Axon cytoskeleton ultrastructure in chronic inflammatory demyelinating polyneuropathy

Introduction: To detail the extent and pattern of axon cytoskeleton alterations in chronic inflammatory demyelinating polyneuropathy (CIDP).Methods: Nerve biopsies from 7 cases of CIDP, including 4 cases with severe fiber loss, were compared with 5 controls by morphometric transmission electron microscopy (TEM).Results: Despite demyelination of single fibers, myelin ultrastructure was otherwise normal. Contrary to immunolabeling, TEM revealed a decrease in neurofilament (NF) density in every case, although there were pronounced variations among fibers even in the same sample. The NF decrease reached the same extent in large‐ and small‐diameter fibers. It was observed in normally myelinated fibers, suggesting they were demyelinated at a distance from the section. Minimal inter‐NF distance increased roughly inversely to NF density. Microtubules increased in 3 cases previously characterized by increased growth‐associated protein (GAP‐43) immunolabeling.Conclusion:These data demonstrate the severity and constancy of axonal lesions, and especially of NF, in residual fibers in our cases of CIDP. Muscle Nerve 44: 332–339, 2011     

Cytoskeleton abnormalities in axonopathies of unknown aetiology: correlations with morphometry

To determine if specific axonal cytoskeleton abnormalities could be demonstrated in axonopathies without aetiology, nerve biopsies from five controls and nine cases were analyzed by morphometry and immunocytochemistry with anti-neurofilament (NF, subunits L, M, H) and anti-beta tubulin (TUB) antibodies. Morphometry revealed either large fiber atrophy (decrease in large fiber density with increased density in small fibers), degeneration of large fibers (decrease in large fiber density and in total density of fibers) or of all diameter fibers. NF immunostaining density decreased (by 21-89%) only in cases with fiber loss, in parallel to myelinated fiber density as determined by morphometry. On the contrary, the density of fibers labelled for TUB increased significantly in all except two cases by 52-102% over controls. Nevertheless, in these two cases--with a severe loss of fibers--as well as in other cases, the ratio of the density of fibers labelled for TUB and NFL (TUB/NFL) increased by 48-404%. Thus, the total density of myelinated fibers was always inversely correlated with the TUB/NFL ratio. Similar abnormalities have been described only after axotomy; our cases could thus be compared to .     

Chronic inflammatory polyradiculoneuritis and the axonal cytoskeleton: morphometric and immunocytochemical data

We report morphometric and immunocytochemical data obtained from nervous biopsy in 7 patients with chronic inflammatory demyelinating neuropathy (CIDP), compared to 5 controls (without neurological involvement). Fiber loss was present in all cases and reached 50 p. 100 or more in 4 cases. The g myelination ratio was elevated in 3 cases only, indicating demyelination. The number of fibers labelled for the L subunit of neurofilaments was normal in cases with moderate fiber loss and dropped down for densities < 3900/mm2 (4 cases). Labelling with anti-GAP43 antibody was considerably increased in 3 cases, but did not correlate with fiber density or disease duration. These data confirm the importance of axonal lesions in CIDP and offer the opportunity to discuss their pathophysiological mechanisms.     

Chronic inflammatory demyelinating polyradiculoneuropathy with autonomic involvement

We report a case of chronic acquired neuropathy predominantly affecting sensory and autonomic nerves. Investigations showed a demyelinating polyradiculoneuropathy with axonal degeneration and depletion of postganglionic noradrenergic fibers in the rectal mucosa. Intravenous immunoglobulin and corticosteroid administration were effective in alleviating symptoms and improving electrophysiological abnormalities. This neuropathy may be a novel variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), in which autoimmunoreactivity is directed not only against myelin but also against axon- or ganglion-composing protein. Autonomic nerve involvement does not exclude a diagnosis of CIDP.     

Necrotizing vasculitis of the peripheral nervous system: comparison of the axon cytoskeleton abnormalities with other types of neuropathies

Morphometric and immunocytochemical data obtained from nerve biopsies in six patients with necrotizing angiopathic neuropathy were compared with the data obtained in five control patients without neurologic disease. The density of myelinated fibers were greatly decreased in all patients (more than 55 p.cent), and reached 70 p.cent in four patients. The g myelination ratio was elevated in one patient, indicating demyelination. The number of fibers immunolabeled for the neurofilament (NF) light chain (L) was also decreased from 31 to 96 p.cent. Labeling for medium (M) and heavy (H) NF subunits was less affected. On the contrary, the number of fibers expressing beta-tubulin (TUB) increased by 38 to 141 p.cent and the ratio of the number of fibers expressing TUB and NFL (TUB/NFL) was increased 3 to 33-fold (p<0.05). We have previously reported similar, though less pronounced, anomalies in axonopathies of unknown cause. These results suggest that diverse etiologies may lead to the same type of lesions of the axon cytoskeleton.     

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti-MAG neuropathy. Skin biopsies were performed in 14 patients with anti-MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti-MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti-MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti-MAG neuropathy, both large- and small-diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers.     

Tumor necrosis factor-α in peripheral nerve lesions

Immunocytochemical expression of tumor necrosis factor-α (TNF-α) was examined in nerve biopsy samples of patients with various disorders, focusing on nerve injury. TNF-α was mainly associated with phagocytosing macrophages in acute axonal injury, but the staining was more frequently seen in sections from patients with vasculitis than with metabolic neuropathy. Ramified macrophages outside nerve fibers were also positive for TNF-α in the acute stage of vasculitis. In active demyelinating lesions from patients with chronic inflammatory demyelinating neuropathy (CIDP), macrophages outside nerve fibers showed weak staining with TNF-α, but the cells adhering to myelinated nerve fibers showed definite staining. This may be due, in part, to the smouldering course of CIDP, and expression may be up-regulated transiently during the demyelinating process. These results indicate that macrophages, as the effector cells for both axonal injury and active demyelination, express TNF-α, but their activation mechanisms may vary among vasculitis, metabolic axonopathy and inflammatory demyelination. Received: 7 April 1997 / Revised, accepted: 23 June 1997     

Sensory CIDP presenting as cryptogenic sensory polyneuropathy

The objective of this study was to report that patients with chronic inflammatory demyelinating polyneuropathy (CIDP) can present with a clinical picture of cryptogenic sensory neuropathy. Patients with distal sensory neuropathy and electrodiagnostic studies that are minimally abnormal or consistent with an axonal pathology are usually diagnosed as having cryptogenic sensory neuropathy if no cause for neuropathy can be found. Some of these patients, however, may have sensory CIDP. We reviewed the records of eight patients with CIDP, diagnosed by sural nerve biopsy, who presented with sensory neuropathy and electrodiagnostic studies that were minimally abnormal or revealed changes consistent with axonal neuropathy. All patients reported distal numbness and paresthesias and, on examination, had predominantly large fiber distal sensory loss and normal muscle strength. In most patients, deep tendon reflexes were reduced or absent. Sural nerve biopsies in all patients were consistent with chronic myelinopathy, with quantitative teased fiber analysis revealing segmental remyelination in 13-40% of the fibers. The four patients who received IVIg therapy had improved sensation and gait. Of the remaining four patients, one is being followed, one had spontaneous remission, one was lost to follow-up, and one, with contraindications to therapy, reported disease progression. Sensory CIDP may present as cryptogenic sensory polyneuropathy with normal or axonal electrophysiologic features. Sural nerve biopsy should be considered in patients with progressive, predominantly large fiber sensory neuropathy of otherwise unknown etiology, as they may have sensory CIDP that responds to therapy.     

Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy

OBJECTIVE: To evaluate the clinicopathologic features and prognostic factors of 100 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Comparison of clinical and biopsy findings with functional score evaluated an average of 6 years after referral. RESULTS: CIDP followed a relapsing course in 14% of the patients and a progressive course in 45%. After progressive onset, little change was noted during follow-up in the others. Five patients had symptomatic involvement of the CNS. Teased fiber preparations of nerve biopsy specimens showed that 68 patients had purely demyelinative lesions, 20 had mixed axonal and demyelinative lesions, and 5 had predominantly axonal lesions. Axonal loss was a common finding, with 47% of the patients retaining less than half of the normal density of fibers. Inflammatory infiltrates, found in 18 samples, were prominent only in 4. Of the 83 patients evaluated an average of 6 years after onset, 56 were in good condition; 24 had deteriorated and failed to respond to treatment, including 9 patients who died as a consequence of their neurologic deficit. Progressive course, CNS involvement, high proportion of fibers showing active demyelination on nerve biopsy, and axonal loss overall correlated with higher disability. CONCLUSION: Axonal loss is the major long-term pejorative prognostic factor in CIDP.     

Axonal lesions and PDGF-enhanced remyelination in the rat corpus callosum after lysolecithin demyelination

In multiple sclerosis (MS), demyelination is often accompanied by axonal lesions, which largely account for patient disability. We therefore studied the consequences of demyelination induced by lysophosphatidylcholine (LPC) on the axonal cytoskeleton, particularly neurofilaments (NF) and tubulin, in the adult rat corpus callosum. Immunocytochemistry showed that NF immunolabelled fibres decreased by 49% in the LPC injured area at day 15. Since it has been previously demonstrated that PDGF improves remyelination, we performed a comparative study between LPC controls and PDGF-treated (1 microg) animals. In these later animals, immunolabelling for NFL and NFM (NFH subunit excepted) was increased by 142 and 63%, respectively, indicating reduction of axonal abnormalities. These results extend the potential therapeutic role of PDGF in MS.     

Involvement of the ventral horn cells in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuritis]

The lumbar ventral horn cells and myelinated fibers in the ventral spinal roots of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuritis (CIDP) were morphometrically analyzed. In all six cases, central chromatolytic changes in the ventral horn cells were commonly observed. In addition, two out of four GBS cases and one of two CIDP cases showed a significant reduction in the ventral horn cell population, particularly in neurons with a large diameter. The cases with significant motoneuron loss also showed a remarkable reduction in the number of myelinated fibers in the ventral spinal roots, and severe axonal degeneration was observed in cases in acute phase. Astrogliosis of the ventral horn was also seen in some cases. The present study suggested that motoneuron loss in the primary demyelinating diseases like GBS and CIDP is the consequence of the axonal pathology of the motoneuron axons. These observations are helpful to understand motoneuron loss in certain motoneuron diseases with preferential involvement of lower motor neurons.     

INTRAMYELINIC EDEMA: AN ELEMENTARY PATHOLOGICAL LESION IN CIDP

Pathological abnormalities of sural nerve biopsies from patients affected by chronic inflammatory demyelinating polyneuropathy (CIDP) include segmental demyelination, inflammatory infiltrates, axonal degeneration, subperineurial edema and Schwann cell proliferation. There are few reports in the literature (Waddy '89, Sabatelli '96) describing edema of the myelin sheath as an additional pathological feature of CIDP. This peculiar abnormality is a prominent finding in several experimental toxic and compression neuropathies. In 1993 Tatum described Intramyelinic Edema in experimental allergic neuritis induced by systemic passive transfer of human IgM anti‐myelin‐associated glycoprotein, and suggested that this change may play a role in the pathogenesis of demyelination. In order to establish whether intramyelinic edema may represent an elementary pathological lesion in human peripheral neuropathies, we reviewed morphological data of sural nerve biopsies from 46 CIDP patients admitted to our Institute from 1988 to 2001 and we compared them with findings from patients affected by other neuropathies. IE was observed in 6 patients with CIDP, but in none of the 500 patients affected by neuropathies of different etiology. In two out of the six patients the neuropathy was associated with IgM‐paraprotein, without anti‐MAG activity. IE was a prominent feature in only one patient while in the remaining patients it was confined to sporadic fibers. In one patient with a mild form of CIDP, IE was the only pathological finding. In the remaining patients it was associated with segmental demyelination and axonal loss. Our findings show that although IE is observed in only a minority of CIDP patients (13% of our series), this pathological finding may be considered a specific abnormality of inflammatory demyelinating neuropathies. We suggest that axonal shrinkage, which is invariably associated with IE, may represent a mechanism of loss of function in CIDP, in addition to segmental demyelination and axonal loss.     

Spontaneous central nervous system remyelination is not altered in NFH-lacZ transgenic mice after chemical demyelination

Harmonious functioning of the nervous system depends on neuron-glia interactions, particularly between the axons and their myelinating cells, i.e., oligodendrocytes (OL) in the central nervous system (CNS). In human demyelinating diseases such as multiple sclerosis (MS), demyelination may be associated with axonal damage, but alterations of the axonal cytoskeleton, which is composed mainly of neurofilaments (NF) and microtubules, are largely unknown, as are the consequences on remyelination. In a model of demyelination induced by lysophosphatidylcholine (LPC), we have shown that demyelination was correlated with a decrease in NF immunolabelling, and that these axonal abnormalities were reduced by platelet-derived growth factor (PDGF)-enhanced remyelination in adult rats. We have analysed the spontaneous remyelination after LPC stereotaxic injection in the CNS of transgenic NFH-lacZ mice, which present axonal atrophy caused by abnormal distribution of NF, associated with hypermyelination in the PNS, and normal myelin thickness in the CNS. Axonal atrophy in the CNS of NFH-lacZ mice was confirmed, but it was not worsened by demyelination. On the contrary, demyelination induced axonal atrophy in wild-type mice, demonstrating that NF are essential for axonal calibre determination. Moreover, an efficient spontaneous remyelination occurred in NFH-lacZ as well as in wild-type mice, indicating that the NF are not necessary for CNS remyelination. These findings point out that NF modifications observed in MS may not be responsible for the lack of remyelination in this disease.     

Minimal and asymptomatic chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: Show the chronic inflammatory demyelinating polyneuropathy (CIDP) is not only clinically heterogeneous but extremely variable in severity. METHODS: Three patients were referred for mild distal paresthesiae lasting more than 6 months and one for inguinal and thigh pain later ascribed to coxarthrosis. Strength was normal in all patients and tactile sensation reduced distally only in one. Tendon jerks were absent, except the knee jerks in one patient, reduced in lower limbs in two and normal in one. RESULTS: Electrophysiology showed a demyelinating neuropathy without motor conduction block. CSF protein content was increased in all patients. Nerve biopsies showed de-remyelination with varying degrees of axonal loss. Genetic studies excluded a demyelinating neuropathy associated with duplication or deletion of the 17p.11.2 segment. CONCLUSIONS: CIDP patients with pure sensory clinical presentation have been described but are generally more severely impaired. However, because of the mildness of symptoms and the unequivocal electrophysiological involvement of motor fibers, we think that in these cases the term minimal CIDP is more appropriate than sensory CIDP. These cases represent the most benign end of the CIDP spectrum. In our series minimal or even asymptomatic CIDP encompasses 8% of cases.     

Chronic inflammatory demyelinating polyradiculoneuropathy: MRI study of brain and spinal cord

CNS demyelinating lesions have been reported in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). There are no studies of cord atrophy in CIDP. Ten patients with CIDP underwent brain and spinal cord MRI to investigate CNS demyelination and cord atrophy. No CNS demyelination was found, but the mean cervical cord area was significantly smaller in CIDP patients vs control subjects. Spinal cord atrophy may be related to degeneration secondary to axonal loss.     

Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.     

Axonal caliber and neurofilaments are proportionately decreased in galactose neuropathy

Feeding galactose to rats induces nerve conduction abnormalities, increased levels of nerve galactitol, endoneurial edema, elevated pressure and hypoxia of endoneurial fluid, and pathological abnormalities of nerve fibers. To investigate the cellular mechanisms of the fiber lesions and their possible relationship to alterations in the nerve microenvironment, rat peroneal nerves were morphometrically evaluated eight months after the commencement of galactose feeding. Whereas the density of neurofilaments (NF/micron2) in the transverse axonal area of myelinated fibers was not significantly different between the nerves of galactose-fed and control rats, axonal areas and the number of NF/axon, when related to myelin spiral length, were significantly less in nerves of galactose-fed rats. Myelin alterations, characteristic of axonal atrophy, were also significantly increased. The present data provide evidence of a proportionate decrease in axonal caliber and the number of NF/axon in myelinated fibers in experimental galactose neuropathy, suggesting that galactose induces fibers in experimental galactose neuropathy, suggesting that galactose induces either decreased NF synthesis, assembly or transport. The possible role of microenvironmental alterations, including endoneurial hypoxia and hyperosmolarity, in the production of this axonal atrophy is discussed.     

ANTISULFATIDE ANTIBODIES IN NEUROPATHY—CLINICAL AND ELECTROPHYSIOLOGIC CORRELATES

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.     

Superficial radial sensory nerve potentials in immune-mediated and diabetic neuropathies.

OBJECTIVE: The pattern of abnormal median-normal sural sensory nerve action potential (SNAP) is frequently found in acute/chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP), whereas sural/radial SNAP amplitude ratio is sensitive to detect dying-back degeneration. To investigate whether radial SNAP and its amplitude ratio to median or sural SNAP provide additional particular patterns of sensory nerve involvement. METHODS: Superficial radial, median, and sural SNAPs were recorded in 63 normal subjects and in 132 patients with AIDP/CIDP (n = 22), diabetic neuropathy (n = 83), or other axonal polyneuropathy (n = 27). Median/radial and sural/radial amplitude ratios were examined. RESULTS: In normal subjects, median/radial ratio was 0.96 +/- 0.05 (mean +/- SEM), and sural/radial ratio was 0.50 +/- 0.03. Compared with normal controls, the median/radial ratio was lower in patients with AIDP/CIDP (0.64 +/- 0.11; P < 0.001) or diabetic neuropathy (0.75 +/- 0.04; P = 0.08), but similar in those with other neuropathy (0.94 +/- 0.10). The sural/radial ratio was higher in the AIDP/CIDP group (0.71 +/- 0.08; P = 0.10), and lower in the diabetic (0.36 +/- 0.03; P < 0.001) and other axonal neuropathy groups (0.40 +/- 0.07; P = 0.08). CONCLUSIONS: AIDP/CIDP is associated with a reduced median/radial ratio and increased sural/radial ratio, probably reflecting demyelination predominant in the distal nerve terminals. Diabetic neuropathy is characterized by decreases in both median/radial and sural/radial ratios, presumably due to coexistence of carpal tunnel pathology and dying-back degeneration. SIGNIFICANCE: Comparison of multiple SNAP amplitudes provides information about characteristic distribution patterns of sensory nerve involvement in peripheral neuropathies.     

Diagnosis of atypical forms of chronic inflammatory demyelinating polyradiculoneuropathy: a practical overview based on some case studies

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease and the diagnosis is complicated by heterogeneity of the variant forms. Underdiagnosis is undesirable as effective treatments exist. Conversely, overdiagnosis can lead to inappropriate and expensive treatment and delay the initiation of appropriate treatment. Summary: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria are used widely in clinical trials and clinical practice. A limitation of the criteria is the requirement for at least one demyelinating parameter as there are certain situations (e.g. proximally located demyelinating process, secondary axonal loss, predominant involvement of sensory fibers) where this criterion may be not apparent; this can lead to misclassification of the neuropathy as axonal. To prevent this situation, the French CIDP Study Group has proposed a set of clinical and electrophysiological signs that are atypical for chronic idiopathic axonal polyneuropathy and suggestive for CIDP. Greater use of supportive diagnostic tools such as magnetic resonance imaging in clinical practice is not only extending the boundaries of CIDP but also contributing to over-representation of some variants, such as those involving the plexus, and sensory or minimal forms of CIDP. Many misdiagnoses can be avoided by adapting the diagnostic strategy to the clinical phenotype of CIDP. Key Messages: Early and accurate diagnosis of CIDP facilitates the selection of appropriate therapy to improve prognosis. Understanding the limitations of diagnostic criteria and adapting the diagnostic strategy to clinical phenotype can enhance precision and avoid diagnostic pitfalls.