Emerging technologies in neuromuscular ultrasound

Neuromuscular ultrasound is an accepted and valuable element in the evaluation of peripheral nerve and muscle disease. However, ultrasound has several limitations to consider, including operator dependency and lack of a viable contrast agent. Fortunately, new technological advances show promise in resolving these issues. Ultra-high resolution ultrasound enables imaging of the nerve at the fascicular level. Shear wave elastography imaging can provide measures of tissue stiffness that can act as a surrogate measure of nerve and muscle health. Photoacoustic imaging may overcome neuromuscular ultrasound's current lack of contrast agents to detect inflammation and other functional changes within nerve and muscle, while artificial intelligence stands to address operator dependency and improve diagnostic imaging. The basic principles of each of these technologies are discussed along with current research and potential future applications in neuromuscular imaging.     

Nerve biopsy: requirements for diagnosis and clinical value

In many instances, nerve biopsy is not necessary in the diagnostic work-up of a peripheral neuropathy. However, histological examination of a tissue sample is still mandatory to show specific lesions in various conditions involving peripheral nerves. As there are fewer laboratories that examine human nerve samples, practitioners including neurologists and general pathologists may not be completely aware of the technical issues and data that are provided by nerve biopsy. Nerve biopsy is considered an invasive diagnostic method, although, its complications are by far less disabling than most of the disorders that lead to its indications. Nevertheless, the decision to perform a nerve biopsy has to be made on a case-by-case basis, and its results must be discussed between the pathologist and the clinician who is in charge of the patient’s care. In this paper, we review the minimal technical requirements for proper peripheral nerve tissue analysis. Moreover, we provide data on the usefulness of nerve biopsy in various situations including abnormal deposits, cell infiltrates, link between peripheral neuropathy and monoclonal gammopathy, and numerous hereditary disorders.     

Usefulness of sural nerve biopsy in the genomic era

The value of peripheral nerve biopsy is now sometimes questioned due to the high complication rate and the recent development of noninvasive molecular techniques for diagnosis of hereditary neuropathy. However, the disorders that can be diagnosed by genetic analysis are limited and sural nerve biopsy is still a powerful tool for making a correct diagnosis of peripheral neuropathy. Histological evaluation of the sural nerve has long focused on changes of the two major components of peripheral nerves, axons and myelin, as well as on the detection of diagnostic changes such as amyloid deposits, sarcoid tubercles, and vasculitis. In addition to these components, the sural nerve biopsy specimen contains various important cells, including perineurial cells, mast cells, endothelial cells, pericytes, and lymphocytes. Among these cells, the endothelial cells and pericytes form the blood‐nerve barrier (BNB) and investigation of these cells can reveal important information, especially in inflammatory neuropathies. To better understand the biological basis of BNB, we established rat and human immortal cell lines from the endothelial cells and pericytes of endoneurial microvessels. Characterization of these cell lines is now underway at our laboratory. These BNB cell lines should provide useful information concerning the pathophysiology of peripheral neuropathy, and we should obtain a new perspective for the investigation of nerve biopsy specimens after understanding the molecular background of the BNB.     

Usefulness of Ultrasound for Detecting Suspected Peripheral Nerve Lesions in Diagnosis of Peripheral Neuropathy : Case Report and Brief Review of the Literature

Ultrasound scanning of a peripheral nerve along its expected course is a simple and useful method for determining the cause of peripheral neuropathy. We present 3 cases of peripheral neuropathy in which the pathology was detected by simple ultrasound scanning of the affected nerve. There were 2 cases of entrapment neuropathy due to mucoid cyst and 1 case of nerve sheath tumor. All lesions were visualized by simple ultrasound scanning of the involved peripheral nerve. Our results suggest that if a lesion affecting the peripheral nerve is suspected after history and physical examination or electrophysiologic studies, ultrasound scanning of the peripheral nerve of interest throughout its course is very helpful for identifying the causative lesion.     

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy – a review of the literature

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot–Marie–Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo‐echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.     

Invited review: peripheral neuropathy in Sjogren's syndrome

Our experience and review of the literature reveal that Sjogren's syndrome (SS) is an important, poorly recognized cause of peripheral neuropathy. Several forms of peripheral nerve dysfunction occur in SS including trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensory neuropathy, distal sensorimotor peripheral neuropathy and a pure sensory neuronopathy syndrome. Rarely, chronic relapsing inflammatory polyneuropathy and multiple cranial neuropathies appear. Clinical evidence of glandular involvement is often minimal or absent when patients with SS develop peripheral neuropathy; and the diagnosis of the underlying condition is elusive. We review clinical and laboratory features of this disorder and suggest appropriate evaluation of patients with neuropathy and suspected SS.     

Peripheral neuropathy of mitochondrial myopathies.

Peripheral neuropathy has attracted relatively little attention in mitochondrial myopathy. However, mitochondrial myopathies are clinically heterogeneous disorders that can affect multiple systems including peripheral nerves other than the skeletal muscle. In addition to the survey of the literature, we studied 6 cases of mitochondrial myopathy with peripheral neuropathy; 3 cases of oligo-systemic involvement confined mainly to skeletal muscles and peripheral nerves, and 3 cases of multi-systemic involvement diagnosed as myoclonus epilepsy with ragged-red fibers (MERRF) or mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). This study suggests that peripheral neuropathy may be relatively common and has similar clinical and laboratory features in a broad spectrum of mitochondrial myopathies. The clinical manifestation is usually of mild sensorimotor neuropathy with frequent subclinical involvement. Sensory disturbances are more evident than manifestations of motor neuropathy which is usually subclinical. It is also noteworthy that there exist some cases of oligo-systemic involvement, which present with peripheral neuropathy as main clinical manifestations. Electrophysiological findings include decreased nerve conduction velocities and neuropathic electromyograms. Peripheral nerves show loss of myelinated fibers, particularly of large ones, and the remaining fibers have disproportionately thin myelin sheaths with or without onion-bulb formation. Thus the pathological process is axonal degeneration with demyelination resulting from involvement of both neurons (axons) and Schwann cells.     

Peripheral neuropathy in the spontaneously diabetic WBN/Kob rat

We report that the morphological characteristics of the periperhal neuropathy in WBN/Kob rat, a diabetic animal model that develops persistent diabetes, were primary segmental demyelination and secondary axonal degeneration. These findings are similar to those in human patients with diabetes mellitus and unlike those in rodents with streptozotosin-induced diabetes. However, these changes were also indistinguishable from those of age-dependent neuropathy. In the spontaneous peripheral motor neuropathy of rats, pressure neuropathy from housing in wire-mesh cages has also been reported to be indistinguishable from the peripheral neuropathy in plantar nerve or tibial nerve. Therefore, we examined phrenic nerves that were free from the pressure of body weight in rats and described the changes with light and electron microscopy. The morphological changes of the nerve fibers consisted of myelin blebbing or distention, and early remyelination. The changes were seen with age. On morphometric analysis, a marked reduction of fiber occupancy was observed in WBN/Kob rats over 23 months old. The present study demonstrated that the peripheral neuropathy of WBN/Kob rats is myelinopathy. Since the phrenic nerve was not affected by pressure neuropathy anatomically, this study indicates that the peripheral neuropathy of WBN/Kob rats is not pressure neuropathy. Received: 15 January 1996 / Revised, accepted: 13 June 1996     

Lymphoma and peripheral neuropathy: a clinical review

Lymphoma occasionally affects the peripheral nervous system. When it does, the diagnosis can be elusive since many patients present without known lymphoma. Most peripheral nerve complications are due to non-Hodgkin's lymphoma (NHL), which infiltrates nerves causing axonal damage. This disorder can affect nerve roots and cranial nerves, often associated with lymphomatous meningitis. NHL may also infiltrate peripheral nerves and cause plexopathy, mononeuropathy, or generalized neuropathy. These neuropathies may resemble an asymmetric mononeuropathy multiplex or a generalized disorder such as chronic inflammatory demyelinating polyradiculoneuropathy. When NHL infiltrates diffusely, the term neurolymphomatosis is used. Hodgkin's lymphoma (HL), by contrast, rarely infiltrates nerves. More often, HL causes immunological disorders of the peripheral nervous system such as inflammatory plexopathy or Guillain-Barré syndrome. Other rare lymphomas such as intravascular lymphoma and Waldenstrom's macroglobulinemia can also affect peripheral nerves in specific ways. In addition, other malignant and nonmalignant lymphoproliferative disorders enter into the differential diagnosis of lymphomatous neuropathy. This review discusses the multiple peripheral nerve presentations of lymphoma from the clinician's point of view and provides a guide to the evaluation and diagnosis of these uncommon, challenging disorders.     

Electrodiagnosis of peripheral neuropathy

Electrodiagnostic studies are an important component of the evaluation of patients with suspected peripheral nerve disorders. The pattern of findings and the features that are seen on the motor and sensory nerve conduction studies and needle electromyography can help to identify the type of neuropathy, define the underlying pathophysiology (axonal or demyelinating), and ultimately help to narrow the list of possible causes. This article reviews the electrodiagnostic approach to and interpretation of findings in patients with peripheral neuropathies.     

High-resolution sonography of the peripheral nervous system – a review of the literature

High-resolution sonography is capable of depicting peripheral nerves and the brachial plexus. In this study we review the literature on this subject. Normal peripheral nerves have a characteristic echotexture. Most nerves are readily visualized, although this is not always the case with the nerves of the lower extremity. The main pathological changes that can be demonstrated are nerve enlargement and increased hypoechogenicity. In order to demonstrate nerve enlargement, measurements should be performed and compared with a set of reference values. Several neuropathies have been studied by means of ultrasonography. However, many studies concern case reports and show methodological shortcomings. The best studied peripheral neuropathy is the carpal tunnel syndrome in which ultrasonography seems to have an additional value when combined with nerve conduction studies. Nerve enlargement has also been demonstrated in radial neuropathy at the humerus and in ulnar neuropathy at the elbow. The role of sonography in various hereditary and inflammatory neuropathies is uncertain although diffuse nerve thickening could be demonstrated. Further systematic studies are needed to determine the role of sonography in the diagnostic process of the various neuropathies. It would be important to study the subcategories of patients in whom electrodiagnostic studies are normal or show equivocal findings.     

Neuromuscular complications of connective tissue diseases

The connective tissue diseases, such as rheumatoid arthritis, Sj?gren's syndrome, systemic lupus erythematosus, systemic sclerosis, and vasculitis, may cause various disorders of the peripheral nervous system. In this review, the clinical effects of the connective tissues diseases on nerve and muscle are examined with particular attention to mononeuritis multiplex, distal symmetric neuropathy, fulminant motor neuropathy, compression neuropathy, sensory neuronopathy, and trigeminal sensory neuropathy.     

Peripheral neuropathy in genetic mitochondrial diseases

Peripheral neuropathy is an underrecognized but common occurrence in genetic mitochondrial disorders. To gain insight into the frequency and clinical presentation of this complication, nerve conduction studies were performed on 43 subjects with congenital lactic acidosis enrolled in a controlled clinical trial of oral dichloroacetate. Median and peroneal motor conduction studies and median and sural sensory conduction studies were performed on each patient. The mean amplitude of the peroneal motor nerve (P < 0.001) and the conduction velocities of the median (P < 0.001) and peroneal (P < 0.001) motor nerves were uniformly lower in our subjects than in healthy literature control subjects. There were no significant differences in sensory nerve conduction studies. A generalized reduction in motor nerve conduction velocity was the dominant electrophysiological abnormality in the patients in this study and was independent of age, sex, or congenital mitochondrial disorder. We postulate that cellular energy failure is the most likely common cause of peripheral neuropathy in patients with genetic mitochondrial diseases, owing to the high demand for adenosine triphosphate via aerobic carbohydrate metabolism by nerve tissue.     

Magnetic resonance imaging of the peripheral nervous system

The diagnostic work up of patients with peripheral neuropathy largely depends on clinical and electrophysiological investigations. In contrast to disorders of the CNS, magnetic resonance imaging (MRI) has not been widely used as a diagnostic tool in the PNS except for detection of nerve compressing mass lesions. Normal nerves appear isointense to the surrounding tissue on T1- and T2-weighted (w) MRIs, but upon injury the nerves become hyperintense and thus visible on T2-w MRI. These signal alterations can be exploited to diagnose nerve damage in vivo and to follow regeneration. In patients with peripheral nerve disorders, MRI has been especially useful in detecting focal intrinsic and extrinsic nerve lesions and may reveal treatable conditions even in the absence of gross electrophysiological alterations. This clinical review provides practical guidelines on the performance of nerve imaging by MRI and will focus on focal lesions exemplified by case presentations.     

Peripheral neuropathies associated with chronic renal failure

A variety of peripheral nerve disorders may be associated with chronic renal failure. The polyneuropathy due to uremic toxins is a distal, motor and sensory polyneuropathy in which there is segmental demyelination, axonal degeneration, and segmental remyelination. The nature of the uremic toxin and the underly mechanism of these changes is unknown. The incidence in patients with "end-stage" renal disease has fallen in recent years, severe cases now being rare, perhaps due to refinements in chronic hemodialysis, transplantation, and other therapies. However, while chronic hemodialysis stabilizes uremic neuropathy, manipulation of hemodialysis schedules may not alter its course, according to current assessment. Successful renal transplantation improves both the clinical and electrophysiological signs, even in severe uremic neuropathy.     

Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice

The small heat shock protein HSPB1 is a multifunctional, α-crystallin-based protein that has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. Missense mutations in HSPB1 result in axonal Charcot-Marie-Tooth disease with minimal sensory involvement (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN-II). These disorders are characterized by a selective loss of motor axons in peripheral nerve resulting in distal muscle weakness and often severe disability. To investigate the pathogenic mechanisms of HSPB1 mutations in motor neurons in vivo, we have developed and characterized transgenic PrP-HSPB1 and PrP-HSPB1(R136W) mice. These mice express the human HSPB1 protein throughout the nervous system including in axons of peripheral nerve. Although both mouse strains lacked obvious motor deficits, the PrP-HSPB1(R136W) mice developed an age-dependent motor axonopathy. Mutant mice showed axonal pathology in spinal cord and peripheral nerve with evidence of impaired neurofilament cytoskeleton, associated with organelle accumulation. Accompanying these findings, increases in the number of Schmidt-Lanterman incisures, as evidence of impaired axon-Schwann cell interactions, were present. These observations suggest that overexpression of HSPB1(R136W) in neurons is sufficient to cause pathological and electrophysiological changes in mice that are seen in patients with hereditary motor neuropathy.     

Hereditary and acquired polyneuropathies. Electrophysiologic aspects

The electrophysiologic evaluation of patients with polyneuropathy may, in an increasing number of disorders, provide data that are critical to both diagnosis and treatment, especially in acquired demyelinating neuropathies. In general, the data will permit the presence or absence of neuropathy to be determined, and provide information concerning etiology, severity, pathology, and prognosis of peripheral nerve disease.     

Ultrasonography of MADSAM neuropathy: focal nerve enlargements at sites of existing and resolved conduction blocks

Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies.     

Morphological features of nerves in skin biopsies

Skin biopsy is an effective test for diagnosis of peripheral nerve disorders. The most commonly reported indication of abnormality in a skin biopsy is reduction of epidermal nerve density. Morphological changes of epidermal nerves and the underlying subepidermal nerve plexus provide added evidence for the presence of neuropathy. We determined the prevalence of epidermal axon swellings, dermal axon swellings, and a unique type of epidermal nerve that we call a crawler, in a group of normal subjects, diabetic subjects, and patients with idiopathic small fiber neuropathy. Other morphologic features examined include thinning of the subepidermal nerve plexus, sprouts at nerve terminals, encapsulated endings, and immunoreactive basal cells.