Ingested IFN-alpha: results of a pilot study in relapsing-remitting MS.

OBJECTIVE: To investigate whether ingested human recombinant interferon-alpha2a (IFN-alpha2a) was safe and whether treatment reduces the number of gadolinium-enhanced lesions on serial MRI in patients with active relapsing-remitting MS (RRMS). METHODS: Entry criteria included clinically definite RRMS and one or more gadolinium-enhanced lesions on a screening MRI. RESULTS: Of 80 patients screened, 33 were eligible and 30 patients were enrolled for treatment. Patients were randomized (10 per group) to placebo, 10,000 or 30,000 IU IFN-alpha2a ingested on alternate days for 9 months. They were examined clinically and with monthly cerebral MRI. Sample size projections were based on the assumption of a parenteral IFN-like effect, a 90% reduction of enhancing lesions evident within 1 month of the initiation of treatment in the active treatment groups sustained during the 9-month study as the primary outcome variable. RESULTS: There was no significant effect on enhancing lesions. However, post hoc analysis suggested a possible treatment effect in the 10,000 IU group. By direct monthly comparison of placebo and 10,000 IU group in treatment month 5, there were 73% (p < 0.05) fewer enhancements in the 10,000 IU group than in the placebo group. There was a decrease of tumor necrosis factor-alpha protein secretion at months 4 and 5. Relapses and adverse events were not different among the treatment groups. Ingested IFN-alpha2a did not induce systemic anti-IFN-alpha antibodies. CONCLUSIONS: This trial showed no benefit based on the primary outcome measure. Because changes were detected in immune response and post hoc analysis suggested that a smaller dose could have an effect, IFN-alpha may deserve further study.

Peripheral nerve injury after brief lithotomy for transurethral collagen injection.

Two patients with prior prostate surgery sustained peripheral nerve injuries after transurethral collagen injection for the treatment of urinary incontinence. In the first patient, brief lithotomy positioning caused a gluteal compartment syndrome and sciatic neuropathy. In the second patient, obturator neuropathy was due to leakage of collagen along the course of the obturator nerve. This is the first report of peripheral nerve injury in patients undergoing transurethral collagen injection.

Benign monomelic amyotrophy of the lower extremity: report of two cases and literature review.

Benign monomelic amyotrophy is an uncommon cause of progressive mildly disabling atrophy and weakness of a limb. It predominantly affects the distal upper limb of young men. We present two women with benign monomelic of amyotrophy of the lower extremity. Although thedisorder seemed clinically confined to a leg, we confirmed by electromyography chronic denervgation of the contralaterral extremity of both patients and in the arm of one patient.We review the literature and discuss the differential diagnosis. Benign monomelic amyotrophy is a diagnosis of exclusion that requires consideration in young women with unilateral leg atrophy.

Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation.

The A-to-G mutation at position 8344 in the transfer RNAlysine mitochondrial DNA gene is associated mostly with the myoclonic epilepsy and ragged red fibers syndrome. We describe a five-generation family with this mutation and 19 affected members with a variant neurologic syndrome of ataxia, myopathy, hearing loss, and neuropathy. Along with axial lipomas and diabetes mellitus, hypertension is a frequent somatic feature, suggesting that mitochondrial mutations may contribute to hypertension in these patients.

Systemic complement depletion reduces inflammation and demyelination in adoptive transfer experimental allergic neuritis.

The effect of systemic complement depletion by cobra venom factor (CVF) was evaluated in adoptive transfer experimental allergic neuritis (AT-EAN). Spleen cells of rats immunized with a neuritogenic peptide SP26 were injected into naive rats. On days 3 and 6 after cell transfer AT-EAN rats were treated with CVF or saline intraperitoneally. AT-EAN rats treated with CVF had significantly lower scores for histological inflammation (0.25 +/- 0.25 vs 1.9 +/- 0.4, mean +/- SEM, P < 0.03) and demyelination (0.13 +/- 0.13 vs 1.6 +/- 1.4, P < 0.02) than saline-treated AT-EAN rats. Immunocytochemistry of lumbosacral nerve roots showed significantly less ED1-positive macrophages (0.5 +/- 0.3 vs 1.6 +/- 0.6, P < 0.04) and CD11bc-positive (expressing complement receptor 3 or CR3) inflammatory cells (0.6 +/- 0.4 vs 1.7 +/- 0.5, P < 0.03). Our data suggest that complement plays a crucial role in inflammatory demyelination since systemic complement depletion significantly reduces recruitment of macrophages into the nerve and subsequent macrophage-mediated demyelination.

Insights into Campylobacter jejuni-induced Guillain-Barré syndrome from the Lewis rat model of experimental allergic neuritis.

Experimental allergic neuritis (EAN) is considered the in vivo model of Guillain-Barré syndrome (GBS) and has been extensively studied in the Lewis rat. Both cellular and humoral components of the immune response are implicated in the inflammatory demyelination of peripheral nerves that characterizes EAN. The recognition of Campylobacter jejuni infection as a frequent antecedent event in GBS, and in particular its association with anti-ganglioside antibodies and a primary axonal neuropathy, has raised many questions about the specific disease mechanisms involved. While C. jejuni can produce an acute motor neuropathy in chickens, confirming the relationship between C. jejuni infection and acute neuropathy, no detailed information is available from this animal model. Insights from experimental studies relating to the effector phase of Lewis rat EAN that may be relevant to C. jejuni-induced GBS are discussed.

Preclinical analysis of radiolabeled anti-GD2 immunoglobulin G.

BACKGROUND: Unlabeled murine monoclonal anti-GD2 immunoglobulin (Ig)G (14G2a) reactive with nervous system diganglioside and neuroblastoma, melanoma, and small cell lung carcinoma produces tumor regression. However, serious acute abdominal pain, paresthesia, hypotension and hypertension, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and occasional motor weakness occur. Studies in preclinical animal models can elucidate the mechanism of the observed neurotoxicity and lead to anti-GD2 antibody treatment with a higher therapeutic ratio. METHODS: One mg of 14G2a or control IgG was labeled with 1-2 mCi of indium-111 and administered intravenously to beagles (n = 8). In 2 dogs, additional high dose (200 mg) unlabeled 14G2a was given over 5 days. Whole body gamma camera images and SPECT scans were obtained repeatedly over 7 days. On Day 7, sciatic nerve conduction studies were performed, and after euthanasia radioactivity was determined in major organs. RESULTS: Unlabeled high dose 14G2a administered to mice, rats, or rabbits did not cause neurotoxicity within 3 weeks. GD2 antigens were shown by immunochemistry to be present in brain and peripheral nerve tissues of rodents and beagles. After in vivo administration of radiolabeled 14G2a, canine lymph nodes showed specific uptake, but only minimal radioactivity was found in the nervous system. Dogs that received additional high dose unlabeled 14G2a showed much higher lymph node uptake and follicular lymph node hyperplasia. Low motor response amplitudes on nerve conduction studies were noted. CONCLUSIONS: A radioisotope label on IgG and its visualization in a large series of animal models indicate that a low protein dose of anti-GD2 IgG will not cause neurologic side effects in patients. High protein dose anti-GD2 IgG may enhance antineoplastic effects and contribute to neurotoxicity through stimulation of normal lymphocytes with subsequent release of cytokines.

Soluble complement receptor 1 (sCR1) is not as effective as cobra venom factor in the treatment of experimental allergic neuritis.

To further investigate the role of complement activation in Experimental Allergic Neuritis (EAN), the effect of systemic complement blockade by soluble CR1 (sCR1) was compared to complement depletion by Cobra Venom Factor (CVF) in EAN rats immunized with bovine peripheral nerve myelin. EAN rats treated with CVF (n = 10) had significantly reduced clinical scores compared to rats treated with sCR1 (n = 9) or saline (n = 10) (score: sCR1 0.66 +/- 0.7; CVF 0; saline 0.6 +/- 0.8; mean +/- SD). CVF treatment more effectively decreased inflammation and demyelination compared to sCR1 treatment which had only a partial effect (inflammation: sCR1 1.8 +/- 1.4; CVF 0.3 +/- 0.7; saline 1.9 +/- 1.2; demyelination; sCR1 1.3 +/- 1; CVF 0.1 +/- 0.6; saline 1.7 +/- 1.2). In lumbosacral nerve roots significantly less infiltrating ED1 positive macrophages and CD11bc (expressing complement receptor 3 or CR3) positive inflammatory cells were present in CVF treated EAN rats while there was a limited decrease in inflammation in the sCR1 treated animals compared to the saline treated rats (ED1: sCR1 1.4 +/- 1.2; CVF 0.5 +/- 0.6; saline 1.7 +/- 1.2; CD11bc: sCR1 1.9 +/- 1.2; CVF 0.9 +/- 1; saline 2.1 +/- 1.2). Our findings suggest that complement depletion by CVF is more effective than complement blockade by sCR1 in reducing the severity of inflammatory peripheral nerve demyelination.

Oral administration of type I interferon modulates the course of experimental allergic neuritis.

We investigated the effect of oral administration of type I interferon (IFN) in experimental allergic neuritis (EAN) in Lewis rats immunized with bovine peripheral nerve myelin. Starting at 7 days preceding immunization, rats were fed daily until sacrifice either with 5000 U rat IFN-alpha/beta or mock-IFN. The clinical severity of EAN was significantly reduced in IFN-alpha/beta fed animals compared to mock-IFN fed controls. Demyelination, but not inflammation, was decreased in IFN-alpha/beta fed compared to mock-IFN fed rats at day 20 after immunization. In situ IFN-gamma production and inflammation were reduced when evaluated by immunocytochemistry at day 13 after immunization. Spleen cells from IFN-alpha/beta fed compared to mock-IFN fed EAN rats showed significantly reduced proliferation to stimulation with Con A or peripheral nerve myelin. IFN-gamma production in draining lymph node cells was significantly reduced after stimulation with bovine peripheral nerve myelin. Our data suggest that oral administration of IFN-alpha/beta reduces the severity of EAN, possibly by a reduction in IFN-gamma production.

Electrophysiological studies in Guillain-Barré syndrome: correlation with antibodies to GM1, GD1B and Campylobacter jejuni.

A retrospective study of 50 patients with Guillain-Barré syndrome (GBS) correlated analysis of serial motor nerve conduction studies with the presence of antibodies to Campylobacter jejuni, GM1 and GD1b, determined by ELISA. GBS patients with antibodies to C. jejuni (n = 8), GM1 (n = 4), or GD1b (n = 4) showed electrophysiological features suggestive of demyelination with prolonged distal motor latencies and temporal dispersion/conduction block similar to GBS patients without these specific antibodies. Three of 50 GBS patients had poor recovery with inability to walk at 1 year after onset of symptoms. All three patients had antibodies to C. jejuni, but not to GM1 or GD1b. Although later on in the clinical course distal motor responses were absent in two of these patients, reflecting extensive axonal degeneration, early nerve conduction studies showed findings suggestive of demyelination. We suggest that demyelination of peripheral nerve may be the initial disease mechanism in GBS independent of the presence of antibodies to C. jejuni, GM1 or GD1b.

Complement depletion affects demyelination and inflammation in experimental allergic neuritis.

The effect of systemic complement depletion by cobra venom factor (CVF) on experimental allergic neuritis (EAN) was studied in rats immunized with variable amounts of bovine peripheral nerve myelin. Low-dose myelin EAN rats treated with CVF i.p. (n = 10) had lower clinical scores (0.3 +/- 0.7 vs. 1.1 +/- 1.1), less demyelination (0.4 +/- 0.8 vs. 1.9 +/- 1.1) and inflammation (0.6 +/- 1.2 vs. 2 +/- 1) than EAN animals treated with i.p. saline (n = 10). Endoneurial infiltrates had fewer ED1-positive (phagocytic) macrophages (0.4 +/- 0.5 vs. 1.6 +/- 1.1) and CD11bc-positive (expressing iC3b receptor or CR3) cells (1 +/- 0.8 vs. 2.5 +/- 0.8) (mean +/- S.D.) detected by immunocytochemistry. This effect was partially abrogated by immunizing animals with a higher dose of myelin. Our studies suggest that complement may play a role in the recruitment of macrophages into the endoneurium and in opsonizing myelin for phagocytosis.

Anti-peripheral nerve myelin antibodies and terminal activation products of complement in serum of patients with acute brachial plexus neuropathy.

OBJECTIVE: To determine if complement-fixing antibodies to peripheral nerve myelin (anti-PNM antibodies) and terminal complement activation products were increased in serum of patients with brachial plexus neuropathy compared with normal controls. DESIGN: Case series. SETTING: University medical center. PATIENTS: Three patients (aged 6, 39, and 51 years) with acute brachial plexus neuropathy were studied during the acute and recovery phase of their disease. METHODS: Anti-PNM antibodies were measured in serum samples obtained from three patients and 25 normal controls with the C1 fixation and transfer assay. Soluble terminal complement activation products, SC5b-9, were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples of one patient with brachial plexus neuropathy and of five normal controls. RESULTS: Both serum anti-PNM antibodies and soluble terminal complement activation products were increased in the acute phase of brachial plexus neuropathy compared with normal control values and decreased several months later during clinical recovery. CONCLUSION: Complement dependent, antibody-mediated demyelination may participate in the peripheral nerve damage of brachial plexus neuropathy.

Serum antibodies to GM1, GD1b, peripheral nerve myelin, and Campylobacter jejuni in patients with Guillain-Barré syndrome and controls: correlation and prognosis.

Serum antibodies to monosialoganglioside (GM1), disialoganglioside (GD1b), and Campylobacter jejuni, measured by enzyme-linked immunosorbent assay and serum antibodies to peripheral nerve myelin, measured by the C1 fixation and transfer assay, were studied in 58 acute-phase patients with Guillain-Barré syndrome (GBS), 42 disease controls, and 29 normal controls. Anti-peripheral nerve myelin antibodies were elevated in 57 of 58 patients with GBS compared with controls, whereas only 8.6% had increased antibody titers to GM1 and 10.3% to GD1b. Only low antibody titers (GM1) or no antibodies (GD1b) were found in controls. More GBS patients (17.2%) than controls (7%) had antibodies to C jejuni. Poor recovery with inability to walk at 1 year after onset of symptoms was seen in 3 (5%) of the patients with GBS. All 3 patients had serological evidence of recent C jejuni infection but no antibodies to GM1 or GD1b. GBS patients with antibodies to GM1 or GD1b had excellent recovery. Our data indicate that antibodies to GM1 or GD1b do not necessarily mediate the extensive axonal damage seen in these severely affected patients.

Serologic evidence of previous Campylobacter jejuni infection in patients with the Guillain-Barré syndrome.

OBJECTIVE: To determine if patients with the Guillain-Barré syndrome are likely to have had Campylobacter jejuni infection before onset of neurologic symptoms. DESIGN: A case-control study. SETTING: Several university medical centers. PATIENTS: Case patients met clinical criteria for the Guillain-Barré syndrome between 1983 and 1990 and had a serum sample collected and frozen within 3 weeks after onset of neurologic symptoms (n = 118). Disease controls were patients with other neurologic illnesses (n = 56); healthy controls were hospital employees or healthy family members of patients (n = 47). MEASUREMENTS: Serum IgA, IgG, and IgM antibodies to C. jejuni were determined by enzyme-linked immunosorbent assays. Assays were done in a blinded manner. RESULTS: Optical density ratios > or = 2 in two or more immunoglobulin classes were seen in 43 (36%) of patients with the Guillain-Barré syndrome and in 10 (10%) of controls (odds ratio, 5.3; 95% CI, 2.4 to 12.5; P < 0.001). Increasing the optical density ratio or the number of immunoglobulin classes necessary to yield a positive result increased the strength of the association. The number of patients with the Guillain-Barré syndrome who had positive serologic responses was greatest from September to November (P = 0.02). Male patients were three times more likely to have serologic evidence of C. jejuni infection (P = 0.009); the proportion of patients with the syndrome who had a positive serologic response increased with age. CONCLUSIONS: Patients with the Guillain-Barré syndrome are more likely than controls to have serologic evidence of C. jejuni infection in the weeks before onset of neurologic symptoms. Campylobacter jejuni may play a role in the initiation of the Guillain-Barré syndrome in many patients.

Electrophysiologic studies in the Guillain-Barré syndrome: effects of plasma exchange and antibody rebound.

Nerve conduction studies (NCS) and antiperipheral nerve myelin antibody (A-PNM Ab) titers were measured serially in 29 patients with Guillain-Barré syndrome (GBS), of whom 21 were treated with plasmapheresis. Data were obtained from 3 to 6 days until 1 to 2 years after onset of symptoms. Within 3 to 6 days, mean NCS were abnormal. They improved some by 1 week and became maximally abnormal by 4 to 8 weeks, during which time A-PNM Ab fell to low levels. In 5 patients plasmapheresed, A-PNM Ab fell and then increased at 4 to 8 weeks, followed by significant deterioration of NCS (P = 0.01) compared with those without antibody rebound at 18 weeks. These results suggest that, in monophasic GBS, there may be two mechanisms of conduction dysfunction such as early paranodal retraction and later demyelination. In some patients plasmapheresed, A-PNM Ab may rebound associated with further conduction dysfunction. These patients may benefit from further plasmapheresis.