C5b-9 TERMINAL COMPLEX ACTIVATION IN CHRONIC INFLAMMATORY DEMYELINATING NEUROPATHY

Aim of the Study : Amplify neurological balance in patients with recent vertebral spinal cord disease to establish the extension and gravity of damage on anterior horn cells, motor and sensory roots and the presence of entrapment neuropathies.
Materials and Methods: Fourteen consecutive patients (13 males and 1 female), mean age: 42.9 years (range 24–65), an interval of time from lesion>1 and < 3 months with cervical lesions in nine cases and lumbosacral lesions in five cases. Central and peripheral nervous system and/or systemic diseases preceding trauma were excluded. Besides neurological evaluations and vertebral NMR/CT, standard EMG were performed: motor (M) and sensory (S) nerve conductions (NC), F-wave study, and extensive muscular needle study differentiated in relation to cervical or lumbosacral side of lesion.
Results: In cervical traumas 5 subjects showed complete medullar transversal lesion (C8-T1 in 4 cases, C7 in 1 case) and 4 subjects incomplete lesion. EMG data: show amplitude CMAP in 5 subjects, MNC reduction in 4 patients, F-Wave absence in 1 case. Normal SNC in 7 cases. No observed relation between gravity of clinical palsy and EMG alterations. At needle examination frequently presence of alterations often also over and under clinical level spinal cord lesion. In lumbar trauma we verified 3 cases with complete medullar palsy and 2 cases cauda equina syndrome as clinical aspects. EMG data: extreme MNC alterations in 2 of 3 cases with medullar palsy (normal in 1 case). In 2 cases with cauda equina syndrome we observed strict concordance between clinical and EMG aspects.
Conclusions: EMG can usefully propose as systematically associated investigation in patients with post-traumatic spinal cord diseases in order to define the localization and the gravity of neurological lesion and the contribution of lower motor neuron lesion to clinical palsy.     

AUTOMIC FAILURE AND NORMAL PRESSURE HYDROCEPHALUS IN A PATIENT WITH CHRONIC DEMYELINATING INFLAMMATORY NEUROPATHY

We described a male child of two years and three months affected by assial hypotonia, psicomotor retardation, muscular distal hypotrophy with hyporeflexia, dystonic movements and deafness. He was born from non-consanguineous parents by spontaneous caesarian twin delivery at 38 weeks. His sister is healthy. He came to our observation at 16 months of age. Screenings for metabolic diseases and CSF neurotransmitters and lactate were normal, whereas the serum lactate was mildly increased. Brain MRI showed delayed myelination, with the normal lactate at the spectroscopic study. EEG showed interemispheric asymmetry with epileptic discharges. EMG showed a neurogenic pattern. Molecular DNA analysis for Spinal Muscular Atrophy was negative. Muscle biopsy showed neurogenic injury and an absence of ragged red fibers; enzymatic assay showed a severe deficiency of Complex I (2.8 nmol/min/mg protein, n.v. 17–33) and a mild deficiency of Pyruvate Dehydrogenase (PDHC=0.47 nmol/min/mg protein, n.v.0.8-2).
The clinical features of patients with a dysfunction in mitochondrial metabolic pathways are variable. A PDHC deficiency leads to a graduated spectrum of neurological involvement starting from severe forms with death in the neonatal period, Leigh disease and carbohydrate-induced episodic ataxia. The most common features associated with a PDHC defect are delayed development and hypotonia. Patients with Complex I deficiency show a variable phenotype from fatal infantile encephalomyopathy to adult-onset myopathy; neurodegenerative disorders are also described: Parkinson's disease, dystonia and Leber's optic neuropathy. A combined PHDC and Complex I deficiency is rarely reported. We can make the hypothesis that a defect of a single enzyme (Complex I) can play a role on the other enzyme deficiency. The presence of a primitive PHDC and Complex I deficiency is unlikely be hypothesized since the parents are not consanguineous and a double genetic defect is improbable.     

INFLAMMATORY DEMYELINATING NEUROPATHY IN C57BL/KaLwRij MICE

Neuropathies associated with monoclonal gammopathy (MG) in humans have been extensively studied in the past few years, but experimental models have proved difficult to create. C57BL mice are prone to develop benign MG and it has been reported that some of these mice with benign IgG MG present an inflammatory demyelinating neuropathy (IDN). In order to verify such findings, the serum and the sciatic nerve of the first group of 28 C57BL/KaLwRij mice were examined: none of 10 mice with normal serum showed ultrastructural abnormalities in the sciatic nerve, while lesions of IDN were present in three out of 10 mice with benign IgG MD, in two out of seven with benign IgM MG, and in a mouse with Waldenström–like lymphoma. The second group of animals was studied in the same way; it was composed of seven C57BL mice with transplanted multiple myeloma, and six C57BL mice with Morbus Waldenstrom–like lymphoma. In none of these animals, which were younger than those of the first group, was any lesion of IDN observed.     

COST-BENEFIT RATIO OF INTRAVENOUS IMMUNOGLOBULIN TREATMENT IN CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

Intravenous immunoglobulin (IVIG) is considered an efficacious but expensive treatment in dysimmune polyneuropathies. Nevertheless, to date, no studies have been conducted on the cost of this therapy. We retrospectively studied 21 patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (idiopathic-CIDP and CIDP-MGUS), comparing the clinical response and costs of IVIG therapy with those of plasma exchange (PE). Patients were treated either with IVIG (400 mg/Kg/die for five days) or PE (6 exchanges in 3 weeks). Responders continued the same therapy, which was progressively tapered down to one IVIG infusion or one PE monthly. IVIG nonresponders received PE and vice versa. Patients were followed for a period ranging from 3 to 67 months (median: 29 months). The modified Rankin disability scale was used to determine functional impairment at baseline and during treatment.
Eleven of 21 patients (52%) improved with the first choice of treatment. Of the remaining 10 patients, 3 benefited from the alternative treatment; 2 patients who did not respond to the alternative treatment were again treated with the first choice therapy and subsequently improved; 2 patients on IVIG abandoned the therapy. One nonresponder to IVIG is currently receiving PE. The overall response rate to the two therapies was similar. The mean cost per patient was 1,128,000 lire/session for PE therapy (excluding equipment and medical staff costs) and 1,204,000 lire/dose for IVIG therapy. However, the responders to PE required a longer treatment than responders to IVIG.     

UNMYELINATED NERVE FIBER DEGENERATION IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.     

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP) ASSOCIATED WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Up to now four patients with acute, purely motor, demyelinating neuropathy and conduction blocks have been described. Three cases had Campylobacter Jejuni (CJ) enteritis. In two ab anti-GM1 were detected, along with ab anti-GalNAc-GD1a in one. Two men (41 and 20 years old) developed weakness respectively ten days after enteritis and rubella. Examination showed in both proximal and distal weakness in all limbs with no sensory loss. Tendon reflexes were normal in the first patient, and brisk in the second. CSF proteins were increased. Serological tests did not support a recent CJ infection. High titres of IgG anti-GD1a and IgM anti-GM1 were found in the first patient. Electrophysiological examination showed, since the first days after onset, partial motor conduction block in ulnar nerves of the first patient and in eight motor nerves of the second patient. Sensory conductions were normal even across the sites of conduction block. Four plasmaphereses were performed. In the first patient conduction blocks gradually improved to disappear in 3 weeks without excessive temporal dispersion of proximal motor responses. In the second patient conduction blocks disappeared in 8–16 weeks with development of excessive temporal dispersion in 4  /  8 nerves.
We deem that acute motor neuropathy with conduction block is a GBS variant in which only motor fibers are involved with early conduction block in intermediate nerve segments. Our electrophysiological findings indicate that conduction block may be of the "anaesthetic type" followed by fast recovery or may progress to de-remyelination with a slower course.     

NEUROPHYSIOLOGICAL DETERMINATION OF THE CARPAL TUNNEL SYNDROME IN PATIENTS WITH CHRONIC DEMYELINATING POLYNEUROPATHY

Clerici R., De Riz M., Corrà B., Baron P.L., Scarpini E., Conti G., Scarlato G.
Department of Neurological Sciences, Univ. of Milan, IRCCS Ospedale Maggiore, Milano
The specific spinal cord lesion caused by vitamin B12 deficiency is known as subacute combined degeneration (SCD). This is a rare cause of demyelination of the dorsal and lateral columns of spinal cord and even more rarely of peripheral nerves, optic nerve and brain.
We report a case of SCD in a vegetarian 55-year-old fe- male who presented with 6 weeks history of gradually progressive paresthesia involving thoracoabdominal skin below C5 dermatome and both lower limbs and postural instability due to a mild impairment of deep sensation. Hematological tests revealed abnormal Medium Corpuscular Volume (MCV) without anaemia and low vitamin B12 levels. The cause of this deficiency was secondary to atrophic gastritis. A spinal cord MRI demonstrated two T2-weighted hyperintense signal alterations (C1-C3 and C3-C4). She was treated with parenteral vitamin B12 supplements and experienced gradual improvement in her clinical symptoms. Repeat MRI of cervical spinal cord after 5 months showed a relevant decrease in the areas of abnormal signal. In other documented cases reported in literature, there was a precocious clinical improvement, while the MRI lesions recovered with a delay. However, it is essential to recognize SCD among the different demyelinating diseases and treat it as soon as possible.     

E-CADHERIN AND β-CATENIN COMPLEX IN ANIMAL MODELS OF HEREDITARY DEMYELINATING PERIPHERAL NEUROPATHY

E‐cadherin, a major adhesive glycoprotein in Schwann cells (Fannon et al., 1995), is localized at the paranode, at Schmidt‐Lanterman incisures in the peripheral nerve along with β‐catenin, and associated with adherens‐type junctions. To investigate the functional role of E‐cadherin/β‐catenin complex in Schwann cells biology, we studied expression and localization of E‐cadherin and β‐catenin complex in sciatic nerve from normal mice and from animal model of hereditary demyelinating peripheral neuropathy. We found that E‐cadherin mRNA and proteins levels are regulated in normal mouse sciatic nerve during development like other myelin proteins. Furthermore, E‐cadherin expression in regenerating nerve is mediated by axonal/SC interaction. On the contrary, β‐catenin mRNA and protein levels did not change during development and following nerve lesion. Moreover, E‐cadherin/β‐catenin complex localization is altered in P0 knockout mice (P0‐/‐). In fact, E‐cadherin was diffusely distributed throughout the fibers in an unusual beaded pattern of staining, and β‐catenin was found in the perinuclear region of P0 ‐/‐ Schwann cells. Furthermore, E‐cadherin/β‐catenin complex localization is altered in peripheral nerve from other model of primary demielination where myelin compaction is lacking, such as Trembler‐J mice, while it is normally localized in Trembler mice, where demyelination is less severe and compaction is preserved. In conclusion, it appears that the process that leads to a restricted localization of E‐cadherin at the paranodal region is highly regulated and is disrupted in the peripheral nerve lacking compaction. Therefore, compaction contributes to the process of reorganization of the Schwann cells membrane during myelination and formation of a mature paranode. Altered E‐cadherin/β‐catenin complex localization, associated with absence of adherens junctions lead to changes in the structure of the paranodal region with important consequences on the molecular architecture of the Node of Ranvier, which lead to an altered transmission of impulses along axons, having important consequences in the pathogenesis of hereditary demyelinating peripheral neuropathy.     

EOSINOPHILIC ROD-LIKE STRUCTURES IN MYELINATED FIBERS OF HAMSTER SPINAL ROOTS

Eosinophilic rod-like structures in myelinated fibers of hamster spinal roots
The spinal roots of homozygous mutant hamsters carrying the recessive gene for hind leg paralysis as well as normal controls were studied at both the light and electron microscopic levels. Eosinophilic rod-like inclusions essentially identical to those seen in human brains were observed in the inner loops of Schwann cells of myelinated fibers of the spinal roots. The electron microscope revealed inclusions with the characteristic 'lattice-like' structure as well as other purely filamentous bodies. Both mutant and normal hamsters displayed these changes but they were more frequent in mutant animals.     

PERSISTENT MULTIPLICATION OF AXON-ASSOCIATED CELLS IN THE SPINAL ROOTS OF DYSTROPHIC MICE

Perkins C. S., Bray G. M. & Aguayo A. J. 1980 Neuropathology and Applied Neurobiology 6, 83–91
Persistent multiplication of axon-associated cells in the spinal roots of dystrophic mice
Axons which lack Schwann cells characterize the spinal roots of dystrophic mice. In these nerves, two types of cells are associated with large axons– typical Schwann cells which ensheath and myelinate individual axons and 'uncommitted' cells which closely contact some axons but do not unsheath them normally. Although neonatal Schwann cell multiplication in dystrophic spinal roots is less than normal, the 'uncommitted' cells continue to multiply in adult animals. Thus, these cells are presumably responsive to the mitogenic stimulus of axons, but are unable to extend radially and longitudinally to form a myelin sheath. This disorder of axon-sheath cell interactions could be due to an intrinsic abnormality of Schwann cells or a failure of the mechanisms whereby axons induce Schwann cell differentiation.     

A MODEL OF CHRONIC SPINAL CORD COMPRESSION IN THE CAT

Fish C.J. & Blakemore W.F. (1983) Neuropathology and Applied Neurobiology 9 , 109–120
A model of chronic spinal cord compression in the cat
An experimental method of producing chronic compression of the cat spinal cord is described. A ligature placed around the lumbar spinal cord of 3-month-old kittens restricts the growth of the spinal cord to produce compression with a slow onset and an insidious progression. The methods of following the clinical progress of affected animals and of sampling the spinal cord after perfusion fixation are presented. The sampling method used allowed analysis of the three dimensional distribution of the pathological changes caused by the compression. These changes were not symmetrically distributed: the spinal cord caudal to the ligature became swollen and extensive partial demyelination occurred under the ligature and caudal to it, in the swollen region of the cord, whereas cranial to the ligature there was only minimal damage. It is concluded that the method produces a useful model of chronic compression of the spinal cord, which will be of value in studying partial demyelination.     

INCREASED DIAMETER OF DEMYELINATED AXONS IN CHRONIC MULTIPLE SCLEROSIS OF THE SPINAL CORD

In an autopsied case of chronic multiple sclerosis, many axons in some demyelinated plaques of the spinal cord had remarkably increased diameters and reduced argentophilia. The increase in axonal diameter extended for some distance and was restricted to the demyelinated areas. A review of 22 autopsy cases of chronic multiple sclerosis revealed similar findings in the plaques of the spinal cord in seven cases. They were also noted in the brain but much less frequently. On electron microscopy, the neurofilaments in these enlarged demyelinated axons were not closely packed but were separated by an increased amount of electron-lucent axoplasm. It is thought that this finding may be a manifestation of increased water content in the axoplasm secondary to increased permeability of the demyelinated axolemma.     

CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN THE GUINEA-PIG: IN-VITRO ANALYSIS OF MENINGEAL INFLAMMATORY CELLS

Inflammatory cells from the meninges of guinea-pigs with chronic relapsing experimental allergic encephalomyelitis (CREAE) have been isolated and compared to a similar cell population obtained from guinea-pigs with acute EAE. A mean of 6.2 x 10(6) cells were recovered from the brains of animals with CREAE while a similar number of cells (8.0 x 10(6)) was obtained from animals with acute EAE. Only 5.3% of the cells from animals with CREAE were found to be phagocytic in contrast with 28% of the cells obtained from animals with acute EAE. The meningeal inflammatory cells from guinea-pigs with CREAE did not respond, in the lymphocyte transformation test, to specific antigens or to mitogen. Peritoneal exudate cells (PECs) from these animals did, however, proliferate in the presence of tuberculin and of mitogen, but not with the brain antigen myelin basic protein (MBP). In contrast, the meningeal inflammatory cells from animals with acute EAE did respond to mitogen and PECs from the same animals responded to both the specific antigens and to the mitogen. The meningeal inflammatory cells and PECs from the guinea-pigs with CREAE did, however, behave in a similar manner to similar cell populations obtained from guinea-pigs fully protected against clinical signs of acute EAE.     

ENLARGEMENT OF THE RECEPTIVE FIELD SIZE TO LOW INTENSITY MECHANICAL STIMULATION IN THE RAT SPINAL NERVE LIGATION MODEL OF NEUROPATHY

Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15–50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.     

ALTERED BRAIN WAVE ACTIVITY IN PERSONS WITH CHRONIC SPINAL CORD INJURY

This study investigated brain wave activity associated with spinal cord injury (SCI). Electroencephalograms (EEG) were compared between 10 individuals with SCI and 10 age and sex matched able-bodied controls using a 64-channel EEG montage. SCI participants had chronic (>12 months) paraplegic clinically complete injuries. The 64 channels of EEG data were spread diffusely over the cortex and were compared for delta (2–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) wave components of the EEG frequency spectra. No significant magnitude or directional changes were found in the delta (2–4 Hz) or theta (4–8 Hz) wave frequency bands between these two groups. However, significant and consistent decreased alpha wave (8–13 Hz) and increased beta wave activity (13–30 Hz) were found in the SCI participants across the cortex compared to the able-bodied control group. These findings suggest that the SCI group have increased neural processing compared to the able-bodied individuals, which may be related to ongoing reorganization of brain structures following SCI.     

GLIAL BUNDLES IN SPINAL NERVE ROOTS: A FORM OF ISOMORPHIC GLIOSIS AT THE JUNCTION OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

A morphologic study of the spinal nerve roots was undertaken in three cases of Werdnig-Hoffmann disease to investigate the phenomenon of glial bundle formation. The glial elements extended along the ventral roots as discrete cylindrical bundles comprising a large number of parallel astrocytic processes and sparsely scattered cell bodies all enclosed by a basal lamina. The bundles tapered off at a variable distance from the root exit zones. The early stage of glial bundle formation was characterized by the protrusion of astrocytes into the neurilemmal tubes containing degenerated myelinated axons. It was concluded that axonal degeneration, evoking a glial reaction, was the initial event in this process. Subsequently, the reactive astrocytes from the vicinity of the root exit zones enter the neurilemmal tubes previously occupied by myelinated axons and migrated into the domain of the peripheral nervous system in an orderly fashion. Thus glial bundle formation might be considered a special form of isomorphic gliosis occurring in Werdnig-Hoffmann disease and also in several other conditions all sharing a common feature, namely, degeneration of axons within the spinal nerve roots.     

EXPERIMENTAL TRACTION INJURIES OF VENTRAL SPINAL NERVE ROOTS. A SCANNING ELECTRON MICROSCOPIC STUDY

The aims of this experimental scanning electron microscopic study were to identify the levels at which cervical ventral nerve roots, or the rootlets by which they are attached to the spinal cord, rupture under traction and to document the resulting damage. This information would provide the basis of a rationale for repairing rootlet avulsions which may follow brachial plexus traction injuries in man and which cause severe impairment of upper limb function. Traction was applied to C4 to T1 ventral roots until rupture occurred, in 10 freshly fixed and three living anaesthetized Wistar albino rats and in one human post-mortem specimen. Rupture occurred at the rootlet-cord junction in 80% of cases. Most individual myelinated fibres broke at the central-peripheral nervous system (CNS-PNS) transitional node which, in the cervical region, lies at the bottom of an endoneurial invagination surrounding each fibre and extending deep to the cord surface. Fibre rupture at more distal levels occurred internodally, and a length of axon commonly protruded well beyond the level of sheath rupture. Some sheaths broke cleanly across but the torn surfaces of others tapered, perhaps because of rupture at Schmidt-Lanterman incisures. The cellular and connective tissue rootlet sheaths ruptured where they were continuous with the pia mater. Ruptured fixed and unfixed tissues were ultrastructurally similar. It is clear from the findings of this study that regeneration would take place entirely in a PNS environment. The endoneurial invaginations would ensure that sprouts emerging from transitional nodes would be guided distally into rootlets surgically apposed to the torn transitional zone.