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Competence in muscle biopsy evaluation is a core component of neuropathology practice. The practicing neuropathologist should be able to prepare frozen sections of muscle biopsies with minimal artifacts and identify key histopathologic features of neuromuscular disease in hematoxylin and eosin-stained sections as well as implement and interpret a basic panel of additional histochemical, enzyme histochemical, and immunohistochemical stains. Important to everyday practice is a working knowledge of normal muscle histology at different ages, muscle motor units, pitfalls of myotendinous junctions, nonpathologic variations encountered at traditional and nontraditional muscle sites, the pathophysiology of myonecrosis and regeneration, and approaches to distinguish muscular dystrophies from inflammatory myopathies and other necrotizing myopathies. Here, we provide a brief overview of what every neuropathologist needs to know concerning the muscle biopsy.

Spinal muscular atrophy (SMA) encompasses a group of disorders with loss of spinal motor neurons.The report describes the neuropathological findings including brain and spinal cord at autopsy in a five-and-half-month-old boy with suspected type 1 SMA. The anterior motor neurons, Clarke's column at all the levels of spinal cord showed neuronal loss and degeneration while neurons at all the deep grey nuclei were preserved apart from variable degree anoxic changes. Skeletal muscle biopsy revealed features of neurogenic atrophy consistent with SMA. A differential diagnosis like storage disorders was excluded using electron microscopy. No extra-neural manifestations were seen. Neuropathological features at autopsy have seldom been reported in the literature.

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.

Introduction: Botulinum toxin A (BoNTA) is routine treatment for hypertonicity in children with cerebral palsy (CP). Methods: This single-blind, prospective, cross-sectional study of 10 participants (mean age 11 years 7 months) was done to determine the relationship between muscle histopathology and BoNTA in treated medial gastrocnemius muscle of children with CP. Open muscle biopsies were taken from medial gastrocnemius muscle and vastus lateralis (control) during orthopedic surgery. Results: Neurogenic atrophy in the medial gastrocnemius was seen in 6 participants between 4 months and 3 years post-BoNTA. Type 1 fiber loss with type 2 fiber predominance was significantly related to the number of BoNTA injections (r = 0.89, P < 0.001). Conclusions: The impact of these changes in muscle morphology on muscle function in CP is not clear. It is important to consider rotating muscle selection or injection sites within the muscle or allowing longer time between injections. Muscle Nerve 53: 407–414, 2016

Introduction We injected embryonic stem cells into mouse tibialis anterior muscles subjected to botulinum toxin injections as a model for reversible neurogenic atrophy. Methods Muscles were exposed to botulinum toxin for 4 weeks and allowed to recover for up to 6 weeks. At the onset of recovery, a single muscle injection of embryonic stem cells was administered. The myofiber cross-sectional area, single twitch force, peak tetanic force, time-to-peak force, and half-relaxation time were determined. Results Although the stem cell injection did not affect the myofiber cross-sectional area gain in recovering muscles, most functional parameters improved significantly compared with those of recovering muscles that did not receive the stem cell injection. Conclusions Muscle function recovery was accelerated by embryonic stem cell delivery in this durable neurogenic atrophy model. We conclude that stem cells should be considered a potential therapeutic tool for recovery after extreme skeletal muscle atrophy. Muscle Nerve 51: 346–352, 2015

Back pain is recognized as a common and often recurrent problem in people and horses. Although there are many inciting causes of back pain, these often lead to a common pathway involving changes in neuromotor control and neurogenic atrophy of m. multifidi. The multi-layered and multi-directional fibres of this muscle stabilize the intervertebral joints in the face of bending and torsional moments. Inactivation and atrophy result in spinal instability and micromotion of the joints that predispose to further injury and degenerative changes, thus setting the scene for recurrent episodes of back pain. This review explores similarities between human and equine back pain, especially with regard to pathophysiology and prevention.

Recurrent laryngeal neuropathy (RLN, laryngeal hemiplegia, laryngeal paralysis, 'roaring') is common in the equine industry with a prevalence ranging from 2.6-11% in light breeds (Raphel 1982; Lane 1987; Morris and Seeherman 1990) up to 38% in draught breeds (Brakenhoff 2006; Perkins 2009). There are a number of different surgical treatments currently available and more being developed. This article aims to discuss factors affecting choice of treatment and then provide an evidence-based approach to describe surgical approaches, success rates and morbidity. Specific details of surgical methods are not given as they are readily available in surgical textbooks (Stick 2006; McGorum 2007).

The influence of insertion of a needle into muscle on the activity of creatine kinase and fructose-1,6-diphosphate aldolase in serum was measured in 23 patients undergoing electromyography because of suspected neurogenic (n = 18) or myogenic (n = 5) muscular atrophy. Myogenically atrophied muscle was easily vulnerable. In neurogenic atrophy and in healthy muscle the lesion was demonstrable in enzyme changes only when muscular work followed the insertion of the needle. Activity of so-called muscle enzymes is not only changed after intramuscular injections but also due to insertions of thin electrodes (electromyography). The vulnerability of muscules may provide information on the activity of an atrophying process.

Concerning individual neuromuscular conditions, electron microscopy may be considered “essential,” “helpful,” or “wasteful.” “Essential” electron microscopy should provide a clear diagnosis, because of the disease specificity of the ultrastructural findings, in particular as to inclusions within muscle fibers, such as cylindrical spirals and reducing bodies. Electron microscopy may be “helpful” in detecting ultrastructural features preceding typical light microscopic findings, for instance, undulating tubules in endothelial cells. Congenital, metabolic, and inflammatory myopathies may often be more easily and more reliably diagnosed by means of the electron microscope. Diagnostically “wasteful” electron microscopy may pertain to muscular dystrophies, neurogenic atrophy, and myotonic diseases.

Botulinum toxin is a powerful and often used agent to treat dynamic rhytides. Focal and reversible neurogenic atrophy is considered to be the relevant mechanism of action.To investigate the loss and regain of muscular volume in relation to clinical wrinkle severity as assessed using standardized scales.The facial procerus and corrugator supercilii muscles were injected in two drug-naïve men with 20 U of onabotulinumtoxinA at five injection points (onA). Two men served as controls (one with the same volume of placebo injection using saline solution, one without any intervention). All subjects underwent 3 Tesla magnetic resonance imaging before and after the injection and 1, 4, 6, 10, and 12 months after the injection. Standardized photographs were taken at each test point.Volumetric muscle analysis revealed a 46% to 48% reduction in procerus muscle volume lasting for 12 months after a single dose of onA; glabellar line severity returned to the drug-naïve status after 6 to 10 months.The gap between long-term focal muscular atrophy and regained function remains to be elucidated. Future studies will be needed to investigate the complex interaction between focal neurogenic atrophy and potential compensatory functional muscle changes.

Light and electron microscopic studies were performed on neuromuscular biopsy specimens from 12 neurologically affected seropositive patients, 7 with the acquired immune deficiency syndrome (AIDS), 2 with AIDS-related complex, and 3 with no symptoms except for neuropathy. All patients had an axonal injury associated or unassociated with demyelination and peripheral neurogenic atrophy. Capillary lesions were consistently present, which seems to be a new finding. Moreover, tubuloreticular inclusions (TRIs) were found in endomysial (9 of 12 cases) and endoneurial (7 of 12 cases) vessels. Statistical analysis showed that TRIs in more than 20% of endomysial vessels correlated with a survival time shorter than 12 months (P = 0.028). Thus the quantification of TRIs seems to be one of the vital prognostic elements in this patient population.

Twelve patients with congenital nemaline myopathy were examined by ultrasonography and computed tomography (CT) and 4 of them by low-field magnetic resonance imaging (MRI) to investigate the distribution and nature of muscle involvement and to evaluate the yield of these techniques. A pattern of selective muscle involvement was consistently found. Ultrasonography revealed abnormally high muscle echogenicity. In contrast to the controls with simple disuse and/or neurogenic atrophy, CT revealed low muscle density in our patients. MRI confirmed that this pattern reflects patchy, fatty degeneration, a new finding in congenital nemaline myopathy. Ultrasonography appears useful for screening, provided that the dorsiflexors of the feet are examined. CT and MRI can be used to demonstrate abnormalities in mild cases, to select the biopsy site, and for follow-up. MRI, because it provides good soft tissue contrast, is useful for determining fatty infiltration.

Summary The lesser diameter of the fibers, separately of type 1 and type 2 fibers, and the capillary density evaluated as number of capillarieslarea and number of capillaries/fiber were quantitatively estimated in muscle biopsies from 12 patients with systemic sclerosis. Nine patients with polymyositis or rheumatoid arthritis and six patients with muscle dystrophy and neurogenic atrophy served as controls. The results showed that patients with systemic sclerosis had low values of the lesser diameter of the fibers. This reduction was most obvious in type 2 fibers. The capillaries were also significantly reduced when compared with the control groups. When considering the capillaries1fiber ratio, seven out of eight patients with values lower than 0.7 belonged to the systemic sclerosis group. In systemic sclerosis the capillary density values were not significantly correlated with those of the lesser diameters of the fibers.

Membrane-bound cytoplasmic crystals were found in the intrafusal fibers of a muscle spindle from a patient with neurogenic atrophy. The crystals have a periodicity of 10 nm and an intersecting axis angle of approximately 80 degrees. This makes the crystals similar to those described in alveolar soft part sarcoma (ASPS). Because the crystals in ASPS may not be quite as specific as previously believed, and because similar crystals have been described in various other neoplasms, the present findings should not be taken as evidence for a muscle spindle derivation for ASPS.

Forty cases of 'wasted leg syndrome' were studied clinically and electrophysiologically. Muscle biopsy was examined in nine cases, majority of patients were adults engaged in heavy manual work. The illness was noticed incidently with a strictly unilateral wasting of the whole lower limb (in 65% of cases), of all muscles below the knee (in 22.5% of cases) or of quadriceps muscles only (in 12.5% of cases). The nerve conduction studies and the electromyographic pattern suggested anterior horn cell disorder. Neurogenic atrophy was seen in 7 out of 9 muscle biopsies. A follow up in 12 patients (2-6 years) revealed no progression of the disease. It is suggested that possibly these cases represent an entity, clinically different from other anterior horn cell disorders.

A child is reported with Behcet's disease who presented with skin and joint manifestations, oral ulcers, brainstem syndrome and neurogenic muscular atrophy. The neurogenic muscular atrophy was confirmed by electrophysiologic, histologic and histochemical studies. Electron microscopy of muscle showed a vasculopathy. The possible etiology of the muscle lesions is discussed. The relevant literature on muscle and peripheral nerve involvement in Behcet's disease is reviewed. It is proposed that neuromyopathy be added to the neurological manifestations of Behcet's disease. To our knowledge, this is the first case of neurogenic atrophy reported in Behcet's disease.

Clinical evidence of skeletal muscle involvement is frequent in systemic lupus erythematosus (SLE). In order to characterize the manifestations of SLE in skeletal muscle, a biopsy series on 19 patients with SLE was studied in terms of the histologic, histochemical, and direct immunofluorescent features of skeletal muscle. The results were correlated with clinical and laboratory data. The histologic spectrum included inflammatory myopathy, vasculitis, perifascicular atrophy, and neurogenic atrophy. Histochemical examination revealed type I fiber predominance in 44 per cent of patients and selective type II fiber atrophy in 33 per cent. Direct immunofluorescent examination of skeletal muscle biopsy specimens revealed immunoglobulin and complement deposition in vessel walls, in sarcolemmal basement-membrane areas, and within non-necrotic muscle fibers. The histologic, histochemical, and immunochemical findings are correlated with the findings in other organ systems.

In vitro studies with diffusates obtained following dialysis of serum samples have enabled us to confirm the presence of inhibiting and activating factors influencing CPK activity. Activating factors are commonly found in many neuromuscular disorders like Duchenne muscular dystrophy (DMD), spinal muscular atrophy and hypothyroid neuromyopathy, and inhibiting factors in dermatomyositis. These findings are further elaborated during serial serum CPK studies after EMG in 3 cases of neurogenic atrophy and 1 case of DMD. The in vivo inhibitory and activating influence of serum factor(s) at 96 and 160 hr respectively after EMG was confirmed by in vitro studies with the diffusates of these serum samples. The functional variations of these diffusates are shown to be related to differences in the composition of these diffusates suggested by paper chromatography.

The authors give an account of x-ray examinations of the limb musculature of 70 patients suffering from neurogenic muscular diseases, 42 suffering from primary muscular diseases and 45 suffering from senile degeneration of the muscles. Different degree of damage to different parts of the same muscle could only been observed in one case of neurogenic atrophy (in the post-poliomyelitic state) and in two cases of senile degeneration, while it was found in 11 cases (20%) for the other muscular diseases. In the latter cases the more severe muscle damage, which could be demonstrated radiographically, was always found in the part of the muscle adjacent to a tendon. On the above reasons the authors consider that radiographically demonstrable partial or uneven damage to any particular muscle can be used as a new diagnostical information in distinguishing muscular diseases from neurogenic muscular atrophy.

The muscle biopsy was obtained from a 6 8-yea r-o Id worn an with genera I ized weakness and a history of rheumatoid arthritis (on low-dose steroid therapy), hypertension, and adult-onset diabetes mellitus. Histochemical studies on frozen tissue revealed mild neurogenic atrophy. Ultrastructural studies on glutaraldehyde-fixed tissue were notable only for focal collections of pleomorphic, multilammelated structures within the external lamina (Figs.

Muscle biopsies from juvenile diabetics were studied by electron microscopy and the results correlated to earlier published light microscopical abnormalities of the same biopsies. A total of 32 striated muscle biopsies from 29 juvenile recent, short-term and long-term diabetes were examined. The ages ranged from 16 to 43 years with a diabetes duration from 1 week to 32 years. The material was compared with biopsies from healthy persons of the same ages. The electron microscopy revealed degenerative changes of the striated muscle fibres which signify a neurogenic atrophy. No myopathic alterations were found. The capillaries in both the recent and long-term diabetics showed an extremely pronounced pinocytosis indicating an increased metabolic activity. In the long-term group the intramuscular capillaries both from upper and lower extremities displayed a definitely thickened basement membrane. In the recent and short-term group the capillary wall alterations were debatable. The motor end plate in the recent diabetics revealed minimal alterations. Contrary to this the long-term group showed severe alterations with occasional disappearance of the nerve fibres.

Pneumoencephalography was carried out in 23 patients with various muscular disorders, i.e. spinal neurogenic atrophy, classified as Wohlfart-Kugelberg-Welander's and Charcot-Marie-Tooth's diseases, and muscular dystrophy. EEG-registrations and psychological testing were carried out. Pneumoencephalography revealed ventricular enlargement and cortical changes in 17 out of 23 cases. Changes were found in all three groups studied; cortical changes were, however, only found in the neurogenic atrophy groups. Cases where there clearly might be exogenous causes for ventricular dilatation were excluded. The changes found, therefore, supposedly form an integral part of the disease process. It should be emphasized that the precaution does not entirely exclude a traumatic etiology in some cases. EEG-registrations (pathological in three out of 20 cases) as well as psychological evaluation (pathological in six out of 14 cases) supported the assumption of organic brain changes. Pneumoencephalography, however, seemed to be the most sensitive parameter for unveiling brain involvement in these disorders.

A case of sporadic ulcerative mutilating acropathy is described. Muscle biopsy showed signs of neurogenic atrophy. Motor nerve conduction velocity was slightly reduced. The muscles of the foot were completely unresponsive to electric stimulation of both femoral nerves. The content of free amino acids in serum and cerebrospinal fluid was determined by ion exchange chromatography, and compared with a control group. While in serum no significant changes were found, in CSF most amino acids showed great alterations, mainly consisting in an increase. It is suggested that the primary disturbance may be located in the spinal nerve roots.

Two patients with chronic neurogenic quadriceps amyotrophy are reported. A 61-year-old woman had symmetrical wasting and weakness of the quadriceps femoris of eight years' duration. A biopsy revealed neuropathic changes, and electromyograms showed neurogenic as well as myopathic patterns in the quadriceps and other muscles. A 29-year-old woman had long-standing wasting limited to the quadriceps and hip muscles. EMG and biopsy were compatible with neurogenic atrophy. She had a brother suffereing from a more widespread and severe form of the disease. These cases suggest that chronic neurogenic quadriceps amyotrophy is a forme fruste of Kugelberg-Welander disease.

All the diagnostic muscle biopsy cases were collected from the file of Department of Pathology, Seoul National University Hospital during June 1976 to December 1978. Slides were reviewed and correlated with clinical informations. Two hundred seventy four cases showed pathological changes, which were classified into six large groups (Table 1). Neurogenic atrophy was most common, 97 cases (35%), including 71 cases of motor neuron disease and 22 cases of peripheral neuropathy. Muscular dystrophy was seen in 92 cases (34%), and Duchenne type was the commonest among them (51 cases). Fifty seven cases showed inflammatory myopathy, making 20% of all cases. There were four cases of congenital myopathy and 13 cases showed various muscle diseases.

Carnitine level and carnitine palmityl transferase (CPT) activity were investigated in muscles of patients with infantile and juvenile spinal muscular atrophy and polyneuropathies. A significant decrease of both carnitine and CPT was found in the infantile spinal muscular atrophy, but not in the other neurogenic muscle atrophies. These findings were compared with the experimental effect of denervation and reinnervation upon the lipid metabolism in soleus and extensor digitorum longus (EDL) of adult and newborn rats. Twenty-one days after denervation free and total carnitine decreased significantly in both EDL (P less than 0.001) and soleus (P less than 0.05) of adult animals. CPT activity was significantly decreased in the soleus 50 days after denervation (P less than 0.005). Long-term reinnervation restored the level of carnitine fraction and CPT activity. L-carnitine treatment for 21 days restored the level of free carnitine to normal in the soleus of denervated adult animals. Denervation in newborn rats influenced carnitine concentration in soleus and EDL to a lesser extent; the treatment with L-carnitine raised short-chain acylcarnitines in denervated muscles, while reinnervation restored carnitine level within 50 days.

A case of a severe and fatal form of arthrogryposis multiplex congenita with a full necropsy examination is presented in which the central nervous system and many muscles of the four extremities were examined histologically. The most striking feature was a great reduction in the muscular tissue of the limbs with a marked increase in the adipose tissue. The muscular changes were thought to be caused by neurogenic atrophy, and microscopy of the spinal cord revealed developmental abnormalities, including degenerative changes of the anterior horn cells. Neonatal and fatal cases of arthrogryposis multiplex congenita reported in the literature are briefly reviewed, and the characteristics of the present case and its relation to other congenital neuromuscular disorders are discussed.

Progressive sensorimotor neuropathy developed in two patients exposed to prolonged (chronic) inhalation of n-hexane (glue sniffing). Sural nerve biopsies showed loss of axons; remaining axons were either normal or showed accumulation of filaments of 90 to 100 A thick, widened nodes of Ranvier, and focal enlargements. The muscle biopsy revealed neurogenic atrophy. Intramuscular nerve twigs and end-plates, studied in one patient, showed loss of axons and nerve terminals. Unmyelinated axons also showed accululation of 60 to 100 A thick filaments. The similarities between the pathologic findings in the peripheral nerve of these patients and those with acrylamide neuropathy suggest that the n-hexane inhalation produces a dying back neuropathy.

A patient had symmetrical weakness and atrophy of the quadriceps muscles, simulating quadriceps myopathy, but due to neurogenic atrophy. Review of the literature on quadriceps myopathy suggests that, rather than being a specific entity, such cases represent a clinical syndrome with a heterogeneous pathologic basis.

Idiopathic faecal incontinence in middle-aged people has been found to be commonly associated with neurogenic damage to the anal sphincter musculature. Because neurogenic atrophy of skeletal muscle is a common feature of ageing, we have investigated the possibility that faecal incontinence in elderly people might be due to age-related denervation of the anal sphincter musculature. The technique of single fibre electromyography was used to measure the motor unit fibre density in the external and sphincter muscle in ten patients aged 78 to 99 years. Those patients whose continence was impaired had a markedly increased fibre density. Our findings suggest that neurogenic damage to the anal sphincter musculature may so reduce its functional reserve in elderly people that incontinence occurs when other factors, such as looseness of stool or depression of cerebral function, co-exist.

F-waves were determined in the peroneal nerves of 17 normal subjects, 11 amyotrophic lateral sclerosis (ALS) patients, and 13 patients with other disorders causing neurogenic atrophy (NA) in extensor digitorum brevis muscle. F-waves were examined with regard to latency and waveform. Latency was increased above normal for both ALS and NA patients (P less than 0.024 and P less than 0.003, respectively). In normal subjects, the mean number of repeated responses (same latency and waveform) was 1.9 (r = 1.0-5.0), where 1.0 corresponds to no repeated response. In ALS patients, repeated responses were 2.9 (r = 1.2-7.8), which is not significantly different from normal (P less than 0.099). In NA patients, repeated responses were 6.5 (r = 1.6-23), which is significantly above normal (P less than 0.041). A dominant waveform occurred in 21.5% (mean) of responses in normal subjects (r = 4%-58%). In ALS and NA, corresponding values were 40.3% (r = 10%-88%) and 44.1% (r = 17%-100%), both of which were significantly above normal (P less than 0.014 and P less than 0.012, respectively). The distribution of F-wave latencies is often nonrandom in normal, ALS, and NA subjects. The dominant F-wave that was present in normal subjects and significantly increased in ALS and NA subjects may result from decreased numbers of motoneurons capable of contributing to the F-response and would seem to be a useful additional measure of abnormality.

Clinical and experimental observations have established that damaged or degenerating muscles will release its contents, particularly enzymes, into the general circulation, and that this process can be measured by an increase in the level of certain enzymes in the serum. Assay of serum enzymes in the assessment of muscle disease has been employed most widely in the study of muscular dystrophy both to establish the diagnosis early 1,2 and to discover maternal carriers of the sex-linked form. 3,4 However, it is clear that at least some muscle enzymes are released into serum by other myopathies, particularly acute myositis, 5,6 and even by neurogenic atrophy. 5,6 That the source of the serum enzymes is indeed the muscle has been established by a number of findings. Dreyfus et al 7 showed that the venous aldolase level was sometimes slightly higher than the arterial aldolase in cases of muscular dystrophy. The isoenzymes of

Muscle has been obtained from various members of two families who are known to carry the trait for malignant hyperpyrexia. The muscle of such carriers has been found to be abnormal histologically, histochemically and ultramicroscopically, although there was no evidence of muscle disease on clinical examination. We have found that the pattern of abnormality is different in the two families, the major difference being largely related to fibre size. Both show histochemical evidence of neurogenic atrophy with reinnervation. The electron-microscopic study confirms the presence of fibre breakdown, and reveals the presence of abnormal mitochondria and membrane changes which are in keeping with a neuropathic disorder. In most cases in our studies we have confirmed that the myopathy can be established by findings of an elevated creatine phospho-kinase level in the serum. Carriers with normal levels are also identified by family studies and it has been shown that muscle abnormalities are present in these subjects as well.

G. B. A. Duchenne's description of pseudohypertrophic muscular paralysis contains not only the first clear account of this disease, but also the first report of a practical instrument of muscle biopsy. Duchenne (1806-1875) was a French neurologist who was led to a careful study of neuromuscular diseases through his interest in the effects of electrical stimulation on muscle. 1 His painstaking observations, combined with an intuitive grasp of his field, enabled him to make many important contributions to nosology at a time when the distinction between primary muscle disease and neurogenic atrophy of muscle was poorly appreciated. Duchenne's muscular dystrophy remains a well-defined clinical entity, but other forms of muscular dystrophy have since been described. 2,3 Although Duchenne did not recognize the hereditary character of the disease, the muscular dystrophies have subsequently been shown to have a genetic basis, and techniques are now available to detect genetic carriers. 4 Duchenne