Nerve Biopsy Studies Research Articles

Subtle Changes in Cutaneous Nerves and Sural Nerve Biopsy in a Patient With Fabry's Disease

We report the clinical manifestations, and sural nerve and skin biopsy findings in a patient with Fabry's disease who had normal renal function. The patient had a typically painful neuropathy with an increase of sensory thresholds in quantitative sensory tests and a low level of serum alpha-galactosidase. Although the sural nerve biopsy revealed electron-dense bodies in the perineurial cells, normal axon and myelin structures and even the fiber density of large and small myelinated fibers were noted. However, the cutaneous nerve biopsy study showed early changes in the small-fiber neuropathy. The data indicate that a cutaneous nerve biopsy study can be an adjuvant diagnostic tool in some patients with Fabry's disease and a normal renal function.

Formes autosomales récessives de la maladie de Charcot-Marie-Tooth

In some countries with a high prevalence of consanguineous mariage, autosomal recessive inheritance probably accounts for the vast majority of all forms of CMT. Like dominant forms, autosomal recessive forms are generally subdivided into demyelinating forms (autosomal recessive CMT1: AR-CMT1 or CMT4) and axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has identified several novel CMT-related genes (GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin and lamin). Given the clinical, electrophysiological and histological heterogeneity of this disease, numerous culprit genes probably remain to be discovered, leading to an even more complex classification. Clinical and histological features often point to the involvement of a particular gene. Nerve biopsy and molecular studies can contribute to the diagnosis, but this approach is highly time-consuming and can only be performed in specialized laboratories.

0353 The sural nerve biopsy and nerve conduction study in polyneuropathy: The 3-year retrospective, clinical, electrophysiological, and neuro-pathological study

0353 The sural nerve biopsy and nerve conduction study in polyneuropathy: The 3-year retrospective, clinical, electrophysiological, and neuro-pathological study

Peripheral Nerve Biopsy Study in 19 Cases with 17p11.2 Deletion

In most cases of hereditary neuropathy with liability to pressure palsy (HNPP) the diagnosis is now assessed by molecular detection of 17p11.2 deletion. However, the family history may be missing and the clinical presentation is not always informative. In such cases, a peripheral nerve biopsy showing the characteristic focal myelin sheath thickening ("tomaculae") may be helpful. We present a retrospective study of peripheral nerve biopsies performed in 19 patients suffering from either a mononeuropathy or a generalized sensory-motor polyneuropathy, and for whom the finding of tomaculae led to a search for 17p11.2 deletion, which was confirmed secondarily. Tomaculae and other coexisting neuropathological lesions such as uncompacted myelin, "onion bulb" formations, and axonal degeneration are described and discussed in the view of previously reported data. It appears that demyelinating lesions with tomaculae are strongly suggestive of HNPP but are not specific as they may be observed in other conditions. Moreover, these features may be overlooked if axonal degeneration is marked.

Intérêt de la biopsie nerveuse pour le diagnostic des formes atypiques de polyradiculonévrite inflammatoire démyélinisante chronique : 8 cas

The objective of the study was to define how could be helpful a nerve biopsy for identification of atypical cases of chronic inflammatory demyelinating polyneuropathy (CIDP). An ad hoc committee in 1991 defined the clinical, electrophysiological and pathological criteria for diagnosis of CIDP. In common with other authors, we regard the rather specific electrophysiological criteria as being too restrictive, and we think that a significant number of patients may therefore not benefit from effective treatment or be excluded from therapeutic trials. The Inflammatory Neuropathy Cause and Treatment (INCAT) group (2001) has proposed new electrophysiological criteria of CIDP, which are more sensitive and do not loose any specificity. Over a period of three years (January 1999 to December 2001), we classified 44 patients into two categories: those presenting the strict criteria of the ad hoc committee and those who we regarded as cases of CIDP who did not meet these strict criteria. All these patients benefited from one or more clinical and electrophysiological examinations; extensive biological workup and genetic study when appropriate excluded other causes of neuropathy. Nerve biopsies were taken from all patients and samples were included in paraffin and epon for systematic light and electron microscopic examination. Out of 44 patients, 24 fulfilled the INCAT electrophysiological criteria with only 12 of these cases fulfilling the criteria of the ad hoc committee. Eight patients did not fulfill any of the widely accepted electrophysiological criteria of CIDP. However, study of nerve biopsies of these eight patients revealed histological features characteristic of CIDP according to histological criteria (AAN-1991). Among these patients, six have been treated and five responded favorably to conventional treatments for CIDP. Without information from the nerve biopsy, these patients would not have been treated effectively because their electrophysiological profile was indicative of axonal impairment interpreted erroneously as primary.

Measurement of somatic neuropathy for clinical practice and clinical trials.

Distal sensory polyneuropathy is a common and unpleasant complication of diabetes mellitus. It is the main initiating factor for foot ulceration. The increasing prevalence of diabetes has important associated health implications, both in terms of morbidity and mortality, and results in the consumption of scarce medical resources. Identification of somatic neuropathy in clinical practice is therefore important for targeted educational and other interventions. In this article, we describe methods for detecting somatic neuropathy in clinical practice and highlight those tests that are proven to be predictors of foot ulceration. The approach for detecting and characterizing somatic neuropathy for clinical trials, however, differs significantly. These methods must ideally have high levels of reproducibility, sensitivity, and specificity. Currently, several neurophysiologic tests are employed in clinical trials in order to accurately characterize diabetic neuropathy. The recent introduction of the computer-assisted programs for the measurement of sensory modalities for clinical trials has been a major advance. Due to their invasive nature and associated morbidity, nerve biopsy studies are no longer used in clinical trials. Recently, using magnetic resonance imaging (MRI), significant spinal cord atrophy has been demonstrated in established neuropathy. If this observation proves to be an early feature, then a relatively rapid, noninvasive MRI technique may be used in the future to characterize diabetic neuropathy.

Life-threatening orthostatic hypotension in a case with bulbo-myelo-radiculo-neuropathy

A 59-year-old female developed acute autonomic failure accompanied by life-threatening orthostatic hypotension. Reduced plasma noradrenaline levels and enhanced pressure response to noradrenaline infusion were compatible with a diagnosis of acute pan-dysautonomia. However, nerve conduction tests clearly revealed motor and sensory nerve involvement and abnormal F-responses. A sural nerve biopsy and catecholamine fluorescence study of the rectal mucosa revealed relatively preserved postganglionic unmyelinated nerve fibers. Six weeks later, the patient developed another episode of bulbar palsy and right hemiparesis; the MRI showed lesions in the medulla oblongata and right cervical spinal cord. The prognosis of acute pan-dysautonomia is usually unsatisfactory, but the present patient showed good steroid-responsiveness probably because impaired preganglionic sympathetic myelinated fibers and medulla oblongata recovered quickly.

¿Puede la biopsia de nervio sural orientar el tratamiento en la polineuropatía desmielinizante crónica inflamatoria?

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired neuropathy characterized by demyelination of the peripheral nerves and roots. The course of the illness is progressively chronic or of relapses and remissions. Biopsy of the sural nerve is not essential for diagnosis. It is therefore not necessary to carry it out on all occasions, but probably permits a more rational approach to treatment. To show whether biopsy of the sural nerve is useful for orientation of the treatment required in cases of CIDP. We studied a total of 16 patients admitted to hospital with a diagnosis of CIDP. They had neurophysiological studies, sural nerve biopsy and other studies to rule out other diagnoses. The patients were assigned to the therapeutic protocols recommended. During 8 years of follow up we compared the response to treatment with intacglobin/plamapheresis, steroids and cytostatic drugs. It was highly significant (p< 0.001) that the patients with axon lesions on sural nerve biopsy did not respond to treatment with intac globin/plasmapheresis or steroids but did respond to cyclophosphamide, without any serious adverse effects being seen. Axonal histopathological lesions of CIDP at the onset of the disease may require cytostatic treatment since they do not usually improve on standard treatment. Sural biopsy is usually invaluable in such cases.

Prospective study of the usefulness of sural nerve biopsy

OBJECTIVEThis study aimed to determine the usefulness of sural nerve biopsy in neurological practice.METHODSThe first prospective study of sural nerve biopsy in 50 consecutive patients was undertaken. The investigating neurologist...

Chronic inflammatory demyelinating polyneuropathy associated with dysglobulinemia: a peripheral nerve biopsy study in 18 cases.

The possible occurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) in association with an identified dysglobulinemic status is recognized and a causal relationship between the two has been suggested. We had the opportunity to study 18 patients presenting with CIDP and dysglobulinemia. This was an IgG monoclonal gammopathy (IgG MG) in 8 cases, an IgM monoclonal gammopathy (IgM MG) in 8, an IgG-IgM biclonal gammopathy in 1 case and an IgM monoclonal cryoglobulinemia in another. A peripheral nerve biopsy specimen was available for all patients and the morphological findings in these specimens in the cases of CIDP with IgG MG or cryoglobulin did not differ from those without, whereas characteristic features were observed in the cases of CIDP with IgM MG and anti-myelin associated glycoprotein activity.

Peroneal neuropathy after weight loss.

The objectives of this study were to evaluate the clinical and electrophysiological findings in peroneal mononeuropathies following a weight-reduction diet. Thirty patients with acute peroneal palsy and weight loss were studied. Complete nerve conduction studies (NCS) were performed in upper and lower limbs. NCS showed conduction block (CB) of the peroneal nerve at the fibular head that recovered in 29 patients within 3 weeks to 3 months. Severity of CB was correlated with clinical weakness. Three patients had abnormalities consistent with polyneuropathy (PNP). NCS in asymptomatic relatives confirmed familial neuropathy. Nerve biopsy and molecular study were consistent with hereditary neuropathy with liability to pressure palsies (HNPP). One of these peroneal palsies (6 months) recovered after neurolysis. Weight loss might be a risk factor in peroneal mononeuropathies. NCS is a tool in the diagnosis of the site and severity of the nerve injury. Testing should be considered for relatives of patients with PNP because peroneal mononeuropathies may be the first expression of HNPP.

Acute axonal form of Guillain–Barré syndrome in a multiple sclerosis patient: chance association or linked disorders?

Multiple sclerosis (MS) is characterized by inflammation, demyelination and gliosis, involving the central nervous system (CNS) and commonly sparing the peripheral nervous system (PNS). Coexistence of CNS and PNS chronic demyelination has been rarely demonstrated in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) and in MS, but the occurrence of acute polyradiculoneuropathy in a patient with MS is even more unusual. We describe the case of a woman with relapsing-remitting MS who presented with an acute severe tetraparesis. Cerebrospinal fluid (CSF) examination together with neurophysiological data and sural nerve biopsy study demonstrated an axonal form of Guillain-Barré Syndrome (GBS). It remains unresolved if the association of an axonal form of GBS and MS is fortuitous or, on the contrary, is indicative of the coexistence in some individuals of common pathogenetic mechanisms.

Chronic Inflammatory Demyelinating Polyneuropathy: Immunopathological and Ultrastructural Study of Peripheral Nerve Biopsy in 42 Cases

The authors recently reexamined the peripheral nerve biopsies from 42 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). There were 27 males and 15 females, aged from 9 to 84 years, and 13 had relapses. No patient had vasculitis, monoclonal gammopathy, tumor, diabetes mellitus, Lyme disease, familial neuropathy, HIV, or any other immune deficiency. In the endoneurium, perivascular inflammatory cell infiltrates were present in only one case, but scattered histiocytes marked by KP1 on paraffin-embedded fragments were present in every case and there were no T-lymphocytes. At ultrastructural examination macrophage-associated demyelination was observed in 17 cases, of which 6 had relapses separated by intervals of several months or years. Axonal lesions without associated primary demyelination were observed in 4 cases and 3 of these had relapses. Thirty-two patients had mixed lesions of demyelination and axonal involvement. This study confirms other recent data indicating that in all cases of CIDP, macrophages are present in the endoneurium. Macrophage-associated demyelination is the characteristic feature of demyelinating forms. On the other hand, isolated primary axonal forms, which have been known since 1989, are relatively frequent and prone to relapses.

Progressive spinal muscular atrophies.

Spinal muscular atrophy is the most common autosomal-recessive genetic disorder lethal to infants. It was first described in the 1890s. Since then our understanding of the disorder has progressed significantly. Progression of the disease is due to loss of anterior horn cells, thought to be caused by apoptosis. Diagnosis is based on the course of the illness, as well as certain changes seen on nerve and muscle biopsy and electrodiagnostic studies. More recently, our understanding of the genetics of this disorder has provided a noninvasive approach to diagnosis. This method of testing has its downside, but the quest for a more sensitive analysis is still underway. Even though our knowledge of this disease has come a long way since its first recognition, the therapies available to these children are still only supportive. Again, researchers eagerly look for new therapeutic interventions to allow for improved quality of life and an extended life span.

Electrophysiological and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency

The authors report a comparative study of peripheral nerve conductions and nerve biopsy and somatosensory evoked potentials between 15 patients with Friedreich's ataxia and 15 patients with Friedreich's ataxia phenotype with selective vitamin E deficiency. The patients in the two groups are of similar age, age of onset, and clinical phenotype. Peripheral motor nerve action potential amplitude, and conduction velocities are within normal ranges in the two groups. In the Friedreich's ataxia group there is an early and severe peripheral sensory axonal neuronopathy, characterised by an important reduction of the amplitude of sensory action potential, and important loss of myelinated fibres with complete disappearance of large myelinated fibres without any regenerative process. In the Friedreich's ataxia phenotype with selective vitamin E deficiency group there is slight-to-moderate axonal sensory neuropathy with normal to moderate decrease of large myelinated fibre density and important regeneration in nerve biopsy. Somatosensory evoked potentials are markedly involved in the two groups asserting a severe involvement of somatosensory pathway in lumbar, thoracic and cervical spinal cord. These findings suggest that the pathological mechanism involved in the two diseases are different: central peripheral axonopathy in Friedreich's ataxia and central distal axonopathy in Friedreich's ataxia phenotype with selective vitamin E deficiency.

Fate of Schwann cells in CMT1A and HNPP: evidence for apoptosis.

The fate of Schwann cells in Charcot-Marie-Tooth (CMT) neuropathies was addressed in this study of nerve biopsies from patients with proven PMP22 duplications and deletions. In frozen sections, apoptotic nuclei were detected using the TUNEL method. In adjacent sections, anti-neurofilament 68kD antibody was used as an axonal marker, while the antibodies to NKH-1 and low-affinity nerve growth factor receptor P75NTR were used as Schwann cell markers. In addition, plastic sections were used to determine the densities of myelinated fibers and Schwann cell nuclei. In all biopsies from CMT1A, TUNEL-positive nuclei appeared in clusters. In adjacent sections, areas of TUNEL-positive nuclei matched with areas devoid of neurofilaments and NKH-1-positive Schwann cell silhouettes, suggesting that the apoptotic nuclei belonged to nonmyelinating Schwann cells. In addition, quantitative studies on plastic-embedded sections showed a significantly reduced number of total Schwann cells compared with controls, strongly favoring a loss of Schwann cell by apoptosis. In HNPP, the number of total Schwann cells was increased and a significant Schwann cell apoptosis was observed in only 2 patients. Examination of plastic sections and teased nerve preparations from these cases suggested that the Schwann cell apoptosis might be related to the regenerative state of the nerve resulting from the process of sprout pruning. No strict correlation between p75NTR expression and apoptosis was found. These studies indicate that factors regulating Schwann cell number in early postnatal development continue to be important for Schwann cell survival throughout life.

Clinicopathological features of chronic inflammatory demyelinating polyradiculoneuropathy in childhood

The clinical, electrophysiological, and pathological findings, and the therapeutic characteristics in ten children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), whose onset age was less than 16 years, were evaluated. The clinical progression pattern of the initial phase divided the patients into two groups. One group (six patients) showed a subacute progression for up to 2 months after onset and a subsided progression over 3 months. Three patients in this group had a preceding febrile episode. The other group (four patients) showed a chronic insidious progression for more than 3 months. The former group of patients revealed a favourable response to corticosteroid therapy as compared with the latter group. However, other clinical and laboratory features at the peak impairment were not distinguishable between these two groups. Motor dominant neuropathy was common to all patients, and only three cases showed sensory disturbance on the distal limbs. No cases revealed cranial nerve involvement. Motor and sensory nerve conduction and sural nerve biopsy studies revealed the demyelinating nature of the neuropathy. These clinicopathological features suggest that the subacute progression form frequently associated with prodromal episode and rather favourable corticosteroid response is characteristic in childhood CIDP, while the chronic insidious progression form is indistinguishable from the common adult CIDP.

A case-control and nerve biopsy study of CREST multiple mononeuropathy.

From 536 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis), seven were identified as having peripheral neuropathy not attributable to another cause. Peripheral neuropathy developed 0 to 25 years after their first symptoms of scleroderma. Unexplained neuropathy in CREST patients (seven patients) was more frequent than in control subjects (two patients) matched for age, sex, time of evaluation, and geographic referral region. Multiple mononeuropathy occurred significantly more frequently in the CREST group (six patients) than in the control group (0 patients). Four sural nerve biopsy specimens from the CREST patients demonstrated multifocal fiber loss and perivascular inflammation; one was diagnostic for necrotizing vasculitis and two others were highly suggestive for necrotizing vasculitis. The density of myelinated fibers in three nerves from CREST patients was significantly decreased, whereas the index of dispersion (a measure of multifocal fiber loss) was increased, and the frequency of axonal degeneration was significantly increased. Based on these clinical and pathologic findings, we conclude that in the CREST syndrome multiple mononeuropathy, although occurring infrequently, occurs more frequently than by chance and necrotizing vasculitis is the cause of this multiple mononeuropathy.

Hereditary demyelinating neuropathy of infancy: a genetically complex syndrome

We read with interest the recent paper by Tyson et al. (1997). They report on nine patients with infantile hereditary demyelinating peripheral neuropathy. In two of them, nerve biopsy study revealed histological abnormalities characteristic of hereditary neuropathies with focally folded myelin sheaths (Ohnishi et al., 1989). The clinical picture they observed in these two individuals was extremely severe with involvement of both proximal and distal muscles of lower and upper limbs. The oldest patient aged 16 years was seriously handicapped and wheelchair-bound. Since both the patients’ parents were consanguineous, an autosomal recessive inheritance was presumed. The molecular study failed to demonstrate any of the mutations recently reported in hereditary demyelinating neuropathy (Raeymaekers et al., 1992; Nelis et al., 1994), namely duplication in chromosome 17p11.2–12, point mutations in the four exons of the PMP-22 and the six exons of the P0 myelin genes. Therefore, Tyson et al. (1997) argued that a mutation at another still unknown locus or loci seems possible. The observation of Tyson et al. (1997) further confirms that hereditary neuropathy with focally folded myelin sheaths, also called Charcot–Marie–Tooth (CMT) type 4B (CMT4B) (Thomas, 1994), represents a quite common disorder within the heterogeneous group of autosomal recessive demyelinating neuropathy of infancy. Of note, clinical and neuropathological findings of these two patients reported by Tyson et al. (1997) were strikingly similar to those of a large inbred pedigree with 10 patients reported by our group (Quattrone et al., 1996), as well as to most familial cases reported in the literature (for review, see Quattrone et al., 1996). Based on these findings, therefore, it seems that familial cases with CMT4B display a rather homogeneous clinical picture, characterized by infantile onset with progressive symmetrical distal and proximal muscular weakness, starting at the lower extremities and eventually involving the hands and forearms. A striking feature of all these familial cases is the non-random nature of age at onset, with the majority clustering around 2 years of age. Despite these phenotypic similarities, however, recent molecular studies have demonstrated that there are several

Motor nerve biopsy studies in motor neuropathy and motor neuron disease

Motor nerve biopsy studies in motor neuropathy and motor neuron disease