Cyclosporine and multiple sclerosis.
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Cyclosporins↗
Biomedical subjects
M P Pender
Publications and source records attributed to M P Pender.
Apoptosis in the nervous system in experimental allergic encephalomyelitis.
We report here for the first time the occurrence of apoptosis of cells in the spinal cord in experimental allergic encephalomyelitis (EAE), an autoimmune, T-cell-mediated demyelinating disease. Four different forms of EAE were studied in the Lewis rat: (i) acute EAE induced by inoculation with whole spinal cord and adjuvants; (ii) acute EAE induced by inoculation with myelin basic protein (MBP) and adjuvants; (iii) acute EAE induced by the passive transfer of MBP-sensitized spleen cells; (iv) chronic relapsing EAE induced by inoculation with whole spinal cord and adjuvants followed by treatment with low-dose cyclosporin A. Cells undergoing apoptosis were recognized at light and electron microscopy by the presence of either crescentic masses of condensed chromatin lying against the nuclear envelope or rounded masses of uniformly dense chromatin. They were found in both the white and grey matter of the spinal cord in all 4 forms of this disease. Although it was not possible to identify definitively the types of cells undergoing apoptosis, the size and location of some of the affected cells suggested that they were oligodendrocytes. As there is now a large body of evidence that T-cell-induced target cell death takes the form of apoptosis, it is attractive to hypothesize that oligodendrocyte apoptosis is occurring in EAE as a result of oligodendrocyte-directed T-cell cytotoxicity. However, other apoptotic cells were located within the myelin sheath, meninges and perivascular spaces and were clearly not oligodendrocytes but were most likely blood-derived mononuclear cells. The sparsity of their cytoplasm and the absence of phagocytosed material suggested that they were mainly lymphocytes rather than macrophages. Apoptosis has been shown to be involved in deleting autoreactive T-cells during the normal development of tolerance. Thus apoptotic deletion of myelin/oligodendrocyte-specific lymphocytes in the central nervous system in EAE might explain both the subsidence of inflammation and the acquisition of tolerance in this autoimmune disease.
Animals↗
The pathophysiology of chronic relapsing experimental allergic encephalomyelitis in the Lewis rat.
Electrophysiological studies were performed in Lewis rats with chronic relapsing experimental allergic encephalomyelitis (EAE) induced by inoculation with guinea-pig spinal cord and adjuvants and treatment with low dose cyclosporin A. During clinical episodes there was conduction failure in the central nervous system (CNS), namely the spinal cord dorsal columns, and in the afferent fibres in the peripheral nervous system (PNS). The following observations indicated that the conduction failure was mainly due to demyelination-induced conduction block: (1) rate-dependent conduction block in the CNS and PNS; (2) temporal dispersion due to slowing of PNS conduction; (3) restoration of PNS conduction by cooling; (4) restoration of CNS conduction by ouabain; (5) previously demonstrated histological evidence of primary demyelination in the dorsal columns, dorsal root ganglia and dorsal roots; and (6) the temporal association of restoration of conduction with remyelination. However, it is likely that CNS and PNS axonal degeneration, which occurs in this disease, also contributed to the conduction failure. In clinical remissions there was restoration of conduction in the CNS and PNS which can be explained by ensheathment/remyelination by oligodendrocytes and Schwann cells, respectively. In most rats during clinical episodes the cerebral somatosensory evoked potential was reduced in amplitude and prolonged in latency, which can be accounted for by demyelination and axonal degeneration in the CNS and PNS components of the afferent pathway. In 2 rats with episodes of EAE, however, this potential was markedly increased in amplitude, which might have been due to demyelination-induced conduction block of descending pathways that normally inhibit synaptic transmission in the afferent pathway. In well-established remission there was residual conduction failure in the CNS and PNS which can be mainly accounted for by axonal degeneration.
Animals↗
Cronkhite-Canada syndrome associated with peripheral neuropathy.
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Aged↗
Sensorimotor peripheral neuropathy in rheumatoid arthritis.
We describe 3 patients with severe sensorimotor neuropathy complicating rheumatoid arthritis. Two patients had evidence of vasculitis and an axonal neuropathy. These patients were unusual in that the neuropathy occurred early in the course of rheumatoid arthritis. The third patient had a demyelinating neuropathy with a high cerebrospinal fluid protein level, and is a probable example of a chronic inflammatory neuropathy occurring in rheumatoid arthritis. All patients improved or were stabilized with corticosteroid therapy.
Aged↗
Lack of neurological abnormalities in Lewis rats with experimental chronic serum sickness.
Serum sickness in man may occur after treatment with foreign proteins such as tetanus or diphtheria antisera, and in some patients leads to neurological complications such as neuropathy or encephalomyelitis. Many of the effects of serum sickness are associated with the deposition of antigen-antibody complexes in the tissues. Chronic serum sickness in the rabbit has previously been shown to cause perivascular inflammation and demyelination in the nervous system. We induced chronic serum sickness in the Lewis rat by daily intraperitoneal injections of bovine serum albumin (BSA) in male rats that had previously received footpad inoculations of BSA. Two animals died of anaphylaxis and 15 were observed for periods of 39 to 142 days. Three animals injected with 3 mg or 4 mg/day of BSA, and 6 animals injected with up to 16 mg/day of BSA had no clinical abnormalities when sacrificed. Six animals were injected with 36 to 40 mg BSA/day and, at the time of sacrifice, were lethargic and had ruffled fur, but no neurological signs. In these animals, the production of chronic serum sickness was confirmed by the presence of immune complex deposits in the kidneys. In the nervous system, there was no evidence of inflammatory cell infiltration either in the parenchyma or the vessel walls. Immunofluorescence studies identified deposits of immunoglobulin in the choroid plexus of chronic serum sickness rats but not in controls. Staining with antibodies to immunoglobulin, complement and BSA showed marked staining of blood vessels of the nerve roots of the animals with chronic serum sickness.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The neuropathology of chronic relapsing experimental allergic encephalomyelitis induced in the Lewis rat by inoculation with whole spinal cord and treatment with cyclosporin A.
Chronic relapsing experimental allergic encephalomyelitis was induced in Lewis rats by inoculation with guinea-pig spinal cord and complete Freund's adjuvant followed by treatment with low-dose cyclosporin A. In most animals, tail and limb weakness developed in a relapsing remitting pattern but in some these signs were persistent or progressive from onset. Histological studies during the early stages of clinically active disease (less than 25 days after inoculation) revealed inflammation and primary demyelination in the central nervous system (CNS), particularly the spinal cord, and in the peripheral nervous system (PNS), specifically the ventral and dorsal roots and dorsal root ganglia. Animals studied in the later stages of clinically active disease (greater than 28 days after inoculation) had extensive spinal cord demyelination but minimal PNS demyelination. In these animals, large plaques of demyelination with gliosis and prominent plasma cells occurred particularly in the thoracic spinal cord, and lesions of different ages were present within the spinal cord, CNS and PNS remyelination by oligodendrocytes and Schwann cells, respectively, was present in all animals studied later than 18 days after inoculation (the time of the first remission, if it occurred). In both early and late clinically active disease electron microscopy revealed macrophages invading and destroying CNS myelin sheaths. Active demyelination was sometimes found in regions of CNS remyelination, suggesting that remyelinated fibres were being attached. Axonal degeneration occurred in the spinal cord. During clinical remission there was CNS and PNS remyelination and much less inflammation; however, active demyelination still occurred to a limited degree.
Animals↗
Improvement in chronic hepatocerebral degeneration following liver transplantation.
Chronic progressive hepatocerebral degeneration with spastic paraparesis, dementia, dysarthria, ataxia, tremor, and neuropsychiatric symptoms follows long-standing portal-systemic shunting, is associated with structural changes in the central nervous system, and does not respond to conventional therapy for hepatic encephalopathy. A case of advanced chronic liver disease with severe, progressive hepatocerebral degeneration after 23 yr of portal-systemic shunting is reported in whom there was significant objective improvement in intellectual function and in the chronic neurological signs 3 mo after orthotopic liver transplantation and further improvement 12 mo after transplantation.
Adult↗
Familial occurrence of multiple sclerosis with thyroid disease and systemic lupus erythematosus.
Multiple sclerosis (MS) has some features which suggest it is an autoimmune disease. Autoimmune diseases frequently occur in families, and patients and families often have more than one type of autoimmune disease. However, there are few reports of MS occurring in patients or families with other autoimmune conditions. It is difficult to make a separate diagnosis of MS in a patient who has a systemic autoimmune disease such as systemic lupus erythematosus (SLE) or Sjögren's syndrome, because these diseases can affect the nervous system directly. However, it is possible to make independent diagnoses of MS and an autoimmune disease confined to another single organ in the same patient, or diagnoses of MS and SLE (or other autoimmune diseases) in different family members. Here we describe clinically definite MS in 2 sisters, one of whom had Graves' disease, and the other of whom had a daughter with SLE and with a high titre of anti-thyroid antibodies. Other female family members over 4 generations had histories of thyroid disease, MS and Addison's disease. Available family members were HLA typed. The MS patients were positive for HLA DR2. All but one of the affected family members were related to the proband on the maternal side, and all of these affected females shared an HLA haplotype. However, this haplotype was also present in unaffected individuals. Thus HLA type alone cannot account for the familial occurrence of these disorders. We conclude that, in this family, MS, like autoimmune thyroid disease and SLE, may be an autoimmune disease developing in genetically predisposed individuals.
Adult↗
The effects of prophylactic cyclosporin A on experimental allergic neuritis (EAN) in the Lewis rat. Induction of relapsing EAN using low dose cyclosporin A.
Experimental allergic neuritis (EAN) was induced in Lewis rats by inoculation with bovine intradural root myelin plus adjuvants. Animals treated with high dose (30 mg/kg) cyclosporin A (CsA) 3 times per week did not develop clinical EAN during the period of CsA treatment, but had an episode of EAN after cessation of CsA treatment. Animals treated with low dose (4 mg/kg) CsA 3 times per week developed EAN during the period of treatment, and after cessation of CsA treatment all of these animals developed relapsing EAN with disease continuing for up to four episodes. In contrast, 30-40% of untreated animals had a mild second episode of EAN but no further attacks. Histological studies performed in treated and untreated animals at the time of clinical episodes revealed inflammation and demyelination in the spinal roots and dorsal root ganglia. When animals were challenged with a second inoculation at age 7 months, one of 15 untreated control animals but none of the CsA treated animals developed an episode of EAN.
Animals↗
Hypothermia due to an ascending impairment of shivering in hyperacute experimental allergic encephalomyelitis in the Lewis rat.
Severe hypothermia and an ascending impairment of shivering are previously undescribed clinical signs in hyperacute experimental allergic encephalomyelitis (EAE) in the Lewis rat. These occurred in hyperacute EAE induced by inoculation with guinea pig spinal cord homogenate and heat-killed Bordetella pertussis. Hypothermia was first detected on day 6-7 post-inoculation, within 12-24 h of the onset of neurological signs, and became more severe as the disease progressed. Rectal temperatures less than or equal to 30 degrees C were common at ambient temperatures of 19-22 degrees C. Shivering was assessed by palpation and by cold tremor electromyography. Shivering was absent in the tail by day 6-7 post-inoculation. The impairment then progressed to affect the hindlimbs, thorax and occasionally the forelimbs. Shivering was absent in hindlimbs with only mild or moderate weakness. Histological studies revealed perivascular inflammation with polymorphonuclear and mononuclear cells, oedema, fibrin deposition, haemorrhage, primary demyelination and axonal degeneration in the spinal cord, dorsal root ganglia and spinal roots. The brainstem was also involved but the cerebral hemispheres, including the hypothalamus, were spared. The close relationship between the severity of hypothermia and the extent of shivering impairment indicates that reduced shivering is an important cause of hypothermia in hyperacute EAE. It is concluded that this impairment of shivering is due not to hypothalamic damage but to lesions elsewhere in the central and peripheral nervous systems.
Animals↗
Demyelination and early remyelination in experimental allergic encephalomyelitis passively transferred with myelin basic protein-sensitized lymphocytes in the Lewis rat.
Histological studies were performed on Lewis rats with experimental allergic encephalomyelitis (EAE) passively transferred by myelin basic protein (MBP)-sensitized syngeneic spleen cells in order to determine the relationship between demyelination and neurological signs. Neither inflammation nor demyelination was present on the day prior to the onset of neurological signs but both were present in the spinal roots and spinal cord on the day of onset of tail weakness (4 days after passive transfer). Demyelination and the neurological signs both increased over the next 48 h. There was evidence that the caudal roots were more severely affected than the rostral roots. The peripheral nerves were spared. Demyelination in the spinal cord was concentrated in the dorsal root entry and ventral root exit zones. The initial stages of repair of demyelinated spinal root fibres by Schwann cells were observed on the earliest day that clinical recovery commenced (day 7). At this time some demyelinated fibres were closely associated with debris-free Schwann cells, and occasional fibres were completely invested by 1-2 layers of Schwann cell cytoplasm. Remyelination (compact myelin lamellae formation) by Schwann cells was first observed in the spinal roots on day 9. By the time of complete clinical recovery (day 11) the majority of affected spinal root cores had thin new myelin sheaths. Repair of central nervous system myelin by oligodendrocytes was slower than peripheral nervous system myelin repair. Investment of demyelinated spinal cord axons by oligodendrocytes was observed on day 9, and remyelination by these cells was seen on day 10. We conclude that the neurological signs of passively induced MBP-EAE can be accounted for by demyelination of the lumbar, sacral and coccygeal spinal roots and spinal cord root entry and exit zones, and that the subsequent clinical recovery can be explained by investment and remyelination of demyelinated peripheral and central nervous system fibres by Schwann cells and oligodendrocytes respectively.
Animals↗
Recovery from acute experimental allergic encephalomyelitis in the Lewis rat. Early restoration of nerve conduction and repair by Schwann cells and oligodendrocytes.
Light and electron microscopic histological studies and electrophysiological studies were performed on Lewis rats with acute experimental allergic encephalomyelitis (EAE) induced by whole spinal cord or myelin basic protein to determine the mechanism of clinical recovery. In these animals, total clinical recovery from complete paraplegia may occur as early as 4 days after the onset of hindlimb weakness. These studies indicate that this recovery occurs at a time when there is restoration of nerve conduction in the peripheral nervous system (PNS) and central nervous system (CNS) and when most demyelinated fibres have been invested, and some partially remyelinated, by Schwann cells or oligodendrocytes in the PNS and CNS, respectively. These findings support the hypothesis that the neurological signs of acute EAE are due to demyelination in the PNS and CNS.
Animals↗
An intracranial arteriovenous malformation and palatal myoclonus related to pseudoxanthoma elasticum.
Pseudoxanthoma elasticum is a rare hereditary disorder of elastic tissue with central nervous system manifestations due to occlusive vascular disease and aneurysm formation. Here we report the first recorded case of an intracranial arteriovenous malformation (AVM) in a patient with pseudoxanthoma elasticum. The AVM, which was located in the pons, also had an unusual manifestation, namely palatal myoclonus.
Adult↗
Connective tissue disease mimicking multiple sclerosis.
Systemic lupus erythematosus, primary Sjögren's syndrome and systemic sclerosis may be associated with acute transverse myelitis and chronic relapsing neurological syndromes mimicking multiple sclerosis in the same individuals and/or their relatives. We now present three cases which suggest that there is a wide spectrum of connective tissue disorders mimicking multiple sclerosis and acute disseminated encephalomyelitis. These cases demonstrate that the diagnosis of multiple sclerosis should be kept under constant review by searching for the development of connective tissue disorders in the patients or their relatives.
Adult↗
Progressive encephalomyelitis with rigidity: a case report with magnetic resonance imaging findings.
A 52 year old woman presented with pain in the back and upper limbs and progressive weakness and sensory impairment of the upper and lower limbs. She developed frequent episodes of severe generalised muscle spasms associated with piloerection and hyperventilation. Nerve conduction studies and electromyography were normal. MRI demonstrated a lesion of the cervical spinal cord and lower brainstem. A biopsy of the cord revealed perivascular cuffing with mononuclear cells and inflammatory changes in the parenchyma, with increased numbers of microglia, reactive astrocytes and plasma cells. Following treatment with corticosteroids she showed substantial improvement.
Brain Stem↗
Assessment of demyelination in glycol methacrylate sections: a new protocol for cresyl fast violet staining.
A simple staining technique for nervous tissue is described. Tissue perfused with glutaraldehyde and formaldehyde and postfixed with osmium tetroxide is embedded in glycol methacrylate. One-micrometer sections are stained with 0.05% cresyl fast violet aqueous solution at 60 C for 5 min, washed with tap water and air dried. With this method the details of all nervous tissue elements are clearly demonstrated. The technique is particularly useful for assessing demyelination because the staining of axoplasm allows demyelinated axons to be well visualized.
Animals↗
The pathophysiology of myelin basic protein-induced acute experimental allergic encephalomyelitis in the Lewis rat.
Histological and electrophysiological studies were performed on Lewis rats with acute experimental allergic encephalomyelitis (EAE) induced by inoculation with guinea-pig myelin basic protein (MBP) and Freund's adjuvant. The histological studies showed demyelination in the lumbar, sacral and coccygeal dorsal and ventral spinal roots and to a lesser extent in the spinal cord, including the dorsal root entry and ventral root exit zones. The electrophysiological studies demonstrated reduced conduction velocities between the lumbar ventral roots and sciatic nerve. Conduction block was demonstrated at the ventral root exit zone of the lumbar spinal cord but was less severe than in rats with whole spinal cord-induced acute EAE. Recordings of the M wave and H reflex elicited in a hindfoot muscle by sciatic nerve stimulation showed a normal M wave, indicating normal peripheral nerve motor conduction, but a markedly reduced H reflex. The reduction in the H reflex is accounted for by demyelination-induced nerve conduction block in the dorsal and ventral spinal roots, intramedullary ventral roots and at the dorsal root entry and ventral root exit zones of the spinal cord. Demyelination and nerve conduction abnormalities were well established in the relevant lumbar segments on the day of onset of hindlimb weakness. It is concluded that demyelination in the lumbar ventral roots and to a lesser extent in the lumbar spinal cord, including the ventral root exit zone, is an important cause of hindlimb weakness in myelin basic protein-induced acute EAE in the Lewis rat.
Anesthesia↗