Another tool for the neurologist's toolbox

Because the peripheral nervous system (PNS) can be directly assessed physiologically and pathologically, peripheral neurologists enjoy pointing out that it offers advantages over the CNS in research and in clinical diagnosis. However, nerve biopsies, such as sural biopsies, are invasive, sample only one anatomic site, and are rarely done more than once. For these reasons the goal of multiple assessments of the PNS in time and space has been restricted to physiological testing. The advent of skin biopsy as a diagnostic and investigative tool has changed the picture; as described below, skin biopsies can be done at several sites and several time points, with very good patient acceptance and an exceptional safety profile. Until now their use has been largely focused on assessment of epidermal nerve fibers, which are unmyelinated C or A delta fibers. Lombardi and colleagues now show that punch skin biopsies can be used to assess the myelinated A and A fibers within the skin, and to probe pathogenetic mechanisms of demyelinating neuropathies by looking for antibody binding to myelinated fibers. The specific target of their study was the neuropathy associated with “antiMAG” antibodies. Myelin associated glycoprotein (MAG) is a member of the siglec family of proteins (siglec-4) and is expressed both in the central and, to lesser amount, in the peripheral nervous system. The MAG protein is located on the periaxonal Schwann cell plasmalemma as well as in the mesaxon, paranodal loops and the Schmidt-Lanterman incisures. In these latter sites MAG is thought to prevent compaction of myelin lamellae. The development of antibodies usually occurs in the setting of an IgM monoclonal gammopathy in which the monoclone “sees” glycoconjugates with the HNK-1 determinant. These glycoconjugates include MAG and specific glycolipids, such as sulfated glucuronyl paragloboside (SGPG). The resulting neuropathy has several distinctive features: a distally predominant, slowly progressive sensorimotor neuropathy with prominent gait disorder, sensory ataxia, and tremor, and with an unusual pattern of increased terminal latencies in long nerves, in addition to other markers of demyelination. Typically MAG neuropathy is diagnosed on the basis of these clinical and electrophysiological features in combination with an IgM monoclone and “anti-MAG” antibodies. The blood tests for anti-MAG polyneuropathy can distinguish this disorder from chronic inflammatory demyelinating polyneuropathy (CIDP). In one series, antiMAG antibodies were present in 67% of patients with distal acquired demyelinating symmetric neuropathy. The specificity of a high titer ( 6,000) of anti-MAG is around 90%. Sural nerve biopsies demonstrate IgM deposits at the site of MAG localization (periaxonal Schwann cell membrane, external and internal mesaxons, paranodal loops at the nodes of Ranvier and Schmidt-Lanterman incisures). Other patterns have been reported including IgM binding to areas of compact myelin producing myelin wide-spacing and to non-myelin structures including axons and endoneurial macrophages. The demonstration of IgM deposits in peripheral nerve on sural nerve biopsy is definitive, and can be an important diagnostic step before committing to expensive, potent immunomodulatory therapies, especially in the patient with equivocal or low titer antiMAG antibodies, or an atypical clinical picture. In this issue, Lombardi and colleagues demonstrate the presence of IgM deposits on myelinated nerve fibers in simple punch skin biopsies in patients with anti-MAG polyneuropathy. IgM deposits were more frequent distally in hand and fingertip in glabrous (non-hairy) skin. In contrast, in patients with CIDP and IgM paraproteinemic neuropathies without antiMAG antibodies no deposits of IgM were identified on the cutaneous myelinated fibers. Furthermore, both anti-MAG and CIDP patients showed a significant loss of epidermal nerve fibers in the lower limb, reflecting a degree of axonal loss. Previous studies had demonstrated a loss of epidermal unmyelinated axons in both CIDP and GBS. The study suggests that skin biopsy may be a new technique to allow the investigation of sensory nerve endings in anti-MAG and potentially other immune-mediated neuropathies. The authors also noted that the deposits of IgM were greatest in the most distal skin biopsies. This finding might correlate with the electrophysiological feature of a marked delay of distal latencies in long motor nerves, suggesting that nerve fiber endings in long nerves are particularly affected. Why this pattern should occur is unknown, but one speculation is that it may reflect a spatial gradient in nerve bed median temperatures; IgM binding is increased at cooler temperatures. Until recently, the methods available for assessment of the small sensory fibers in the skin were limited. Cutaneous nerves arise from sensory and motor neurons residing in dorsal root ganglia and the sympathetic ganglia respectively. Bundles of nerves enter the skin in the deep layers of the dermis and course toward the epidermis giving off axons which innervate the associated end organs. Unmyelinated nerve fibers comprise the vast majority of cutaneous nerves. Myelinated nerve fibers terminate at hair follicles, or the specialized