Group psychotherapy and the mosaic adolescent society

Discussion of the influence of peer group mores and values on the adolescent patient's dysfunctional behaviors and treatment outcome. When the group therapist thinks peer, the group will focus on important issues such as inclusion, acceptance and awareness of the contrasting beliefs of the numerous peer subcultures within adolescent society. Strategies and approaches to create a therapeutic group milieu and structure are outlined to enable unwanteds to enter peer groups which support rather than impede the attainment of treatment goals. The need for leadership to be responsive to group members who have not experienced negentropic or functional systems is emphasized.     

Zur Frage des Off-On-Effektes bei Levodopa-Behandlung des Parkinsonismus

Zusammenfassung Tagesschwankungen der Leistungsfähigkeit bei Parkinsonkranken unter langdauernder Levodopabehandlung sind als sogenanntes Off-On-Phänomen bekannt. Reduzierter Proteingehalt in der Nahrung soll diesen Effekt bei Kranken, die nur mit L-Dopa allein behandelt werden, beheben können, nicht aber bei denjenigen, die eine Behandlung mit L-Dopa Dekarboxylasehemmer erhalten (Cotzias et al.). Die Hypothese von Cotzias beruht auf der Annahme, daß eine Transportkonkurrenz zwischen L-Dopa und Aminosäuren zu den Hirnganglien besteht.Um diese Ergebnisse zu prüfen, wurde bei 23 Parkinsonkranken mit Off-On-Phänomen der Einfluß einer proteinarmen Nahrung untersucht.Alle Patienten waren 5–8 Jahre mit L-Dopa vorbehandelt und erhielten zumindest in den letzten 3 Jahren eine Kombinationsbehandlung mit Dopa/Dekarboxylasehemmer. Der Eiweißgehalt der Nahrung wurde auf 25 g pro Tag beschränkt (weniger als 0,5 g pro kg Gewicht) und dies für eine Zeit von 1–4 Monaten.In 6 Fällen konnte eine deutliche Besserung mit Verminderung des Off-On festgestellt werden, in 1 Fall kam es zum völligen Verschwinden des Phänomens. Eine auffallende Besserung der allgemeinen Leistungsfähigkeit konnte in weiteren 5 Fällen beobachtet werden und eine objektive Besserung der Symptome, aber nur während der Off-Periode, festgestellt werden. Die restlichen 12 Fälle haben nicht angesprochen. Bei allen Patienten mit Hyperkinesie wurde eine Steigerung des Symptoms während der Diätperiode beobachtet. Eine Abhängigkeit von Diät zum Alter, Schwere, Dauer der Krankheit und der Dopabehandlung konnte nicht festgestellt werden. Der mögliche Mechanismus des Off-On-Phänomens sowie einige Vorschläge es zu beeinflussen werden dargestellt.

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The off-on phenomenon during treatment of Parkinson's disease with Levodopa

Summary The fluctuation in daily performance of Parkinson patients on long-term L-dopa therapy is known as the so called off-on phenomenon. Cotzias et al. found that a low protein diet is able to control this phenomenon in patients taking L-dopa alone but not in those receiving a combination of L-dopa and decarboxylase inhibitor. The author's hypothesis was based on the competition between the alimentary aminoacids and L-dopa for transport to the brain ganglia.In our attempt to prove the findings of Cotzias group we tested the influence of a low protein diet on 23 Parkinson patients manifesting the off-on phenomenon. All had been pretreated with L-dopa for 5–8 years and taking dopa DI for a minimum of 3 years. The protein intake was limited to 25 g/day (which is less than 0.5 g/kg body weight) for 1–4 months.In 6 cases there was a marked improvment with reduction of the off-on effect, and in one it disappeared completely.A distinct improvement of general capability was seen in the other 5 cases, and an objective improvement of the symptoms was noted, exept during the off period. No response could be observed in the remaining 12 cases. All cases with hyperkinesia showed an augmentation of this symptom during the use of the diet. The diet restriction was not found to be correlated with age, stage, duration of illness or duration of dopa treatment. The possible mechanism of the off-on phenomenon and some suggestions to influence it, are presented.

     

Succinoxidase activity in reticular neurons of hyperactive rats

Summary The succinoxidase activity of single neurons from the reticular formation was measured with the Cartesian diver technique. The average activity of nerve cell bodies from the nucleus gigantocellularis or pontis caudalis from control rats was 4.5 l O₂×10^–4 per hour at 37°C. After rats had received --iminodipropionitrile, the succinoxidase activity of the same type neuron increased to an average of 8.0 l O₂×10^–4. It was suggested that this increase was of etiological significance for the symptoms of hyperactivity which developed later. Also when --iminodipropionitrile had been added to the reticular neurons from normal rats in vitro, the succinoxidase activity increased to 8.4 l O₂×10^–4 per hour.Supported by USPH Grant NB 1305.     

Intelligence and temperament as protective factors for mental health. A cross-sectional and prospective epidemiological study

The Sjöbring system of personality dimensions measuring intellectual capacity, activity, impulsivity and sociability was used to study possible salutogenic (i.e. causes of health) effects. The study comprised 590 subjects investigated in 1947, 1957, 1972 and 1988–1989 in the Lundby project, an epidemiological study in Sweden. Psychiatric diagnoses were made in 1947, 1957 and 1972. Mental health was estimated in 1988–1989 using the concept love well, work well, play well and expect well. The Sjöbring dimensions were clinically assessed in 1972. Both in the concurrent study in 1972 and in the prospective study in 1988–1989 super capacity (high intellectual function), super validity (high activity level) and super solidity (low impulsivity) were statistically associated with lower frequencies of certain psychiatric diagnoses and a higher frequency of positive mental health. These variables are proposed to increase coping capacity, and therefore increase stress resilience.     

A case history analysis of the “manic type” and the “melancholic type” of premorbid personality in affectively ill patients

Summary The use of case histories in examining the premorbid personality of affectively ill patients is especially useful in the case of patients with a predominantly manic course of the disorder, because this kind of affective illness is very rare. The concept of the manic type of premorbid personality is described in detail and contrasted with the concept of the melancholic type often found in patients with a purely depressive course of the illness.     

Apolipoprotein E co-localizes with newly formed amyloid β-protein (Aβ) deposits lacking immunoreactivity against N-terminal epitopes of Aβ in a genotype-dependent manner

Different types of amyloid -protein (A)-containing plaques occur in brains of Alzheimers disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the A peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in A transport and clearance, and the 4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of A deposition. To address the issue of whether binding of apoE to A is involved in initial A deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of -amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed A deposits detectable with anti-A₄₂ but not with antibodies raised against N-terminal epitopes of A. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of A. The failure of N-terminal epitopes of A to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-A complexes, in which the N-terminal epitopes of A are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE 4/4 cases than in non-APOE 4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of A deposits.     

Immunohistological study of senile brains by using a monoclonal antibody recognizing β amyloid precursor protein: significance of granular deposits in relation with senile plaques

Summary Immunochemical analyses revealed that a monclonal antibody Am-3 recognized amyloid precursor protein (APP) in senile plaques extracted from Alzheimer's brain, but did not recognize amyloid protein. Immunohistochemically, however, the staining pattern of Am-3 in frozen section of Alzheimer's brain was almost the same with that of rabbit polyclonal antibody to amyloid peptide which could recognize both amyloid protein and APP. In other words, APP was present in senile plaques of various types, cerebrovascular amyloid and granular deposits. The granular deposits were 5–10 m in size and laminarily distributed in the 1st, 3rd and 4th layers of cerebral cortex. They were especially abundant in 1st and 4th layers where senile plaques were usually fewer in number. Although the distribution in the cerebral cortex was different between the senile plaques and the granular deposits, the number of the granular deposits was well correlated with that of senile plaques. The granular deposits were negative in Congo-red birefringence, but contained amyloid protein as well as APP fragment judging from positive staining by both Am-3 and polyclonal antibody to synthetic amyloid peptide. Thus, they could be regarded as pre-amyloid.     

A study of the capacity of myelinated and unmyelinated nerves to induce experimental allergic neuritis

Summary The capacity of myelin-free Schwann cells to induce EAN was investigated. Human foetal peripheral nerve and human adult abdominal vagus nerve, both containing little or no myelin, failed to induce EAN when injected intradermally (together with Freund's adjuvant) into rabbits. In contrast, human adult sciatic nerve, which is heavily myelinated, induced characteristic signs and histopathology of EAN. Thus in the myelin-free antigens Schwann cell plasma membrane, from which myelin is apparently derived, failed to induce EAN. Reasons for this paradox are discussed.     

Loss of perineuronal net N-acetylgalactosamine in Alzheimer’s disease

The perineuronal net (PN), a specialised region of extracellular matrix, is interposed between the neuronal cell surface and astrocytic processes. It is involved in the buffering of ions, in the development, stabilisation and remodelling of synapses and in the regulating the neuronal microenvironment particularly around the parvalbumin-positive GABAergic neurons. We have investigated the relative preservation of Wisteria floribunda agglutinin (WFA)-positive PNs and parvalbumin-positive neurons in Alzheimers disease (AD), and the relationship of WFA-positive PNs to parenchymal tau, amyloid -peptide (A) and MHC class II antigen (a marker of activated microglia), in paraffin sections of 100 cases with AD and 45 controls. The density of PNs that could be labelled with WFA, which binds to the N-acetylgalactosamine (GalNAc) residues of chondroitin sulphate proteoglycans, was reduced by about 2/3 in AD (P<0.001). In contrast, the density of parvalbumin-positive neurons did not differ significantly between AD and controls. Combined fluorescence imaging showed granular disintegration of WFA labelling around some parvalbumin-positive neurons. There was no significant difference in the amount of phosphorylated tau, A or MHC class II antigen in areas with and without WFA-positive PNs. In AD, there is marked loss of PN GalNAc that is not topographically related to neurofibrillary pathology, parenchymal A load or activated microglia. Although the parvalbumin-positive neurons themselves are relatively spared, the loss of PN GalNAc, which maintains a polyanionic microenvironment around neurons, is likely to impair the function of these inhibitory interneurons. This could in turn lead to increased activity of the glutamatergic and other neurons onto which they synapse.     

Light and electron microscopic studies of “nude” mice CNS after subcutaneous administration of the E variant of the encephalomyocarditis (EMC) virus

Summary Sixteen 3 month old nude mice, 24 of their litter mates and 30 Swiss mice were injected subcutaneously with 0.1 ml suspension of the E variant of the encephalomyocarditis (EMC) virus. While the mortality rate of the litter mates and Swiss mice during 5–7 days after inoculation was more than 40%, none of the nude mice died during the experiment. The surviving animals were sacrificed at 24 h intervals from day one to seven days after injection. Brain suspensions assayed for the presence of the virus yielded significant titers at 24 h in all groups, which increased during 7 days. The litter mates and Swiss mice showed proliferation of lymphocytes and microglial cells in the perivascular areas of the brain during the fifth to the seventh day. The nude mice, on the other hand, displayed no perivascular lymphocytic infiltration during the same periods. Ultrastructurally, all groups showed aggregates of ribosomes in the cytoplasmic matrix on the third day, which became enlarged in size on the 5th day. At 7 days, both litter mates and Swiss mice showed an increased number of necrotic cells, while these changes were not observed in the nude mice. These findings suggest that the high mortality rate in immunologically normal mice was related to the efforts of T cells to eliminate virus-infected cells and to produce extensive necrosis, while T cell-depleted animals showed good survival rates.     

Characterization of amyloid deposits in biopsies of 15 patients with “sporadic” (non-familial or plasma cell dyscrasic) amyloid polyneuropathy

Summary Review of the clinical and laboratory findings of 39 patients with amyloid polyneuropathy (AP) showed 12 cases to be hereditary and 12 to be associated with plasma cell dyscrasia (PCD). The remaining 15, termed sporadic AP, had neuropathy clinically indistinguishable from the other two groups but without a clinicopathologically identified PCD or positive family history. In an attempt to identify the type of amyloid in sporadic AP, the immunoreactivity of amyloid deposits was investigated using specific antisera raised against the following different chemical types of amyloid fibril proteins: variable regions of amyloid light chains (A) and (A), amyloid protein AA, and prealbumin. It was found that the amyloid in sporadic AP had A antigenic determinants in ten cases, A in one and prealbumin in three; in one case, the A nature of amyloid was confirmed biochemically on the extracted amyloid fibrills. Thus, the most common type of AP in our population appears to be the sporadic form. In sporadic AP, the amyloid is most commonly of immunoglobulin light chain origin, even in the absence of overt PCD, and it can be rapidly categorized immunocytochemically to determine therapeutic directions or provide genetic guidance.     

Autoradiographic studies of protein turnover in motoneurons of IDPN-treated rats

Summary Autoradiography was performed in order to envisage the turnover of H³-leucin labeled protein in the perikarya of spinal motoneurons and in the axonal balloons formed after repeated administrations of IDPN (--iminodiproprionitrile) in rats.These results suggested that (1) there was no significant, if any,in situ protein synthesis within the axon balloons, (2) the protein turnover was not appreciably altered in the perikarya of the control and IDPN-intoxicated rats, and (3) the labeled protein collected in the axon balloons seemed to be transported from the perikarya to which they were linked with short axonal segments (30 in average length).Supported in part by U.S. NIH Institutional Research Grant (and Neurology Foundation).     

White matter amyloid in Alzheimer's disease brain

Amyloid -protein (A) deposits in the white matter were investigated by the double immunohistochemical staining for A and neuritic, glial or vascular components. Reactive astroglia and neurite abnormality were absent around A deposits in the white matter (w-A) even those with a core. The association of w-A with blood vessels was not consistent. Aggregates of activated microglia were found to be the sole but a consistent accompaniment of A deposits even in the absence of other components such as neuron, synapse, neurite abnormality and reactive astroglia, as observed in the white matter. This suggests that the aggregates of activated microglia most likely represent one of the factors promoting the process of A deposition.     

Meningiomas with a non-meningotheliomatous component

Summary Seven cases of meningiomas with pseudopsammoma bodies have previously been described in the literature. Two additional cases are presented. Electron microscopy of the cells surrounding the pseudopsammoma bodies reveals an ultrastructure different from that of the meningotheliomatous cells. It is concluded that meningotheliomatous meningiomas with pseudopsammoma bodies are mixed tumours, including a non-meningotheliomatous component, the origin and significance of which is uncertain.     

Ultrastructural investigations of peripheral nerves in neuronal ceroid-lipofuscinoses (NCL)

Summary Specimens of brachial plexus, sural nerve and two cranial nerves of one patient with the Jansky-Bielschowsky type and 3 patients with the Spielmeyer-Sjögren type of NCL were studied by electron microscopy. Significant light microscopic changes were absent in all specimens. Ultrastructurally, curvilinear and/or fingerprint inclusions were present in each case, located chiefly in Schwann cells. These diagnostic findings were, however, overshadowed by masses of lamellar -granule-like cytosomes, usually not mixed with curvilinear or finger-print profiles in the juvenile cases and only rarely associated with curvilinear profiles in the late infantile case. Since secondary changes of axons and myelin sheaths were mild, these lamellar cytosomes might indicate chronic damage to Schwann cells, perhaps by wear and tear as seen in aging as well as NCL. On account of the abundance of -granules in NCL, peripheral nerve biopsy appears less suitable for confirming this diagnosis than biopsy of skin, striated muscle and rectal tissue.These investigations were supported by USPHS grant NS-04607 and by grants from the Children's Brain Diseases Foundation, San Francisco, U.S.A., and the Deutsche Forschungsgemeinschaft, SFB 33.     

Elektronenmikroskopie der Hämangioblastome des ZNS und der angioblastischen Meningiome

Summary 4 hemangioblastomas of the cerebellum, 1 of the choroid plexus, 1 of the spinal cord, and 3 angioblastic meningiomas of the brain were investigated with the electron microscope. They all show a similar histological arrangement of vessels, intervascular cells (Zwischenzellen), and the intercellular space. The vessels of the tumors regardless where they originate from are identical in their appearance. They differ from autochthonous vessels by the irregular form of the endothelium and the presence of pores. The Zwischenzellen of hemangioblastomas are not so uniform as those of angioblastic meningiomas. Corresponding to differences in the nucleus/cytoplasma ratio, the development of the ER and the number of cytofilaments as well as the content of lipid droplets hemangioblastomas can be subdivided in 4 types. Nevertheless they constitute a cytological unity. In 3 hemangioblastomas mast cells were found. glial cells mixed up with tumor cells are present only in the border of tumorous and nervous tissue. The extracellular space is filled either with a protein-rich exsudate or with collagen fibrils. — The electron microscopic findings support the histological identity of hemangioblastomas and angioblastic meningiomas. The relation of Zwischenzellen to the vessel walls, their similarity to endothelial cells, and their tendence to form basement membranes indicate that they derive from blastomatous vessels.

Meinem verehrten Lehrer, Herrn Prof. Dr. Gerd Peterz, zum 8. Mai 1971 zugeeignet.     

Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer’s disease with the neurotrophic compound Cerebrolysin™

Summary. Increased production and reduced clearance of amyloid (A) plays a central role in the pathogenesis of Alzheimers disease (AD). We have recently shown that the neurotrophic peptide mixture Cerebrolysin (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimers disease (AD). Since in AD, potentially toxic A aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against A showed that Cbl decreased amyloid deposition around the blood vessels in a time dependant manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with A in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing A accumulation and promoting the preservation of the cerebrovasculature.     

GSK-3β in cerebrospinal fluid of schizophrenia patients

Summary. Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970s with few definitive results. We have recently found 40% reduced protein levels of GSK-3 in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3 was not successful. In this study we aimed to find whether the reduction in brain GSK-3 is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3 protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients postmortem brain.     

Golgi-like demonstration of “dark” neurons with an argyrophil III method for experimental neuropathology

Summary A silver method is proposed for the selective, well-contrasted and reproducible demonstration of dark neurons in frozen, vibratome and paraffin sections cut at a thickness of 5 to 200 m from aldehyde-fixed brains. The Golgi-like staining of the dendrites enables asorting of dark neurons according to characteristic neuron classifications. The staining procedure includes an esterification with 1-propanol, a treatment with diluted acetic acid and development. The esterification strongly increases the argyrophilia of both dark neurons and mitochondria. Unwanted co-staining of mitochondria is suppressed by the acetic acid treatment, while a special developer is used to render the staining controllable. The applicability of the method to experimental neuropathology is demonstrated by Golgi-like staining of dark neurons in rat brains exposed, before transcardial perfusion-fixation and delayed autopsy, to various pathological conditions including ischemia, hypoglycemia, trauma, status epilepticus, deafferentation and poisoning with kainic acid, colchicine and sodium azide, respectively.     

Die Bedeutung der diskontinuierlichen Zonierung des Immunglobulinbereiches für die Diagnose neurologischer Erkrankungen

Zusammenfassung 1. 340 Patienten, welche bei der agarelektrophoretischen Auftrennung der Liquorproteine eine diskontinuierliche Zonierung im Bereiche der -Globuline zeigten, wurden bezüglich Verteilung dieser clonalen -Zonen auf die verschiedenen neurologischen Erkrankungen untersucht.2. Bei der MS und den anderen entzündlichen neurologischen Erkrankungen findet sich eine Häufung der schnell wandernden Zone ₂ und der mittelschnell wandernden Zonen ₃ und ₄.3. Bei den Discushernien und den zentralnervös-nichtentzündlichen Erkrankungen ist die Zonenverteilung ziemlich flach und undifferenziert, wobei hier wie auch bei Tumoren und Polyneuritiden der relativ hohe ₀-Anteil auffällt als ein Phänomen, das bei zentralnervös-entzündlichen Prozessen nur selten anzutreffen ist. In den wenigen Tumorfällen mit -Zonierung scheint die ₄-Position deutlich zu überwiegen.4. In der Hälfte aller MS-Liquoren mit -Zonierung ist das Totalprotein, in einem Sechstel das Total--Globulin (rel%) normal, und nur bei zwei Dritteln finden sich Plasmazellen. Die elektrophoretische Feststellung von -Zonierung ist in der neurologischen Labordiagnostik folglich ein wichtiges Hilfskriterium.5. Mit zunehmendem Anstieg des -Globulin-Gehaltes im Liquor läßt sich bei MS-Patienten, nicht aber bei allen Krankheitsgruppen, eine Zunahme der Häufigkeit der -Zonierung nachweisen.6. Das Auftreten von -Zonierung ist bei den zentralnervös-entzündlichen Krankheiten und der MS sechsmal häufiger als bei den zentralnervös-nichtentzündlichen Krankheiten.7. -Zonierung scheint beim Gesunden, bei psychiatrischen Erkrankungen, Myopathien, bei gewissen Tumoren (Neurinomen) und metabolisch bedingten Polyneuritiden nicht vorzukommen.

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The significance of discontinuous zonation of electrophoretically separated globulins for the diagnosis of neurological diseases

Summary 1. 340 patients in whom discontinuous zonation of the globulin region was observed after electrophoretic separation of the CSF proteins were examined to see how the distribution of these clonal zones is correlated with different neurological diseases.2. In multiple sclerosis (MS) and other inflammatory diseases of the CNS, zones are most frequently found in the medium positions: ₂, ₃ and ₄.3. In disk hernias and the noninflammatory diseases of the CNS, the dispersion of zone frequency is rather undifferentiated. In these conditions and in tumors of the CNS and polyneuritis, the relatively high proportion of ₀ zones is a conspicuous feature; it is scarcely encountered in inflammatory processes of the CNS. The rare cases of tumors with zonation show a preponderance of the ₄ zone.4. The total protein content is normal in half of all MS fluids with zonation; in one sixth the relative amount of total globulin is also normal, whereas plasma cells are demonstrable in only two thirds. The electrophoretic evaluation of zonation is, therefore, an important tool in neurological laboratory work.5. Increased amounts of globulin in CSF are accompanied by an increased frequency of zonation in some diseases, such as MS, but not in tumors or vascular processes.6. The incidence of zonation is about 6 times higher in MS than in noninflammatory diseases of the CNS.7. zonation seems not to be present in healthy persons, in psychiatric diseases, myopathies, some tumors (neurinoma) and polyneuritis of metabolic-toxic etiology.