α-Synuclein in motor neuron disease: an immunohistologic study

-Synuclein (ASN) has been implicated in neurodegenerative disorders characterized by Lewy body inclusions such as Parkinsons disease and dementia with Lewy bodies. Lewy body-like inclusions have also been observed in spinal neurons of patients with amyotrophic lateral sclerosis (ALS) and reports suggest possible ASN abnormalities in ALS patients. We assessed ASN immunoreactivity in spinal and brain tissues of subjects who had died of progressive motor neuron disorders (MND). Clinical records of subjects with MND and a comparison group were reviewed to determine the diagnosis according to El-Escariol Criteria of ALS. Cervical, thoracic and lumbar cord sections were stained with an antibody to ASN. A blinded, semiquantitative review of sections from both groups included examination for evidence of spheroids, neuronal staining, cytoplasmic inclusions, anterior horn granules, white and gray matter glial staining, corticospinal tract axonal fiber and myelin changes. MND cases, including ALS and progressive muscular atrophy, displayed significantly increased ASN staining of spheroids (P0.001), and glial staining in gray and white matter (P0.05). Significant abnormal staining of corticospinal axon tract fibers and myelin was also observed (P0.05 and 0.01). Detection of possible ASN-positive neuronal inclusions did not differ between groups. Significant ASN abnormalities were observed in MND. These findings suggest a possible role for ASN in MND; however, the precise nature of this association is unclear.     

“Aggressive” and “problem-focused” models of case management for the severely mentally ill

In this paper, the relative merits and limitations of two models of case management (CM) are compared: aggressive and problem-focused. Although aggressive CM has a well-established history of improving the community tenure of deinstitutionalized patients, individuals participating in this treatment are likely to become dependent on health care providers and hence require indeterminate assistance. Problem-focused CM teaches patients how to identify and resolve community-based predicaments thereby making them relatively more independent of the mental health system. Patients receiving problem-focused CM, however, need reasonably competent cognitive functions thereby ruling out participation of the most severely disabled individuals. An interaction of the two approaches is proposed in which aggressive and problem-focused CM is selected depending on the patient's current needs, cognitive deficit, and level of social support.     

The anterolateral funiculus in the spinal cord in amyotrophic lateral sclerosis

We carried out a morphometric study on the myelinated fibers in the anterolateral funiculus (ALF) and lateral corticospinal tract (LCS) in the cervical segment of the spinal cord of 13 patients with classic amyotrophic lateral sclerosis (ALS), 6 of whom had been on a respirator: 5 age-matched subjects were used as controls. The results obtained revealed that: (1) the fiber-size distributions of the myelinated fibers in the ALF and LCS of the control subjects had peaks at 2 m; (2) there were marked and significant losses of large myelinated fibers in the ALF and LCS of ALS patients; (3) the patients who required respirator support showed more severe degeneration in the ALF than those who required none; and (4) the degree of myelinated fiber loss in the LCS did not correlate with either the illness duration or the history of respirator use.     

Variability of morphological features in early infantile polyneuropathy with defective myelination

Summary Four cases of early infantile polyneuropathy with defective myelination are reported. The peripheral nerve was studied by light and electron microscopy; different morphological characteristics have been noticed in these patients. Case 1 presented aspects of defective myelination with atypical onion bulb formation composed of multiple layers of basement membrane. In case 2, defective myelination and atypical onion bulb formation were associated with aberrant hypermyelination. Cases 3 and 4 were brothers, who presented axonal damage and atypical onion bulb formation.     

Ein Fall von „Schlaf-Epilepsie“ bei hyperplastischen Hippocampusformationen

Zusammenfassung Bericht über einen Fall von Schlaf-Epilepsie, der anatomisch eine doppelseitige Hyperplasie der Hippocampusformationen aufwies. Unter Berücksichtigung neuro-anatomischer Bauprinzipien und den Ergebnissen neurophysiologischer Grundlagenforschungen wird versucht, eine Erklärung für die Art der hier im Sinne einer Schlaf-Epilepsie aufgetretenen Anfälle zu geben. Bei der Interpretation der speziellen Hemmstrukturen für den Hippocampusbereich werden vergleichende Befunde bei atrophisierenden Hirnprozessen herangezogen. Schließlich wird das Problem der neuronalen Differenzierung hinsichtlich seiner Kollateralenbildung als Voraussetzung für eine quantitativ regelrechte, synaptische neuronale Verknüpfung im Zusammenhang mit der Erregungsmusterbildung durch hemmende Strukturen erörtert. Eine quantitativ ausreichende neuronale Verknüpfung durch Kollateralen wird dabei u. a. als wesentliche strukturelle Grundlage für die Ermöglichung von Hemmfunktionen im zentralen Nervensystem angesehen. Schließ: lich wird eine Beziehung zwischen der phänotypischen Körperbaudifferenzierung und der feinstrukturellen Differenzierung des zentralen Nervensystems im Sinne der Kretschmerschen Typologie erörtert.

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A case of sleep epilepsy associated with hyperplasia of hippocampal formations

Summary The neuropathologic evaluation of a case of sleep epilepsy revealed a symmetric hyperplasia of the hippocampal formations in the absence of other dysplasias of the central nervous system. This case offers an opportunity to consider morphological aspects and genetic mechanisms in epileptic disorders. The isocortex comprising six layers contains enough neurons to provide self-inhibition while the number of neurons and synapses, respectively, of the two-layered allocortex is not sufficient for self-inhibition. Adjacent structures, especially the fronto-basal neocortex and the other afferent systems of the hippocampus, appear to be important for self-inhibition. The normal excitability of the hippocampal formations is also afforded by a normal neuronal network of the hippocampus and its afferent structures, as well as by the size of the hippocampus and its adjacent structures. The existence of a regular ramification of neurons (collaterals) is probably very important in relation to the number of excitatory and inhibitory synapses. The occurrence of such collaterals of axons is an expression of the morphologic differentiation of the central nervous system. This hypothesis supports the typology of Kretschmer who describet that the athletic, i.e. less differentiated types are especially prone to suffer from epileptic disorders. Further systematic investigations with emphasis on branching of axons and its relation to epileptogenic focuses are necessary.

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Herrn Prof. Dr., Dr. h. c. E. Kretschmer und Herrn Prof. Dr., Dr. h. c. H. Spatz in Verehrung zum Gedächtnis.     

Zur bilateralen Nekrose von Ammonshorn und basalem Schläfenlappen

Zusammenfassung Es wird über einen 70 Jahre alt gewordenen Mann berichtet, der nach einem apoplektiformen Insult ein inkomplettes Korsakow-Syndrom geboten hat, dessen klinische erscheinungen über 25 Jahre ohne Progredienz nachweisbar geblieben sind. Pathologisch-anatomisch haben sich bilaterale Erweichungscysten des Ammonshornes und des Schläfenlappens gefunden. Das Verteilungsmuster der Läsionen legt nahe, daß der Patient damals eine akute nekrotisierende Encephalitis durchgemacht hat.

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Bilateral necrosis of ammon's horn and basal parts of the temporal lobe

Summary A 70-year-old man displayed an incomplete Korsakow's syndrome following an apoplectic insult. The clinical manifestations of the syndrome were present for more than 25 years without further detorioration. Examination of the lesions revealed bilateral soft cysts within Ammon's horn and the temporal lobes. In retrospect the distribution pattern of the lesions suggests that at the time the patient had suffered from acute necrotizing encephalitis.

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Herrn Professor Dr. Fr. Panse zu seinem 70. Geburtstag gewidmet.     

Dystrophin deficiency in a case of congenital myopathy

Summary We studied a 5-year-old boy who had the floppy infant syndrome and a dystrophic pattern on muscle biopsy. According to the clinical presentation and the histopathological findings the diagnosis of congenital muscular dystrophy with associated intellectual retardation was made. Immunohistochemical and immunoblot studies using anti-dystrophin antibodies showed complete absence of the protein in the patient's muscle. DNA analysis using cDNA probes showed a deletion at the 5 end of the dystrophin gene. Our observations on this patient suggest a new phenotypical variant of Duchenne muscular dystrophy.     

Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators

Patients with amyotrophic lateral sclerosis (ALS), who survive longer on a life-support system, exceeding the natural course of this disease, show new features of ALS. We report here a clinico-pathologic study of a 51-year-old patient with sporadic ALS who developed progressive external ophthalmoplegia 3 years after he remained on a respirator and died 5 years later, 13 years after the onset of his illness. The external ophthalmoplegia was initially accompanied by preserved doll's eye phenomenon, which later became absent. Autopsy revealed not only degeneration of the upper and lower motor neuron systems typical of ALS, but also degeneration of the Clarke's dorsal nuclei, spinocerebellar tracts, substantia nigra and inferior olives in addition to intracytoplasmic neuronal inclusion bodies in various areas. The oculomotor and abducens nuclei were variably involved, accompanied by neurogenic atrophy of the extraocular muscles. Our case report is consistent with the idea that ALS comprises a heterogeneous group of disorders, and also indicates that long-term use of respirators may make some patients with this illness prone to developing atypical clinical and neuropathologic features which are not observed during the natural course of ALS.     

Amyotrophic lateral sclerosis with hypertensive attacks: Blood pressure changes in response to drug administration

Blood pressure changes in response to intravenous drug administration were examined in a respirator-dependent 49-year-old patient with sporadic amyotrophic lateral sclerosis (ALS) who developed severe hypertensive attacks. She showed severe hypertension and tachycardia during the daytime and nocturnal hypotension without compensatory tachycardia, which were consistent with the autonomic phenomenon reported in ALS patients. Infusion of phentolamine (2.5 mg) induced an abrupt 90 mmHg decrease in systolic pressure and slight increase in heart rate. Propranolol (1 mg) infusion induced decreases in both systolic pressure (36 mmHg) and heart rate (17 beats/min), although the pressure decrease was transient while the heart rate remained at the decreased level. Infusion of diazepam (10 mg) induced a 47 mmHg decrease in systolic pressure and a 23 beats/min increase in heart rate. These vasomotor responses indicate the distinct participation of abnormally augmented sympathetic tone, and especially of -sympathetic hyperactivity rather than of -sympathetic hyperactivity, in the hypertensive attacks occurring in this ALS patient.     

Cerebrospinal fluid (CSF) findings in amyotrophic lateral sclerosis

Summary The cerebrospinal fluid (CSF) was examined in 90 amyotrophic lateral sclerosis (ALS) patients and in 50 age-matched normal controls. Total protein concentration was significantly higher in ALS patients than in normal controls. CSF IgG and albumin, quantitatively determined by single radial immunodiffusion, were significantly increased in ALS. No difference in serum concentrations was observed between ALS patients and normal controls. On isoelectric focusing a clear-cut fingerprint pattern was observed in 11 of 12 cases. These findings support the hypothesis that blood-brain barrier damage occurs in ALS. The finding of a higher mononuclear cell count in young ALS patients is briefly discussed in the light of the hypothesis that an exogenous agent might be of some relevance in pathogenesis. An alteration of at least one of the CSF parameters considered was found in 45.5% of ALS cases.

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Zusammenfassung In 90 Fällen von amyotrophischer Lateralsklerose und bei 50 auch im Alter entsprechenden Kontrollen wurde der Liquor untersucht. Der Eiweißgehalt war bei den Patienten mit ALS signifikant höher als bei den Kontrollen. Die Albuminfraktion und das IgG, die mit Immunodiffusionsmethoden quantitativ bestimmt wurden, waren bei der ALS im Liquor signifikant erhöht, während sie sich im Serum gleich wie bei den Kontrollfällen verhielten. Bei der isoelektrischen Fokusierung ließ sich ein eindeutiges Finger-print-pattern in elf von zwölf Fällen beobachten. Diese Befunde sprechen dafür, daß bei der ALS eine Störung der Blut-Hirnschranke vorliegt. Es wird kurz auf die Beobachtung einer vermehrten Zahl mononukleärer Zellen bei jungen Patienten mit ALS eingegangen und im besonderen die Frage diskutiert, in wieweit ein exogenes Agents in der Pathogenese eine Rolle spielen könnte. Mindestens eines der obern erwähnten Parameter war bei 45% aller ALS Fälle im Liquor verändert.

     

Familial progressive external ophthalmoplegia with multisystem abnormalities: “new” features raising nosological problems

Summary A 32-year-old female presented with progressive external ophthalmoplegia (PEO) and multisystem abnormalities, strikingly associated with myotonia and muscle hypertrophy. These two features were not found in her brother, who had a complex neuromuscular disorder complicating chronic PEO. In both subjects muscle biopsy revealed ragged-red fibres and myofibres containing glycogen granules, which were never bound by membranes. A severe demyelinating neuropathy was revealed by electrophysiological and morphological studies. Cranial CT scan showed extensive demyelination of the cerebral white matter. Genetic studies demonstrated that this familial syndrome is transmitted as an autosomal recessive trait.     

Effects of riluzole on combined MPTP + 3-nitropropionic acid-induced mild to moderate striatonigral degeneration in mice

Summary. We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP+3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a neuronal rescue strategy by administering riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and riluzole groups (10mg/kg and 20mg/kg), matched by triplets for motor severity. While riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, riluzole has limited neuronal rescue properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP+3-NP-induced SND in mice.     

Muscle phosphoglycerate mutase (PGAM) deficiency in the first Caucasian patient: biochemistry,muscle culture and31P-MR spectroscopy

Muscle phosphoglycerate mutase (PGAM) deficiency has been so far identified in only six patients, five of these being African Americans. We report the results of clinical, morphological, biochemical, muscle culture and³¹P-MR spectroscopy studies in the first Caucasian patient with muscle PGAM deficiency. A 23-year-old man had a 10-year history of cramps after physical exertion with one episode of pigmenturia. Neurological examination and EMG study were normal. ECG and echocardiography revealed hypertrophy of the interventricular septum and slight dilatation of the left chambers of the heart. Muscle biopsy revealed increased glycogen content and some accumulation of mitochondria. Muscle PGAM activity was markedly decreased (6.5% and 9.7% of control value in two different biopsies). Citrate synthase and other mitochondrial respiratory chain enzyme activities were much higher than normal. In contrast to the marked decrease of PGAM activity observed in muscle biopsy, total enzyme activity in the patient's aneural muscle culture was normal, being represented exclusively by BB isoenzyme. The deficiency of PGAM-MM isoenzyme was reproduced in the patient's innervated muscle culture. Muscle³¹P-MR spectroscopy showed accumulation of phosphomonoesters only on fast glycolytic exercise. On aerobic exercise, V_max, calculated from the work-energy cost transfer function, showed an increase consistent with the morphological and biochemical evidence of mitochondrial proliferation. This might represent a sort of compensatory aerobic effort in an attempt to restore muscle power.     

Atypical Antipsychotics as Enhancement Therapy in Rapid Cycling Mood States: A Case Study

Rapid cycling is not an uncommon occurrence in patients with bipolar affective disorder. This variant of the disease is notorious for its treatment resistance, in particular, lithium resistance. A full spectrum of cycloid mood states has been described. The author presents five cases in which the addition of atypical antipsychotics resulted in significant symptom relief. An argument for a preferential use of atypical antipsychotics, with their low risk of tardive dyskinesia, is made. General guidelines for the use of atypical antipsychotics in rapid cycling patients are discussed. Atypical antipsychotic medications in cycloid disorders, including rapid cycling bipolar disease, are discussed.     

Providing outpatient services to criminal procedure law patients: The clinician's perspective

This presentation identifies a number of the elements involved in implementing an effective program for the care and treatment of the Conditionally Released CPL Patient. The component parts to be explored include: societal and agency issues, the identified patient and, issues relating to the clinician and the clinical treatment team. The outpatient clinician fulfills numerous role/task functions. The roles of therapist, educator, teacher, advocate, casemanager, and parole officer will be discussed. Techniques for identifying and working through the worker's own blocks will be discussed as a prelude to establishing a therapeutic alliance. Principles of utilizing authority and contracts as basic therapeutic techniques will also be noted. Recognizing that the patients who comprise the conditionally released CPL 330 category are heterogeneous and multiply disabled, techniques for active focused rehabilitation treatment will be explored.     

Combined 123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients

Summary. 72 consecutive patients with suspected parkinsonian syndromes (PS) were studied by dopamine transporter (DAT) and D2 receptor SPECT in order to evaluate the accuracy of combined SPECT imaging. In the follow-up, the patients were diagnosed as having Parkinsons disease (PD, n=25), dementia with Lewy bodies (DLB, n=6), multiple system atrophy (MSA, n=13), progressive supranuclear palsy (PSP, n=8), corticobasal degeneration (CBD, n=9), and essential tremor (ET, n=11). Using the iteratively estimated optimal cutoffs, DAT was reduced in 57/61 PS patients, whereas all ET patients were identified as normal. Reduced D2 receptor binding had 7/13 patients with MSA, 6/8 patients with PSP, 2/9 patients with CBD and no ET, PD or DLB patients. FP-CIT SPECT allows an accurate detection of nigrostriatal affection in neurodegenerative PS. IBZM SPECT is useful to approve the diagnosis of PSP and MSA although a normal finding cannot exclude an atypical PS. IBZM SPECT seems to be of restricted value in CBD.     

The contribution of oculography to early diagnosis of myasthenia gravis

Summary Saccadic eye movements were examined by infrared reflection oculography in 22 patients with suspected myasthenia gravis. In all of them the diagnosis was confirmed either by electromyography, by the presence of acetylcholinereceptor antibodies (15 cases), by a positive clinical Tensilon test (4 cases), or by the course of the disease (3 cases). The aim of the study was to find out which of the saccade disorders described in myasthenic patients can be found in the early stage of the disease, and to discover their diagnostic value. Typically, saccade abnormalities were also seen in clinically uninvolved eyes. Intrasaccadic disorders mainly consisted of decrescendo of the velocity profiles (two-thirds of the cases) and hypometria (half of the cases). Postsaccadic waver was present in about two-thirds of the patients. The most frequent finding was intersaccadic variation (i.e., variation between repeated corresponding saccades) which occurred in 18 of the 22 patients, and particularly affected the velocity profiles. A standardized fatigue test proved to be useful in accentuating mild, or provoking latent pathology in most of the patients. A standardized combined examination of saccades with Tensilon yielded pathological results less frequently than hitherto described in the literature. In 4 of the 9 patients with purely ocular myasthenia gravis oculography led to the diagnosis. The problems in attempting to delimit the observed saccade abnormalities from those found in other eye movement disorders are discussed.     

Neurofibrillary tangles of Guamanian amyotrophic lateral sclerosis,parkinsonism-dementia and neurologically normal Guamanians contain a 4-to 4.5-kilodalton protein which is immunoreactive to anti-amyloid β/A4-protein antibodies

Summary Neurofibrillary tangles (NFT), one of the neurodegenerative features of Alzheimer's disease, Down's syndrome and normal aging, is a constant, widespread neuropathological finding in Guamanian amyotrophic lateral sclerosis (ALS), parkinsonism-dementia (PD) and in neurologically normal Guamanians, dying of causes other than ALS and PD. NFT in brain tissue sections of patients with Guamanian ALS and PD were immunoreactive to antibodies directed against a 43-amino acid synthetic peptide homologous to amyloid /A4-protein (anti-SP43) associated with Alzheimer's disease. NFT extracted from frozen brain tissues of Guamanian patients with ALS and PD and from tissues of neurologically normal Guamanians were congophilic and birefringent. By negative-stain electron microscopy, NFT preparations contained bundles and/or isolated single, straight, unpaired filaments in Guamanian AlS and occasionally pairing of filaments in neurologically normal Guamanians, measuring 5–20 nm in diameter. Formic acid digestion of NFT preparations, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size-exclusion high-pressure liquid chromatography, showed a protein with an apparent molecular mass of 4-to 4.5-kDa, which by Western blot analysis was immunoreactive to anti-SP43. Immunoabsorption of purified NFT or SP43 with anti-SP43 abolished immunostaining. Our study corroborate previous data that amyloid /A4-protein is present in NFT in Guamanian PD. Furthermore, our data indicate that amyloid /A4-protein is present in NFT in brain tissues of patients with Guamanian ALS and in neurologically normal Gumananians, suggesting a common mechanism of amyloidogenesis with NFT formation in Alzheimer's disease and normal brain aging.Supported in part by the Ministry for Science and Technology of the Federal Republic of Germany and the Fond der Chemischen Industrie, and the Sonderforschungsbereich 194, Deutsche Forschungsgemeinschaft (to D. C. Guiroy)     

The location by early auditory evoked potentials (EAEP) of acoustic nerve and brainstem demyelination in multiple sclerosis (MS)

Summary Tone pips of suprathreshold intensities elicit an acoustic nerve response (I) and six low amplitude brainstem potentials (II–VII) during the initial 10 ms. Seven waves were studied in 40 control subjects and 5 waves (I–V) in 47 patients with MS. The results suggest involvement of the auditory pathway of 24 of 27 patients in the clinically definite, of 5 of 9 cases in the probable and in none of 5 patients in the possible MS groups. EAEPs were normal in 6 cases with a spinal form with one exception where changes of potential were indicative of a midbrain lesion. Dysfunction within the acoustic pathway was observed at the level of the acoustic nerve and in the medulla oblongata, pons and midbrain. The significance of the bilateral EAEP abnormalities found in some patients at different levels is discussed with regard to a polytopic location of the underlying lesion.This work includes part of a thesis of E. Schäfer (University of Mainz)     

The persistence of visual or auditory percepts as symptoms of irritative lesions of the cerebrum of man

Summary In this series of patients the persisting visual or auditory percepts were re-experienced immediately or were replayed many hours or even up to a day or more following the original stimulus. The persisting percepts were almost always experienced in the defective visual or auditory space contralateral to the responsible cerebral lesion. These patients usually had clinical evidence of cerebral irritation and seizures. When clinical seizures were controlled medically and stopped, so then did the persistent visual and auditory sensations. These spontaneous phenomena which we observed clinically were similar to the experiences elicited when the cerebrum of conscious man was stimulated through implanted electrodes. It seems that either spontaneous irritation of the brain or electrical excitation of the cerebrum of conscious man may induce replays of previous visual or auditory percepts which then appear as reality.This paper was read at the twenty fifth International Physiological Association Meetings, Satellite Symposium: Audition and Vision, Comparison between the Systems, August 3, 1971.