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Objective: To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD). Methods: Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: “stimulation on” (STIM) (equated to daily treatment), “stimulation off” (OFF), and “stimulation off/levodopa” (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed. Results: Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition. Conclusion: DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general. Classification of evidence: This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations.

American Academy of Neurology Dedicated to advancing the art and science of neurology, and thereby promoting the best possible care for patients with neurological disorders A Celebration of the First 50 years of the American Academy of Neurology Neurology 1962;12:778-794 In the investigation of neuromuscular disease, histologic examination of skeletal muscle biopsies is generally accepted as an important part both of routine diagnostic procedures and of more specialized research. The purpose of the present report is to establish that the use of histo- and cytochemical technics combined with light microscopy is also an essential aspect of both types of investigation. Substantiating evidence is presented in the form of 6 examples, chosen from recent studies, of cytopathologic changes in neuromuscular disease as demonstrated by these technics. Two fundamental types of abnormalities in skeletal muscle are detectable with histo- and cytochemical technics: (a) a generalized change of a given reaction, for example, loss of phosphorylase activity, and (b) a localized change of activity confined either to a specific type of muscle fiber (as in the new myopathy with rod-shaped structures) or to certain regions of individual muscle fibers (as in target fibers and central core disease). Further, if the cytochemical technics are sufficiently refined, they may be used to demonstrate the functional activity of fine structural components of the muscle cell. On the basis of such data, predictions can often be made as to the fine structural changes which electron-microscopy will reveal. It must be understood, though, that some cytochemical changes might not be accompanied by changes of fine structure and vice versa. Cytochemistry combined with electron-microscopy would give even more detailed information, but this approach has 2 major limitations: (a) only a very few cytochemical reactions are as yet refined enough to be used with electron-microscopy and(b) study of a large …

Background: An important aspect of inclusion-body myositis (IBM) vacuolated muscle fibers (VMF) is abnormal accumulation of amyloid-β precursor protein (AβPP) epitopes and its product, amyloid-β (Aβ), and of phosphorylated tau (p-tau) in the form of paired helical filaments. Lipoprotein receptors and cholesterol are known to play an important role in AβPP processing, Aβ production, and tau phosphorylation. Methods: In 10 IBM and 22 control muscle biopsies the authors immunolocalized low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and low-density lipoprotein receptor-related protein (LRP), and colocalized them with Aβ, p-tau, APOE, and free cholesterol. Results: In each biopsy, virtually all IBM VMF had strong LDLR-immunoreactive inclusions, which colocalized with Aβ, APOE, p-tau, and free cholesterol. VLDLR was increased mainly diffusely, but in approximately 50% of the VMF it was also accumulated in the form of inclusions colocalizing with Aβ, APOE, and free cholesterol, but not with p-tau. LRP inclusions were present in a few VMF. In all myopathies, a subset of regenerating and necrotizing muscle fibers had prominent diffuse accumulation of both LDLR and free cholesterol. At normal neuromuscular junctions (NMJ) postsynaptically, LDLR and VLDLR, but not LRP, were immunoreactive. Conclusions: 1) Abnormal accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle fibers suggests novel roles for them in the IBM pathogenesis. 2) Expression of LDLR and VLDLR at normal NMJ suggests physiologic roles for them in transsynaptic signaling pathways, increased internalization of lipoproteins there, or both. 3) Increased LDLR and free cholesterol in some regenerating and necrotizing muscle fibers suggest a role for them in human muscle fiber growth and repair and necrotic death.

We established monolayer muscle fiber cultures from muscle biopsies of 3 patients with oculopharyngeal muscular dystrophy (OPMD) who had Characteristic intranuclear inclusions (INI-A) in their muscle fibers. Aneural cultures had normal morphology, except for a few muscle fibers that contained small vacuoles. Innervated cultures had large cytoplasmic vacuoles in a number of muscle fibers. Those muscle fibers were breaking easily, and could not be maintained longer them 2 months. Electron microscopy showed unusual intranuclear inclusions (INI-B) not previously reported in aneurally cultured muscle fibers of OPMD or in any normal or disease-control aneural or innervated cultured human muscle fibers. They resembled, but were not identical to, the INI-A, and they occurred in both the cultured fibers and the original muscle biopsies of all 3 patients. Our study demonstrates that (1) nuclear inclusions in OPMD reflect an intrinsic genetic defect; and (2) neuronal influence, advanced maturation, or both, seem to be essential for their induction in muscle fibers.

Electrophysiologic studies were performed on aneurally cultured human muscle cells from seven patients with myotonic muscular atrophy and seven controls. There was no significant difference in resting membrane potential. When the cells were hyperpolarized to -80 mV, there was no significant difference in effective membrane resistance, effective membrane capacitance, normalized membrane conductance, membrane threshold, action potential amplitude, or maximum rate of rise of the action potential. Repetitive discharges were elicited by anodal-break excitation in a few cells from each group. We found no evidence that cultured myotonic atrophy muscle cells are electrically different from control cells.

In monkey extraocular muscles (EOM), a battery of histochemical reactions delineates three muscle fiber types, coarse, fine, and granular. Normal EOM are compared with EOM denervated by intracranial oculomotor nerve section. The experimentally denervated EOM fibers did not show the constellation of histologic responses typical of denervated limb muscle, making a diagnosis of a denervation process in EOM muscle very difficult. Although the denervated fine and granular fibers (but not the coarse fibers) develop diffuse extrajunctional acetylcholine receptors (AChR) following experimental denervation, this is not a reliable criterion of denervation because not all of those fibers developed it and they did not show it beyond a 12-week period following nerve section; moreover, myopathic mechanisms have previously been shown capable of provoking diffuse extrajunctional AChR in limb-muscle fibers.

Immunoreactivity of neuron-specific enolase was measured in cultured embryonic rat motor neurons as an index of neuronal health. Treatment with cerebrospinal fluid from patients with amyotrophic lateral sclerosis and other neuromuscular disorders had no effect on neuron-specific enolase.

Laser Doppler measurements of skeletal muscle blood flow were performed in 12 patients with neuromuscular disorders and 6 controls. The mean resting blood flows and postocclusive reactive hyperemias were similar for the patients with neuropathic disorders and for controls. The patients with myopathic disorders had higher resting muscle blood flows and reactive hyperemias. Correlation of blood flow results and muscle biopsy characteristics suggested that muscle type grouping was not associated with a change in skeletal muscle blood flow, whereas muscle fiber degeneration was associated with an increased blood flow.

Hydrocortisone, despite its lack of effect when used alone in a rat nervemuscle preparation, abolished the increase in muscle single-twitch tension produced by the anticholinesterase drugs neostigmine and pyridostigmine. Once the steroid had abolished the effect of these drugs, equivalent doses of the cholinesterase inhibitors were less effective than they had been before steroid was given. The results of these experiments indicate that a corticosteroid hormone may have an adverse pharmacologic interaction with anticholinesterase drugs in a mammalian nerve-muscle preparation. This significant adverse interaction might be the reason some patients with myasthenia gravis do not respond as well with corticosteroid plus anticholinesterase as with corticosteroid alone.

In a controlled and blind study we were not able to identify any abnormality of erythrocytes of eight patients with Duchenne muscular dystrophy compared with seven approximately age-matched unaffected siblings (six males, one female step-sibling). Erythrocyte morphology was found to be very sensitive to various types of cell treatment. At this time, erythrocyte morphology, evaluated by the techniques used, should not be considered an established diagnostic test for the Duchenne muscular dystrophy patient or carrier.

A 23-year-old woman became quadriplegic and respirator-dependent after 18 years of weakness and rhabdomyolysis. Her muscle tissue and that of a deceased sister contained lipid-laden fibers. Treatment with D, L-carnitine 4 grams per day was followed by a dramatic improvement within 10 days. Muscle function was normal at 8 months and has remained so during 3 subsequent years of L-carnitine 3 grams per day. Pretreatment muscle biopsy had documented low levels of free carnitine and short-chain acylcarnitine compounds. Carnitine palmityltransferase was slightly elevated. The asymptomatic parents had low-normal muscle carnitine levels, slight increase in muscle fiber lipid droplets, osmiophilic lipid-laden Schwann9s cell vacuoles, and myelin lamellae with different periodicities.

We describe the diffuse nonjunctional distribution of AChR molecules of aneurally cultured human and animal muscle and the influence of sera from myasthenia grivis patients and rabbits with experimental autoimmune myasthenia gravis on binding of alphaBT to diffuse nonjunctional AChR. One-hour incubation of myasthenia gravis seria resulted in blocking of the alphaBT-immunoperoxidase staining of their AChRs, while incubation in normal sera did not. Aneurally cultured muscle can aid studies of regenerating fibers in normal muscle compared with those of muscles in neuromuscular diseases, and also act as an environmentally controlled test object for demonstrating the effect of circulating pathogenic factors.

In the process of developing an immunopharmacologic method for identifying a "trophic" protein released from motor nerve terminals, a soluble fraction of peripheral nerve axoplasm was prepared. An attempt was made to eliminate contaminating myelin and basic protein. Antibodies were produced to soluble nerve proteins in all sheep immunized. On boosting, after a 6-week interval, the animals became weak, and some could not stand on the fifth day after injection. A distinct component of neuromuscular blockade was demonstrated electrically and in response to edrophonium. Because this syndrome was (1) in the broadest sense, an experimental allergic neuropathy but produced by a distinctly different antigen than has been utilized previously (the soluble nerve proteins represented the axoplasmic compartment) and (2) a clinical condition associated with a defect in neuromuscular transmission, this may represent a new and potentially important model in the study of neuromuscular and other neurologic diseases.

Hemolysis was investigated in seven patients with Duchenne dystrophy. No increase in red-cell turnover was detected by indirect measurement (hemoglobin, reticulocyte count, plasma hemoglobin, serum haptoglobin) or by turnover of 51Cr-labeled erythrocytes. Our findings fail to support the likelihood of a significant erythrocyte membrane defect.

MAMMALIAN SKELETAL MUSCLE has been studied with histochemical techniques after various experimental procedures such as nerve section,’-4Jo neuronal regeneration,5.6 “foreign” and cross innervation,T-@ and tenotomy.294 The effects of these methods upon the muscle cell were produced by direct involvement of the lower motor neuron innervation or the length of the muscle or both. In the present study, acute complete transection of the high thoracic spinal cord was performed to determine the indirect effects on the gastrocnemius and soleus muscles of adult and newborn guinea pigs. Histochemical and cytochemical changes in the muscles after cordotomy were compared with the effects of peripheral nerve section and skeletal fixation to elaborate on various aspects of the complex nerve-muscle interrelationship.

SUMMARYA patient has been described with Moebius syndrome in whom there was clinical paralysis of the muscles supplied by the third, fourth, sixth, and seventh cranial nerves. Limb muscle biopsy studies and electromyography of the limb muscle suggest denervation of an “anterior horn cell” type of abnormality in the spinal cord. Moebius was also of the opinion that the syndrome was secondary to lower motor neuron abnormality and that the cord could be involved. The hypogonadism of our patient was secondary to a deficiency of gonadotropic hormone.

We have studied four unrelated males with a heritable disorder that we term adrenomyeloneuropathy; limited clinical information is available on a fifth case. All had adrenal insufficiency beginning in childhood and developed progressive spastic paraparesis in the third decade. Hypogonadism of variable severity was present in all four cases appropriately examined. Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances. Late manifestations were cerebellar dysfunction in one case and dementia and hemiparesis in another. A family history of adrenal disease or spastic paraparesis was present in two cases and absent in one; in the other two, no family history was available. Although males are predominantly affected, the mode of inheritance is uncertain. Adrenomyeloneuropathy probably represents a clinically and genetically distinct variant of childhood adrenoleukodystrophy.

An indirect immunoperoxidase technique was used to study by light microscopy the binding of serum from experimental autoimmune myasthenia gravis (EAMG) rabbits to junctionally and extrajunctionally located acetylcholine receptors (AChRs) in human and rat muscles. Binding was restricted to junctional AChR. Alpha bungarotoxin (a-BGT) partially blocked the binding of EAMG serum, while myasthenia gravis serum, carbamylcholine, decamethonium, and tubocurarine did not. A radioimmunoassay showed significant binding of antibodies in EAMG sera to 125l AChR. This binding was not inhibited by a-BGT, nor by carbamylcholine, decamethonium, or tubocurarine. Sera from 10 myasthenia gravis patients did not contain antibodies binding to the 125l AChR. We suggest that EAMG in rabbits induced by Torpedo AChR differs serologically from myasthenia gravis in patients, probably owing to antigenic differences between Torpedo and human AChR, and that antigenic differences also exist between junctional and extrajunctional receptors.

We have identified two distinct and consistent type I fiber subtypes in histochemically normal biopsies (vastus lateralis or biceps brachialis) from 12 healthy persons, both sexes, ages 15 to 42. The type I fibers were uniformly light with the regular ATPase (9.4) and uniformly dark with the acid-preincubated reverse ATPase reactions. However, the subtype IA fibers were stained darker than subtype IB fibers with the nicotinamide adenine nucleotide dehydrogenase-tetrazolium reductase, Oil red O, reduced nicotinamide adenine dinucleotide phosphate-tetrazolium reductase, nonspecific esterase, succinic-tetrazolium reductase, nicotinamide adenine dinucleotide-linked malic-tetrazolium reductase, and "nicotinamide adenine dinucleotide-linked lactic-tetrazolium reductase," and stained lighter with the phosphorylase, periodic acid-Schiff for glycogen, and menadione-mediated alpha-glycerophosphate-tetrazolium reductase reactions. The IB fibers were not as light (or as dark, depending on the stain) as any of the type II fibers. In one pathologic case, all the "hypotrophic type I muscle fibers with central nuclei" were subtype IB. In case of chronic infantile spinal atrophy the muscle showed some type-grouping and marked type I fiber predominance--the great majority of type I fibers were subtype IB, among which were islands (subtype-groups) of IA fibers. Subtyping of type I fibers may be informative in evaluating the pathologic process of certain human neuromuscular diseases.

To determine whether antibodies against spinal cord motor neurons are present in patients with myasthenia gravis, sera from 17 such patients were tested by indirect immunofluorescence. Although an-tinuclear antibody activity was detected in some patients, it was not restricted to neuronal nuclei. The study failed to confirm a previous report of specific antineuronal antinuclear antibodies in myasthenia gravis.

In rats with ischemic myopathy induced by aortic ligation and 5-hydroxytryptamine, there was good correlation of the skeletal muscle concentration of 99mTc-diphosphonate with the increase of plasma creatine phosphokinase and the decrease in muscle potassium. This radionuclide tracer method can be used to quantitate acute injury in individual muscles and provides a basis for clinical nuclear imaging in patients with a variety of disorders involving muscle fiber damage.

Acetylcholine receptor now can be visualized in the muscle sarcolemmal membrane with the use of an immunoperoxidase staining of alpha-bungarotoxin (alpha BT), a substance that binds specifically to the acetylcholine receptor. This technique has allowed new observations in various neuromuscular diseases in which the acetylcholine receptor is affected. In normal muscle, the acetylcholine receptor is confined to the neuromuscular junction. In both experimental denervation and human denervating illnesses, the acetylcholine receptor becomes present diffusely along the muscle sarcolemmal membrane in denervated fibers. In myasthenia gravis, a circulating factor that blocks alpha BT binding to the acetylcholine receptor of either normal neuromuscular junctions or denervated sarcolemmal membranes is present in 68 percent of serums tested.

The fiber-type nomenclature of human skeletal muscle preferred by the author is “type I” and “type II” fibers, based on their light or dark staining respectively with the myofibrillar adenosine triphosphatase reaction (pH 9.4) of Padykula and Herman. All other terms and histochemical reactions have greater disadvantages than this nomenclature. Needs for the future include (1) establishing a consistent histochemical subtyping system for human skeletal muscle fibers, (2) directly correlating in human fibers the basic histochemical types and subtypes with physiologic, biochemical and other parameters, and (3) further identifying histochemical changes that preferentially affect one fiber type or subtype in various human diseases and altered physiologic states.

In rats with experimental ischemic myopathy, there was a significant correlation (r = 0.778, p less than 0.001) between muscle uptake of technetium-99m (99mTc) diphosphonate and tissue calcium concentration. In addition, the accumulation of both calcium and 99mTc-diphosphonate in acutely injured muscles was further increased in rats with vitamin D-induced hypercalcemia. Histologic studies demonstrated staining of damaged muscle fibers with alizarin red, indicating the presence of microcrystalline or ultramicrocrystalline calcium salts. Staining of muscle fibers was most intense in the outer marginal zones of individual microscopic infarcts. Our results suggest that the uptake of 99mTc-diphosphonate in acutely damaged skeletal muscle is directly related to the deposition of calcium salts within the injured muscle fibers.

Certain myasthenic patients may show that their skeletal muscles produce a substance during ischemic exercise that increases muscle weakness when released into the circulation. This phenomenon has been named after Mary Walker, the physician who popularized its demonstration. A new hypothesis explains the Mary Walker phenomenon as follows: Ischemic exercise produces lactic acid that binds calcium-reducing ionized and total serum calcium. The decreased calcium has an adverse effect on skeletal muscle function, especially in patients with myasthenia gravis, whose neuro muscular function is often so precarious it may be interrupted by weak inhibitors. To support this hypothesis we present evidence that infusions of lactate have a greater adverse effect on patients who have myasthenia gravis than on patients who have nonmyasthenic neuromuscular diseases.