A. F. Hahn

Multifocal motor neuropathy improved by IVIg Randomized, double-blind, placebo-controlled study

Objective: To determine the effect of IV immunoglobulin (IVIg) on neurologic function and electrophysiologic studies in multifocal motor neuropathy with conduction block (MMN). Background: MMN is characterized by progressive, asymmetric, lower motor neuron weakness and is probably immune-mediated. IVIg treatment has been shown to have beneficial effects in several open-label studies and in one small controlled trial. However, larger randomized controlled studies are lacking. Methods: The authors recruited 16 patients with MMN. All subjects were given each of two treatments (IVIg [0.4 g/kg/d for 5 consecutive days] or placebo [dextrose or saline]) that were assigned according to a randomized, crossover design under double-blind conditions. Patients were evaluated before and about 28 days after trial treatment for subjective functional improvement, neurologic disability score, grip strength, distal and proximal compound muscle action potential amplitude, and conduction block. Results: Subjective functional improvement with IVIg treatment was rated as dramatic or very good in nine patients, moderate in one, mild in one, and absent in five patients. This improvement was absent after placebo. The neurologic disability score improved by 6.7 ± 3.3 points with IVIg treatment, whereas it decreased by 2.1 ± 3.0 with placebo (p = 0.038). Grip strength on the weaker side was increased by 6.4 ±1.9 kg with IVIg treatment; it decreased by 1.0 ± 0.8 kg with placebo (p = 0.0021). Conduction block worsened by 12.98 ± 6.52 % with placebo, but improved by 12.68 ± 5.62 % with IVIg treatment (p = 0.037). Conduction block was reversed in five patients with IVIg but not placebo. Conclusion: IVIg improved conduction block as well as subjective and objective clinical measures of function in patients with MMN.

Passive transfer studies in Guillain‐Barre polyneuropathy

Serum and lymphocytes from patients with acute Guillain-Barre polyneuropathy were injected into rat sciatic nerves. Serum from 13 of 17 patients produced perivenular demyelination, associated with lymphocytic infiltration. The pattern of demyelination differed from that caused by experimental allergic neuritis serum. The level of serum demyelinating activity was greatest early in the disease and then decreased. The demyelinating factor was heat-labile but not complement-dependent. Circulating lymphocytes did not cause demyelination in eight patients.

Passive transfer of demyelination by experimental allergic neuritis serum

SummarySerum from rabbits with experimental allergic neuritis (FAN) when injected into rat sciatic nerves produced rapidly evolving demyelination followed by remyelination. Myelinating and non-myelinating Schwann cells as well as myelin itself were damaged by 15 min after injection. Myelin degradation was well advanced prior to involvement by macrophages at 12 h. The demyelinating factor was myelin-specific and complement-dependent. The evidence suggests that the FAN antigen may reside in Schwann cell membranes as well as in myelin.

Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy.

Up to 16% of chronic inflammatory demyelinating polyneuropathy (CIDP) patients may present acutely. We performed a retrospective chart review on 30 acute inflammatory demyelinating polyneuropathy (AIDP) and 15 acute‐onset CIDP (A‐CIDP) patients looking for any clinical or electrophysiological parameters that might differentiate AIDP from acutely presenting CIDP. A‐CIDP patients were significantly more likely to have prominent sensory signs. They were significantly less likely to have autonomic nervous system involvement, facial weakness, a preceding infectious illness, or need for mechanical ventilation. With regard to electrophysiological features, neither sural‐sparing pattern, sensory ratio >1, nor the presence of A‐waves was different between the two groups. This study suggests that patients presenting acutely with a demyelinating polyneuropathy and the aforementioned clinical features should be closely monitored as they may be more likely to have CIDP at follow‐up. Muscle Nerve, 2010

Paraparesis following intrathecal chemotherapy

We studied a case of flaccid paraplegia that immediately followed intrathecal injection of cytosine arabinoside diluted in 1.5% bacteriostatic water (1.5% benzyl alcohol in H2O). The complication was reversed by rinsing the CSF space with saline. Autopsy showed fibrosis and remyelination of lumbosacral nerve roots. In acute and chronic animal experiments, we showed that benzyl alcohol in commercially used concentrations can have a local anesthetic and an irreversible toxic effect on nerve fibers. This provides a sufficient explanation for many cases of paraparesis following intrathecal chemotherapy.

Blood-nerve barrier studies in experimental allergic neuritis

SummaryThe integrity of the blood-nerve barrier (BNB) was studied during the development of experimental allergic neuritis (EAN). Lewis rats immunized with bovine nerve or myelin plus complete Freunds adjuvant developed histological lesions of EAN in nerve roots by 10–12 days and in sciatic nerves by 12–14 days. Evans blue-albumin (EBA) and horseradish peroxidase (HRP) were injected i.v. 1 h prior to killing on days 6–18. Perivascular and diffuse endoneurial leakage of the tracers was seen in nerve roots by 10–12 days post immunization (p.i.) and in sciatic nerves by 12–14 days. This coincided with the appearance of endoneurial infiltration with inflammatory cells and endoneurial proteinaceous edema at a time when Schwann cell and myelin changes were still minimal. Therefore, an alteration in BNB permeability occurs early in EAN, coincident with inflammatory cell infiltration. This could be an expression of delayed hypersensitivity, yet it would also facilitate the entry of anti-myelin antibodies into the endoneurium where they could initiate demyelination.

P2-peptide induced experimental allergic neuritis: a model to study axonal degeneration.

SummaryIn experimental allergic neuritis (EAN) severity of clincal disease and pathology correlate with the dose of antigen (Hahn et al., Lab Invest 59:115–125, 1988). To avoid axonal membrane contamination of the antigen, EAN was induced with a synthetic peptide, corresponding to residues 53–78 of bovine P2 myelin protein. Severity of EAN correlated with the dose of peptide in the inoculate. The relationship between demyelination, inflammation and axonal degeneration was studied. Low doses resulted in pure demyelination. Axonal degeneration occurred only with high doses of inflammation. The role of macrophages in producing axonal damage is discussed.

Central lesions in chronic inflammatory demyelinating polyneuropathy An MRI study

To determine the frequency of the possible association between chronic inflammatory demyelinating polyneuropathy (CIDP) and MS, we did magnetic resonance imaging (MRI) of the brain in 19 patients with CIDP. Only 1 patient had clinical signs suggestive of central involvement. Seven of the 19 scans showed 2 or more brain lesions. In 1 case the cause was an infarct and in 5 cases the patients were over 55 years of age and the lesions were not typical of MS. One 38-year-old patient had 2 small subcortical lesions. Typical MS lesions on MRI are uncommon in CIDP.

Nerve biopsy findings in Niemann-Pick type II (NPC)

We read with interest the article by Hahn et al. [3] concerning nerve biopsy findings in Niemann-Pick type II (NPC). We agree with the authors statements that the findings in the peroneal nerve biopsy of their patient were a useful diagnostic tool and that peripheral nervous system involvement in NPC has not been extensively reported in the literature. We have a large experience with morphological diagnostic investigations in neurometabolic disorders including Niemann-Pick disease type A and type C [4, 5]. We would like to stress the usefulness of simple biopsy procedures such as a skin biopsy even when enzymatical assays are not significantly abnormal. In a review article, we summarized the results of skin biopsies in a total of eight NPC patients ranging from 2 to 12 years old with normal total sphingomyelinase assays on cultured fibroblasts (A. Van Elsen, Antwerp and M. T. Vanier, Lyon: personal communications) [2]. Earlier reported skin biopsy findings concerned a family with NPC [1]. Osmiophilic pleomorphic lamellar inclusions were observed in dermal fibroblasts and perivascular histiocytes (Fig. 1A). Unmyelinated axons of dermal nerve bundles, dermal presynaptic endings between smooth muscle fibers, subepithelial axonal endings and terminal axons around sweat glands (Fig. 1B) and vessels were dystrophic and showed many aspecific residual bodies and a few lamellar inclusions. A careful examination revealed similar but less numerous lamellar inclusions in epithelial cells, eccrine sweat glands, Schwann cells of myelinated and unmyelinated axons and melanocytes. Such findings were very helpful in the differential diagnosis and were not observed in 473 skin biopsies including + 200 age-matched controls. We would also like to suggest that the authors do electron microscopy on the biopsied anterior tibial muscle to check the endomysial fibroblasts. Finally, our impression is that the curvilinear inclusions in the vascular endothelial cells shown in Fig. 6 [3] do not resemble the curvilinear bodies of ceroid-lipofuscinosis, at least at the magnification used. To conclude, it should be emphasized that, in difficult cases, a skin biopsy may successfully contribute to the diagnosis and may even be used in some storage disorders to estimate the value of specific therapies [6]. References

Nerve and muscle biopsy Electrophysiology and morphology in polyneuropathy

We correlated the results of biopsy of a muscle nerve, a sensory nerve, and tibialis anterior muscle with electrophysiologic studies in 13 patients with sensorimotor polyneuropathy and 6 patients with normal findings. There were significant correlations between teased fiber changes and conduction abnormalities in both muscle nerves and sensory nerves. The density of large myelinated fibers in the lateral fascicle of the deep peroneal (LFDP) nerve correlated significantly with both the motor unit estimate and compound action potential amplitude of the extensor digitorum brevis (EDB) muscle. Other characteristics of the EDB muscle compound action potential related poorly to teased fiber abnormalities. There was good correlation of needle electrode study of the EDB muscle with teased fiber analysis of the LFDP nerve and with the morphology of the tibialis anterior muscle in 75 percent of the cases, and only minor discrepancies in the remainder. These results emphasize the close relationship between certain structural and electrophysiologic changes in subacute and chronic polyneuropathy.