Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy.

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.

Glial hyaluronate-binding protein in polar spongioblastoma.

Glial hyaluronate-binding (GHA) protein is a 60 kDa glycoprotein isolated from human white matter by affinity chromatography on immobilized hyaluronate. It is localized in white matter astrocytes by immunofluorescence with monoclonal antibodies. Amino acid sequences have not revealed similarities with other proteins except cartilage extracellular matrix proteins, the region of similarity being located within the hyaluronate-binding region. Cryostat sections of 13 intracranial neoplasms removed at surgery were tested for the presence of GHA protein by indirect immunofluorescence with monoclonal antibodies. These included seven astrocytomas, one oligodendroglioma, one medulloblastoma and one spinal cord ependymoma. All tumors were negative with the exception of one astrocytoma in which the GHA protein-positive areas had the typical appearance of polar spongioblastoma, i.e. small cells palisading around blood vessels and very delicate glial fibrillary acidic (GFA) protein-positive fibrils. Conversely, neoplastic as well as reactive GFA protein-positive astrocytes were GHA protein-negative. We suggest that polar spongioblastoma derives from a GHA protein-positive glial precursor and pertinent to this suggestion is the observation that the periventricular germinal layer was found GHA protein-positive in a 22-week human fetus.

Polyneuropathies associated with IgM monoclonal gammopathies.

We studied ten patients with IgM monoclonal gammopathies. Five had M proteins that reacted with myelin-associated glycoprotein (MAG) and five had no recognizable antinerve activity. The neuropathy in the MAG-reactive patients was homogeneous by clinical and laboratory analysis, while the neuropathy in the MAG-nonreactive patients varied considerably. Both groups responded well to immunosuppressive therapy, which lowered the concentration of the serum M protein. The homogeneity of the MAG-reactive patients and their response to sustained lowering of the M protein levels support the concept that the IgM M protein directly damages nerve fibers and is the proximate cause of the polyneuropathy.

Lateral thalamic infarcts.

A patient with occlusion of the proximal posterior cerebral artery (PCA), a lateral thalamic infarct, and hemisensory loss later developed hemianopia and hemiparesis and had extensive PCA territory infarction in the midbrain, the lateral portion of the thalamus, and the occipital lobe noted at necropsy. Two other patients had lateral thalamic infarcts on computed tomography, normal angiographic findings, and presumed thalamogeniculate artery branch occlusion. There are three clinical syndromes associated with lateral thalamic infarction: (1) hemisensory loss, hemiataxia, and involuntary movements; (2) pure sensory stroke; and (3) sensory-motor stroke. Ataxia, adventitious movements, and sensory loss are due to infarction of the lateral, posterolateral, and posteromedial ventral nuclei caused by occlusion of the PCA proximal to the thalamogeniculate artery branches or by occlusion of large thalamogeniculate arteries. Pure sensory and sensory-motor strokes are due to smaller infarcts in the posterolateral-posteromedial ventral complex and adjacent internal capsule caused by occlusion of penetrating artery branches of the thalamogeniculate arteries.

Progressive myopathy in hyperkalemic periodic paralysis.

A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.

Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan: muscle biopsy findings in 4 patients.

Muscle biopsies of 4 patients with the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan showed lymphocytic infiltrates with occasional eosinophils largely restricted to interstitial fibrous tissue and perivascular areas. There was inflammation and fibrosis of muscle spindle capsules in 3 patients. In the 2 sickest patients, there was profound muscle atrophy, affecting both muscle fiber types.

Homolateral hemiparesis as an early sign of cerebellar mass effect.

A patient with Wallenberg's syndrome and an inferior cerebellar infarction developed progressive hemiplegia ipsilateral to the infarction as cerebellar edema emerged. An MRI showed diagonal displacement of the medulla with impaction of the pyramids against the clivus; the hemiplegia resolved after posterior fossa decompression. In the pathologic specimen, the pyramids were flattened and showed small subpial ischemic lesions. Progressive ipsilateral hemiparesis in the setting of cerebellar infarction is an early sign of posterior fossa mass effect similar to the Kernohan's notch phenomenon.

Needle muscle biopsy with the automatic Biopty instrument.

Needle muscle biopsies are less traumatic and easier to do than open biopsies, but their main disadvantage is the small specimen size. One hundred and five patients underwent needle biopsies with a 14-gauge spring-loaded device that guillotines the muscle automatically (Bard Radiology). Fifty patients had more than one muscle biopsy. One hundred and forty-six of 155 specimens contained over 200 muscle fibers, some as many as 500 fibers. Having evaluated various needles, we found the Bard Biopty instrument more efficient than manual needles and open biopsy techniques, and it provides muscle specimens for pathologic interpretation that are comparable with open surgical procedures.

Orbital myositis and giant cell myocarditis.

A 65-year-old woman developed progressive, bilateral ophthalmoplegia, with thickened extraocular muscles on CT. One month later, a cardiac arrhythmia led to her death. Pathologically, the extraocular and skeletal muscles showed diffuse mononuclear cell inflammation, while the heart contained granulomatous myositis. This patient's syndrome of idiopathic, orbital myositis and giant cell myocarditis may be a distinct nosologic entity.

Location of human pyramidal tract in the internal capsule: anatomic evidence.

A patient with a small infarct located posteriorly in the internal capsule had 9 years of weakness of the contralateral face, arm, and leg. At necropsy, it was found that degeneration of the corticospinal tract was almost complete in the midbrain and medullary pyramid. This case supports the increasing evidence that the human pyramidal tract is located in the third quarter of the posterior limb of the internal capsule.

Fatal brainstem stroke following internal jugular vein catheterization.

Neurologic complications of central venous catheterization are uncommon, and there are no reports of cerebrovascular events. We report a case of massive postoperative vertebrobasilar territory stroke following internal jugular vein cannulation due to inadvertent vertebral artery injury. Autopsy revealed thrombosis at the site of puncture wound in the right vertebral artery, with emboli present in the distal basilar artery.

Amyotrophic lateral sclerosis: thyrotropin-releasing hormone and histidyl proline diketopiperazine in the spinal cord and cerebrospinal fluid.

In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.

Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy.

A 64-year-old woman had bilateral facial weakness, mild peripheral neuropathy, incoordination, and impaired balance. A corneal transplant had been performed for corneal lattice dystrophy. Sural nerve biopsy showed mild axonal neuropathy with deposits of amyloid in the perineurium. Histochemical studies showed amyloid protein AA in the nerve, but not in cornea or muscle.

Total body irradiation not effective in inclusion body myositis.

Four patients with inclusion body myositis were treated with 150 rad of total body irradiation given in 5 weeks. One patient responded subjectively and transiently, but no patient showed clear benefit. This treatment is not recommended for inclusion body myositis.

Dissection of the intracranial vertebral artery.

We describe four patients and review prior reports to clarify the clinical, radiographic, and pathologic findings of intracranial vertebral artery (VA) dissection. A 43-year-old man and a 33-year-old woman had chronic bilateral VA dissecting aneurysms. The man had multiple episodes of subarachnoid hemorrhage (SAH) and necropsy showed multiple dissections and defects in the internal elastica. The woman had many brainstem TIAs and strokes during 3 years. Two other patients had SAH and unilateral dissections. Intracranial VA dissection causes four overlapping syndromes: (1) brainstem infarcts are usually due to subintimal dissection extending into the basilar artery, affect younger patients, and often are single fatal events; (2) SAH is due to subadventitial or transmural dissection; (3) aneurysms cause mass effect on the brainstem and lower cranial nerves; and (4) chronic dissections due to connective tissue defects cause extensive bilateral aneurysms and repeated TIAs, small strokes, and SAH.

Nonvasculitic, steroid-responsive mononeuritis multiplex.

We report two patients with mononeuritis multiplex, both of whom had focal inflammation of the perineurium and endoneurium on sural nerve biopsy without necrosis of blood vessel walls, histologic evidence of lymphoid malignancy, or mycobacterial infection. The predominant early sensory symptoms were asymmetric pain and paresthesias; subsequently, muscle weakness developed. Electrophysiologic studies showed an asymmetric sensorimotor axon loss radiculoneuropathy with denervation of limb and paraspinal muscles. Spinal fluid protein was elevated in one patient. There was no cause or underlying systemic disease. Marked improvement occurred with steroid therapy.

Stroke in patients with fusiform vertebrobasilar aneurysms.

We studied seven patients with brainstem infarction and large fusiform vertebrobasilar (VB) aneurysms to clarify the clinical, radiologic, and pathologic features. All presented with pontine infarcts; one also had a cerebellar infarct. VB TIAs preceded brainstem infarction in four patients. Angiography and CT documented VB fusiform aneurysmal dilatation. Four had intraluminal thrombi and one had severe basilar artery stenosis. Two distinct clinical pictures emerged: unilateral pontine infarcts with favorable outcome, presumably related to obstruction of a pontine penetrating artery at its origin from the posterior wall of the aneurysmal basilar artery, and major fatal bilateral pontine infarcts from basilar artery occlusion. Two patients came to autopsy. One had thrombus in the dilated basilar artery and a posterior cerebral artery branch embolus with hemorrhagic occipital infarction; the other had basilar artery thrombus with aneurysmal rupture and subarachnoid hemorrhage. Fusiform VB aneurysms caused brainstem stroke by intraluminal thrombus, local embolism, atherostenosis, and obstruction of paramedian penetrating arteries. Subarachnoid hemorrhage is an uncommon complication.

Intra-operative frozen section technique for pituitary adenomas.

Orange G-hematoxylin stains performed on frozen sections from the sella turcica had a diagnostic accuracy of over 90% when compared to permanent sections on the same tissue. This technique allows the pathologist to make an intra-operative contribution to the establishment of tumor margins in the selective removal of pituitary adenomas.

Quantitative morphometric study of muscle in inclusion body myositis.

Clinical and electromyographic findings do not clearly distinguish inclusion body myositis (IBM) from chronic polymyositis (PM). The rimmed vacuoles and filamentous nuclear and cytoplasmic inclusions that characterize IBM are often sparse and may be overlooked; conversely, these features may occasionally be seen in other diseases. Preliminary studies suggested that muscle fiber hypertrophy occurred more frequently in IBM than in PM. To investigate whether fiber hypertrophy can be used to improve the ability to separate IBM from PM, we report a morphometric analysis of 28 IBM cases, 22 PM and 22 dermatomyositis (DM) cases. The analysis, using a computer automated system, included proportion of hypertrophied fibers and also fiber type proportions, average fiber diameter, proportion of atrophic and angulated fibers, and the co-dispersion index (CDI). The proportion of hypertrophied fibers was greater in IBM than the other two conditions (IBM (mean +/- SEM) 31.0 +/- 4.7% and 12.2 +/- 2.4% for type 1 and type 2 fibers, respectively, compared to 9.8 +/- 3.0% and 3.3 +/- 1.7% in PM, and 7.7 +/- 2.7% and 3.9 +/- 1.9% in DM). These differences were statistically significant (P < 0.05) in both sexes for type 1 fibers and in women for type 2 fibers. Also, the average fiber size and hypertrophy factors for type 1 and type 2 fibers were increased in IBM compared to PM and DM. This study confirms that the presence of muscle fiber hypertrophy in biopsies from IBM patients may help differentiate them from other clinically similar inflammatory myopathies.