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La diagnosi di neuropatia periferica richiede molteplici competenze, cliniche, elettrofisiologiche e, talvolta, neuropatologiche. L’iter diagnostico prevede l’esecuzione di esami complementari mirati, secondo un rigoroso approccio clinico, che deve portare a una classificazione sindromica quanto più precisa possibile. Un’eziologia è talvolta evidente (diabete, alcolismo, chemioterapia recente), ma molte neuropatie rimangono di causa indeterminata dopo una valutazione di prima linea, a volte richiedendo il ricorso a un centro di riferimento. La ricerca dell’eziologia di una neuropatia può giustificare indagini approfondite e richiede che il clinico abbia una solida base di conoscenze per guidare utilmente queste indagini. La conoscenza ha fatto grandi progressi negli ultimi anni nel campo delle neuropatie acquisite ed ereditarie, consentendo un significativo miglioramento nella gestione dei pazienti. Questo articolo traccia le grandi linee della classificazione delle neuropatie periferiche e dettaglia i principi dell’approccio diagnostico e le diverse entità in funzione delle eziologie incontrate.

La biopsia nervosa è una procedura considerata relativamente invasiva, i cui obiettivi sono o determinare direttamente l’eziologia di una lesione nervosa periferica o specificarne il meccanismo. A causa del crescente sviluppo dei biomarcatori sierici, della genetica molecolare e delle tecniche di diagnostica per immagini, le indicazioni per la biopsia nervosa sono diminuite; tuttavia, questo esame conserva un interesse cruciale in determinate situazioni cliniche. È importante che il medico che fa richiesta di biopsia nervosa conosca per grandi linee le tecniche e i risultati attesi, per poter decidere caso per caso sull’indicazione di questo esame. Questo articolo descrive le principali indicazioni della biopsia nervosa, le lesioni elementari e le anomalie riscontrate nelle patologie suscettibili di interessare il sistema nervoso periferico, acquisite o ereditarie. In tutti i casi, la biopsia deve essere eseguita rispettando rigide regole di preparazione dei campioni, indispensabili per la loro analisi. Va anche ricordato che un campione di biopsia nervosa può essere conservato per anni e può essere inviato per l’analisi a un centro di riferimento per interpretare questo esame.

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot–Marie–Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.

In most dysimmune neuropathies, historically the microscopical lesions were described prior to immunological studies. The latter along with neuropathological studies have found some immune, albeit incomplete, explanations of the mechanisms of these lesions which we will describe in two main syndromes: the primitive auto-immune inflammatory peripheral polyneuropathies (GBS and CIDP) and polyneuropathies induced by a monoclonal dysglobulinemia. In some patients who have to be discussed case by case pathology (nerve biopsy) will confirm the diagnosis, may help to delineate the molecular anomalies and identify lesional mechanisms. We will review the high variability of nerve lesions which is characteristic of dysimmune neuropathies. Pathological studies confirm that both humoral and cellular immune reactions against Schwann cell and/or axonal antigens are implicated in primitive dysimmune neuropathies due to a dysfunction or failure of immune tolerance mechanisms. In case of a polyneuropathy associated to a monoclonal dysglobulinemia, pathological and immunological studies have shown that in many patients, the dysglobulinemia did harm the peripheral nerve; knowledge of the pathological lesions and their mechanisms is of major interest for orienting specific treatments.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shares immunologic features with multiple sclerosis (MS). Because IM interferon beta-1a (IM IFN-1a) is an effective and safe treatment for MS, we conducted a dose-ranging efficacy study of IFN-1a in patients with CIDP.

Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2(MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2mutations.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2(KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin.

Before giving a detailed description of the peripheral neuropathies in specific chapters, it appears useful to review some of the possible basic mechanisms which could lead to lesions of the peripheral nerves, the clinical symptomatology, the electrophysiological signs, and what can be expected from nerve biopsy. Specific points concerning aetiologies will be discussed. It should be emphasized that the frequency of diagnosed chronic inflammatory demyelinating polyneuropathy is often underestimated. Such unawareness may be detrimental to the patients who could benefit from treatment with immunomodulators. Despite the lack of specific diagnostic tests, the proposals for new electrophysiological criteria which will increase the diagnostic sensitivity significantly, should make it possible to diagnose a larger number of cases.

Autosomal recessive forms of axonal Charcot–Marie–Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2‐q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 ± 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10–15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5–18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (α2-8)NeuAc(α2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

To characterize the clinical phenotype of LGMD2C in gypsies.

To evaluate the occurrence of malnutrition in patients with ALS, to assess the relation of malnutrition to the neurologic deficit, and to determine the impact of nutritional status on patient survival.

ABSTRACT: Pelizaeus‐Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.

Abstract: The Trembler mouse (Tr) suffers from a dominantly inherited autosomal mutation (glycine to aspartic acid, G150D) affecting the PMP22 gene, which results in an abnormal myelination of the peripheral nervous system. The Tr mouse represents an animal model for the human hereditary neuropathy, Charcot-Marie-Tooth disease. We compared the expression of PMP22, P0, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in nerve biopsies from a 1-year-old heterozygous Tr mouse (Tr/+) with that of a control mouse of the same age. Quantitative and qualitative ultrastructural immunocytochemical analysis showed a significant decrease in PMP22, P0 and MBP and an abnormal location of the MAG in the sciatic nerve of the Tr/+ mouse. We also noted a marked reduction in number of myelinated fibers associated with the presence of two types of myelinated axons: a population of abnormally thin myelin sheaths with lower PMP22 labeling than that observed in myelinated fibers from the control mouse, and some others fibers with normal sheaths for axons of comparable diameter to those of normal mouse with no difference in the PMP22 immunolabeling. This pointed to an involvement of PMP22 in the structure of myelin sheaths.

We studied a patient with epidermoid carcinoma of the lung (treated surgically 1 year earlier) and an acute symmetric pure sensory neuropathy that regressed almost completely within 1 month. Superficial peroneal nerve biopsy 15 days after onset showed evidence of demyelination with perivascular endoneurial inflammation. On ultrastructural examination, lymphocytes were seen passing through endothelial cells of endoneurial capillaries.

Two young patients were referred recently to the authors for investigation of a peroneal atrophy syndrome. Since the first symptoms were observed in infancy, a congenital hypomyelination neuropathy was suspected, and superficial peroneal nerve biopsies were taken. Signs of severe and widespread demyelination/remyelination were observed. These features appeared morphologically similar to those observed in the globular or tomaculous neuropathies. The mechanism of the hypermyelination is discussed.

The authors report on the ultrastructural study of a muscle biopsy carried out in a child 6 years after the first biopsy which had led to diagnosis of “multicore disease”. Clinical evolution following a few years of muscular involvement had been favorable.

This report presents the ultrastructural nerve study of a patient with sensorimotor neuropathy by a shoe glue containing an association of n-hexane and methylethylketone.

The present communication described changes on nerve biopsies from 16 diabetics without neuropathy, except the fact that the ankle jerks were often decreased bilaterally, as it is often encountered in diabetes mellitus. 16 non-diabetic patients with various peripheral neuropathies were also studied; the glucose tolerance tests were always normal in this group and none had any vascular or collagen disease. The three series included patients between 45 to 75 years old. Obervations made on nerve biopsies from these three groups have been compared. The basement membranes of endoneurial capillaries were measured. These measurements have been made on the thinnest part of the basement membranes and pericyte processes were not included. At least 5 capillaries per 1 patient have been studied. Averaging with a computer has permitted demonstration of significant thickenings of basement membranes in diabetic patients without neuropathy; such an observation was not made in non-diabetic patients with various peripheral neuropathies, while the thickenings were the most important in patients with diabetic neuropathy. It must be said that individual variations were encountered in each group. Nerve parenchyma has been carefully studied. In diabetic patients without neuropathy, 14 cases displayed a typical but usually moderate proliferation of Schwann cells. Axon lesions were mild and unfrequent. The exact relationships between thickening of basement membranes of vasa nervorum and lesions of nerve parenchyma need some further informations.

Three cases of painful ophthalmoplegia have been described in which symptoms suggesting a tumor of the orbit justified neuroradiological assessment. Phlebography in each case revealed stenosis of the superior ophthalmic vein in its third portion, and non-opicification of the cavernous sinus. Hirtz incidences revealed contralateral cavernous sinus opacification and venous drainage through the coronary sinus. These neuroradiological findings helped to differentiate this syndrome from other affections which have similar signs and symptoms.

We report the clinical and electrophysiologic characteristics of eight patients (four men and four women) with a hereditary neuropathy with probable thermosensitivity (HTN) of autosomal dominant inheritance. Patients presented reversible episodes of ascending muscle weakness, paresthesiae, and areflexia apparently triggered by an elevation of body temperature over 38.5° C. Mean age at onset was 13 ± 12 (SD; range 6 to 43). Four patients had suffered up to five attacks. EMG and pathologic findings were compatible with a reversible demyelinating neuropathy such as Guillain-Barré syndrome. We excluded loci causing other hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease type I (CMT type I) and hereditary neuropathy with liability to pressure palsies (HNPP), by linkage analysis; thus, HTN is not allelic to either CMT type I or to HNPP.

We studied 10 adults with meningoradiculitis several weeks after a tick bite (Inodes). EMG evidence of denervation was associated with normal motor conduction velocities, prolongation of distal latencies, and low sensory amplitudes, suggesting axonal neuropathy. Sural nerve biopsies confirmed the axonal involvement. Infiltrations of lymphocytes and plasma cells, sometimes forming thick pericapillary cuffs with no accompanying necrosis of vessel walls, were numerous. Many capillaries of the endoneurium, perineurium, and epineurium were affected in this way.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent episodes of acute nerve palsies. We performed a clinical, electrophysiologic, and molecular study of 13 French families with HNPP associated with a chromosome 17∼11.2 deletion in 36 individuals. There were electrophysiologic abnormalities in all symptomatic (n = 28) and asymptomatic (n = 8) deletion carriers, even in childhood. Bilateral delayed distal motor latency of the median nerve at the wrist, reduced sensory velocity in the palm-wrist segment, and delayed distal motor latency or reduced motor velocity in the peroneal nerve was diagnostic in at-risk relatives. This large series confirms the reliability of molecular analysis combined with a simplified electrophysiologic examination for the diagnosis of HNPP associated with 17p11.2 deletion.

This report presents the morphological character of iron deposits in muscle biopsies of three patients who have been suffering from secondary hemochromatosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. Glutamate, a potent cental-nervous-system toxin, has been proposed as one possible factor in this motoneuron disease. Serum from patients with ALS is known to be toxic when added to neurons in culture. We report on the toxicity to rat neurons in culture of cerebrospinal fluid (CSF) from patients with ALS. CSF were obtained from 10 ALS patients, 10 neurological controls, and 10 other controls. ALS CSF was added at dilutions of 50%, 20%, or 10% and neuron survival was assessed after 24 h. The neuroprotective effects of antagonists to two glutamate receptors were also assessed. ALS CSF was significantly neurotoxic, with a neuronal survival rate of only 47% compared with 80% or so for control CSF. This neurotoxicity was blocked by CNQX, an antagonist to the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor but not by two N-methyl-D-aspartate (NMDA) antagonists. ALS CSF contains a specific neurotoxic factor which is AM PA/kainate-like which could have a role in the neuronal degeneration of this disease.

For many years, nerve biopsy has been very useful for clarifying the mechanism and aetiology of human peripheral neuropathies. Recently, this morphological examination has greatly benefited from the contribution of new immunocytochemical, ultrastructural and molecular biological techniques, which can often be used together in studies on inflammatory, paraproteinaemic and genetic neuropathies.

Three female cats, littermates born from clinically normal parents, were examined at 8 to 10 weeks of age because of a slowly progressive posterior ataxia. Another cat from a previous litter from the same parents suffered from similar neurological symptoms. Histopathological examination of the nervous tissues of these animals revealed degeneration of axons and myelinopathy in a distal distribution pattern. Both peripheral nerves and central nervous system were involved. The central nervous system lesions were most prominent in the lateral pyramidal tracts of the spinal cord, the fasciculi gracili of the dorsal column in the cervical spinal cord and the cerebellar vermian white matter. In the PNS numerous degenerating nerve fibers were found in the sciatic nerves but not in the spinal nerve roots. Our findings show that these cats were suffering from a hereditary multisystem degeneration with a distribution pattern of the lesions suggestive of a distal axonopathy.

After a left mastoïdectomy, a six-year-old child remains deeply comatose and dies twelve days later. The anaesthetic used was ether. The pathological findings included completely demyelinated areas, often sharply outlined, in the cerebral white matter and typical anoxic necrosis of the cerebral cortex and of the Sommer sector in the cornu Ammonis.

A 38 year-old man presented with weakness of the lower limbs. Electrophysiology revealed a pronounced demyelinating neuroaphy. Nerve biopsy disclosed de and remyelinating lesions and characteristic lamellar inclusions in Schwann cels and macrophates. There was no familial hostroy of neurologic disorder, and impairment of motor evoked potentials was the only sign of CNS involvement. Arylsulfatase A and cerebroside sulfate sulfatase activities in leukocytes and culture of the patient's fibroblasts were low. The sulfatide loading test also revealed abnormal sulfatide accumulation. This may be the first reported case of adult metachromatic leukodystrphy presenting as peripheral neuropathy.

In leprous neuropathy the perineurium has very often an abnormal multilayered appearance and is infiltrated by many different types of inflammatory cells. We report here 13 cases characterized by an abnormal endoneurial proliferation of fibroblasts which seems to differentiate in perineurial cells. In several instances there is formation of many intrafascicular microcompartments. Such aspects have been described in various, but infrequent, cases of experimental and human neuropathies. It seems that severe Wallerian degeneration, diffuse endoneurial macrophage infiltration and lesion of the perineurium might lead to such a process.

We report the results of glutamate dehydrogenase (GDH) and aspartate aminotransferase (AAT) activities in leukocytes of 24 patients with motor neuron disease (MND) and 20 matched control subjects. In 62.5 of patients suffering from MND, we detected a leukocyte GDH deficiency (± 2 SD) as compared with the mean value obtained in controls. By contrast, there was no difference in leukocyte AAT activities in affected and nonaffected subjects. Abnormal cellular glutamate metabolism might be involved in the pathogenesis of MND.

Three patients from a single family of six siblings had homocystinemia and homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency and had severe recurrent strokes in adult life. Two of the patients died 1 year after clinical onset.

A chronic demyelinating neuropathy with “benign” IgM gammopathy was followed for 6 years in a 63-year-old man. The clinical, biologic, and EMG aspects were similar to those already reported, but a lymphoplasmocytic infiltrate in the nerve connective tissue of this patient has only rarely been observed in benign IgM gammopathy. The paraprotein was not evident in the serum until 5 years after symptoms of the neuropathy started.

Two cases of Addison's disease associated with myasthenia gravis are reported. This association has been described only rarely in the literature. In the first case, there were marked immunological abnormalities. It is most likely that the origin of the adrenocortical insufficiency in the second case is tuberculous. The pathogenetic mechanism of these associations is briefly discussed.

TO THE EDITOR. —We read with interest the article by Oh and Danon (Archives 1983;40:147-150). We also think that uniform type 1 fiber typing is an extreme form of type 1 predominance. Brooke1 considers that type 1 fiber predominance can be implicated when these fibers make up more than 60% of the fibers in the biopsy sample. Moreover, it seems that some of these cases are familial.We examined two brothers and a sister, all less than 11 years old, who had the following features in common: delayed motor developmental milestones, mild proximal muscle weakness, hyporeflexia, normal serum muscle enzyme levels, substantial reduction in mean duration of motor unit potentials, and nonprogression of the disease. Deltoid muscle biopsy specimens showed only a clear predominance of type 1 fibers (78%, 74%, and 67% ). The distribution of type 1 fibers was thus nonuniform, although no other morphologic abnormalities were detected under