospective study, we analyzed the effect of cyclophosphamide (300 mg/m2 body surface daily for 4 days) combined with prednisone (40 mg/m2 body surface daily for 5 days) at 4-week intervals during 6 months in 16 patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS). Eleven patients had an IgM-MGUS and five an IgG-MGUS. During a follow-up period of 3 years, eight patients had improvement and six patients stabilized, based on quantitative neurologic examination, the Rankin disability scale, and electrophysiologic studies. These 14 patients had neuropathy with demyelinating and axonal features. One patient with a purely axonal neuropathy had deterioration despite therapy. One other patients developed severe leukopenia as side effect of cyclophosphamide, necessitating withdrawal of treatment. A difference in response was not present in patient with IgM- or IgG-MGUS, nor in patients with or without autoantibodies against myelin-associated glycoprotein. Nine patients had a bone marrow biopsy before and 1 year after treatment. In eight patients, the monoclonal lymphoid IgM or plasma cell IgG infiltration decreased, while in four the monoclonality disappeared after treatment. In the patient who had neurologic deterioration, repeated bone marrow biopsy showed deposits of amyloid. In conclusion, short-term treatment with intermittent cyclophosphamide and prednisone may have a long-term favorable effect in patients with demyelinating polyneuropathy associated with MGUS.

Chronic idiopathic axonal polyneuropathy. Comparison of patients with and without monoclonal gammopathy.

In order to study whether axonal polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) is a distinct entity, we prospectively studied the clinical, electrophysiological and pathological features of 16 patients with chronic idiopathic axonal polyneuropathy (CIAP) with MGUS (CIAP-MGUS) and compared them with those of 71 patients who had CIAP without MGUS. In patients with CIAP-MGUS the arms were more frequently affected and the disability was worse. On electromyography there was more evidence of denervation in patients with CIAP-MGUS. All other clinical symptoms, signs, nerve conduction parameters and nerve biopsy findings, showed no differences between both groups. Antibodies against myelin associated glycoprotein (MAG), GMI-ganglioside and chondrotoin sulphate were not present. Only one patient with an immunoglobulin M (IgM)-MGUS and a sensory neuropathy had antibodies against sulphatide. In conclusion, axonal polyneuropathy in patients with and without MGUS are essentially indistinguishable rather than different, suggesting that the MGUS may be coincidental in most patients.

Risk factors for subarachnoid hemorrhage: a systematic review.

BACKGROUND AND PURPOSE: Knowledge of modifiable risk factors for subarachnoid hemorrhage (SAH) is important in terms of prevention. We therefore conducted a systematic review of studies on risk factors for SAH, with emphasis on sufficiently precise criteria for the diagnosis of SAH. METHODS: To identify studies we performed a Medline search from 1966 to 1994 and searched the reference lists of all relevant publications. Studies were included only if they fulfilled predefined methodological criteria. Case-control studies were included if the diagnosis of SAH was proved by CT, angiography, or autopsy in at least 70% of patients. Longitudinal studies were included if the criteria for SAH were based on a review of the medical records. RESULTS: Nine longitudinal studies and 11 case-control studies were included. Significant risk factors were as follows: (1) smoking (relative risk [RR] for longitudinal studies, 1.9; 95% confidence interval [CI], 1.5 to 2.3; odds ratio [OR] for case-control studies, 3.5; 95% CI, 2.9 to 4.3); (2) hypertension (RR, 2.8; 95% CI, 2.1 to 3.6; OR, 2.9; 95% CI, 2.4 to 3.7) and (3) drinking 150 g or more of alcohol per week (RR, 4.7; 95% CI, 2.1 to 10.5; OR, 1.5; 95% CI, 1.1 to 1.9). Use of oral contraceptives, hormone replacement therapy, hypercholesterolemia, and physical activity were not significantly related to the risk of SAH. CONCLUSIONS: We conclude that smoking, hypertension, and alcohol abuse are important risk factors for SAH. Reduction of exposure to these risk factors might result in a decreased incidence of SAH.