Status spongiosus of rat central nervous system induced by Actinomycin D

Summary The effect on central myelin of Actinomycin D, an RNA — and, secondarily, a protein-synthesis inhibitor, has been studied by light and electron microscopy. The intracranial injection of this drug produced an extensivestatus spongiosus of the white matter in the cerebrum, cerebellum, brain stem and optic nerve within 48 h.The status spongiosus was due to vacuole formation within the myelin sheath and to enlargement of the extracellular space. Three types of vacuoles were observed: (a) the most common varieties formed between the inner tongue and the remainder of the myelin sheath; (b) a second variety formed by enlargement of the periaxonal space with separation of the axon from its myelin sheath, and (c) a less common type of vacuolization was due to splitting of the myelin lamellae at the interperiod line to form large intramyelinic vacuoles. Myelinic vacuoles were preceded by nuclear and cytoplasmic changes in oligodendrocytes, which included nucleolar segregation, disaggregation, and diminution in number of ribosomes. These changes were similar to those previously reported in a variety of cells exposed to Actinomycin D. It is suggested that myelin vacuoles result secondarily from the Actinomycin D inhibitory effect on oligodendroglial RNA — and protein-synthesis, rather than from a direct effect of this drug on the myelin sheath.Supported by Grants from the National Institute of Health NS 08933, NS 05572, MS 889-B2, and Training Grant NS 05712.     

Spongy degeneration in the central nervous system of domestic animals

Summary Severe spongy degeneration of the central nervous system (CNS) was seen in 11 cattle, 19 sheep, 4 pigs and 1 goat, associated with a variety of hepatic diseases, particularly those caused by hepatotoxic pyrrolizidine alkaloids. It was also seen in a milder form in 2 of 8 horses examined, 1 dog of 5 dogs examined, and in 1 rabbit only of a large number of laboratory animals examined.This paper reports results of experiments which confirmed initially that the CNS disease could be caused by pyrrolizidine alkaloid intoxication. This was done by poisoning sheep and calves withSenecio jacobaea, a plant which contains pyrrolozidine alkaloids, and by poisoning lambs with lasiocarpine.As the disease was seen in hepatoses not caused by pyrrolizidine alkaloids, the hypothesis that CNS spongy degeneration in lambs could follow any hepatic disease irrespective of its cause, was tested by poisoning lambs with allyl formate, an hepatotoxin chemically unrelated to pyrrolizidine alkaloids. Three of 4 lambs poisoned by the allyl formate showed spongy degeneration in their brains.As the CNS spongy degeneration was an apparent form of hepatocerebral disease, an experiment was conducted to show that the neural disease in sheep was caused by hyperammonaemia. CNS spongy degeneration developed in the brains of all sheep infused intravenously with ammonium acetate, and advanced spongy changes developed in the sheep infused for more than 3 days. The cerebral changes were probably temporary, since sheep infused for 5 days and retained for 3 weeks showed marked regression of vacuolation.Hyperammonaemia caused by intravenous ammonium acetate infusion is a simple, rapid model of CNS spongy degeneration. The syndrome, CNS spongy degeneration caused by hepatic failure and hyperammonaemia, is probably one of the morphologic expressions of hepatocerebral disease in domestic animals and could be an analogue of similar congenital and hepatocerebral diseases in man.     

Familial spongy degeneration of the central nervous system (Van Bogaert-Bertrand disease)

Summary Light and electron microscopy study of skeletal muscle and cerebral biopsies from a case of spongy degeneration of central nervous system is reported. The multiple vacuoles present in cerebral gray and white matter correspond to (a) clefts within myelin sheaths resulting from splitting at the intraperiod line and (b) swollen astrocytic perikarya and processes. Unusual mitochondria containing crystalline-like material were observed only in astrocytes. The ultrastructural findings are consistent with cerebral edema. It is suggested that the astrocytes play a primary role in the fluid accumulation while the myelin swelling is a secondary lesion. The possible role of the abnormal astrocytic mitochondria is discussed.The present investigation was supported by Research Grants HD 00588, NB-05572-04 and NB-04613-05 and the Widener Fund.     

Infantile type of so-called neuronal ceroid-lipofuscinosis

Summary Autopsy reports are presented of three cases of a rapidly progressive encephalopathy with clinical onset around one year of age, early amaurosis, and microcephaly. Convulsions were few or absent. The disorder led to an extraordinary degree of brain atrophy, due to total loss of neurons from the cerebral and cerebellar cortex, and an advanced degree of neuronal destruction in most subcortical centres. The giant cells of Betz and the primary motor and sensory neurons were notable exceptions. The surviving neurons, other neuroectodermal cells, and a number of extraneural cell types showed accumulation of autofluorescent sudanophilic granules, resistant to lipid solvents, in their cytoplasm. Ultrastructurally, these granules were of the residual body type, consisting of membrane-bound conglomerations of spherical globules 0.2–0.5 m in diameter, with a homogeneous, finely granular internal structure. These lesions were associated with a pronounced astrocytic and mesenchymal reaction with the presence of large numbers of phagocytic cells in the grey matter of the CNS and, to a lesser extent, in other tissues. In addition, there was almost total loss of myelin from the brain, apparently due to Wallerian degeneration.The characteristic clinical, histological and ultrastructural features differentiate this condition from other progressive encephalopathies of the age group in question, including the late infantile type of the Batten-Vogt syndrome. Recent ultrastructural and biochemical findings indicate that the disease of our patients is identical with the progressive encephalopathy with disturbed polyunsaturated fat metabolism described by Hagberget al. (1968).     

Programmed Neuronal Necrosis and Status Epilepticus

Summary:  We examined the mechanism of neuronal necrosis induced by hypoxia in dentate gyrus cultures or by status epilepticus (SE) in adult mice. Our observations showed that hypoxic necrosis can be an active process starting with early mitochondrial swelling and loss of the mitochondrial membrane potential, followed by cytochrome c release and caspase-9–dependent activation of caspase-3. This sequence of events (or program) was independent of protein synthesis and may be induced by energy failure and/or calcium overloading of mitochondria. We called this form of necrosis "programmed necrosis." After SE in adult mice, CA1 and CA3 pyramidal neurons displayed a necrotic morphology, associated with caspase-3 immunoreactivity and with double-stranded DNA breaks, suggesting that "programmed necrosis" may be involved in SE-induced neuronal loss.     

Protracted Epileptiform Encephalopathy: An Unusual Form of Partial Complex Status Epilepticus

An 11-year-old previously healthy boy had an abrupt onset of partial complex, focal, multifocal, and generalized seizures, with interictal expressive aphasia, extreme emotional lability, agitation, and complex visual and auditory hallucinations. EEGs showed frequent runs of rhythmic high-voltage delta over the right and subsequently over the right and left temporal and frontal regions. All other studies were negative (repeated computed tomography, spinal fluids, viral titers, and cultures). Nadir during the second month showed virtual unresponsiveness, prolonged rhythmic motor and apneic seizures, total anorexia, and sleeplessness. Remission of the electrical and clinical seizure activity and a gradual improvement through a state of agitation and emotional lability occurred during the third and fourth months. One year later he was entirely normal. Compared with the other previously documented cases of prolonged partial complex status, this case is notable for its florid and severe symptomatology, long duration, and final benign outcome.     

Ultrastructure of 6-aminonicotinamide (6-AN)-induced lesions in the central nervous system of rats

Summary Lesions in the CNS induced by 6-aminonicotinamide (6-AN) presented a spongy state of the gray matter and neuronal chromatolysis. With aging of the experimental animals the lesions extended from the phylogenetically early developed structures to those developed later, i.e., from spinal gray matter, dentate nuclei, and brain stem nuclei through limbic structures and striatum to the cerebral cortex. Changes of the neurons were more prominent with aging.Lesions in the CNS of rats at the age, corresponding to the involutional period in the human, were similar to those of Creutzfeldt-Jakob disease (C-J disease) in the presenile age. In recent years, the resemblance between C-J disease and pellagra encephalopathy had been noted by several authors, and they resemble the lesions caused by 6-AN, an antimetabolite of nicotinamide used in our experiment. This evidence, therefore, has led to the hypothesis that dysfunction of NAD(H)- or NADP(H)-dependent enzymes in the CNS of the aged, even if not the primary cause, may be one possible pathogenetic factor of C-J disease.     

Progressive degeneration of the cerebral cortex in infancy

Summary The clinical and pathological features of a case with primary progressive degeneration of the cerebral cortex are presented. Two siblings had nearly identical clinical histories. All three children were born microcephalic and they died at the age of 7, 10 and 18 months, respectively. All showed progressive mental and motor deterioration. Myoclonus and attacks of opisthotonus were prominent features. Postmortem examination was performed in the third child, who died at the age of 10 months. The brain weight was 310 g. The cerebral cortex was severely atrophic, with extensive laminar neuronal loss. The cerebellum was normal. The optic tracts were atrophic. Neuronal loss was observed also in a few other systems but their relation to the primary disease is uncertain. The basal ganglia were normal and the hippocampus showed only slight nerve cell loss.The case is considered to belong to a small group of cases with primary progressive cortical degeneration described by Laurence and Cavanagh (1968). This group should be distinguished from cases with secondary cortical degeneration caused by anoxic damage from recurrent epileptic attacks. The primary cortical degeneration may start shortly before birth, or after a brief periood of normal postnatal development. A positive family history has been reported in most cases, suggesting an inherited metabolic defect as cause of the disease.     

Status dystonicus associated with CLN8 disease

BackgroundStatus dystonicus is an underdiagnosed condition, probably due to heterogeneous etiology, presentation and course. Herein, we report the first case of CLN8 disease in the literature presenting with status dystonicus who responded well to pharmacological intervention.CaseA boy aged five years and three months presented with fever, loss of appetite, intermittent excessive dystonic contractions, opisthotonus with retrocollis, and irritability for three days. His developmental milestones were reported as normal up to the age of three years and six months. At this age, he developed seizures, ataxia, and vision problems. Deterioration in developmental milestones was observed from the age of four. Laboratory tests demonstrated leukocytosis, abnormal renal function, mild metabolic acidosis, elevated creatine kinase and transaminase levels. The brain magnetic resonance imaging demonstrated cerebral and cerebellar atrophy. Homozygous missense mutation of c.709G > A (p.G237R) in the CLN8 gene was revealed. With all these clinical and laboratory findings, he was diagnosed with status dystonicus associated with CLN8 disease. Antibiotherapy, anticonvulsant drugs, and intravenous hydration with alkaline fluids were initiated. Due to irregular breathing, dysphagia, and worsening of dystonic contractions, mechanical ventilation was performed, and baclofen, haloperidol, midazolam infusion and chloral hydrate were administered, respectively. Finally, serum creatine kinase levels decreased, and dystonic contractions improved on the 15th day of hospitalization.ConclusionTo the best of our knowledge, our case is the first report describing the status dystonicus in a patient with CLN8 disease. Our report suggested that neuronal ceroid lipofuscinoses should be kept in mind in the etiology of status dystonicus.     

Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy

PURPOSE: To determine the regional distribution of neuronal damage caused strictly by status epilepticus (SE) without systemic complications, underlying brain pathology, or a history of preexisting epilepsy. METHODS: The medical records and electroencephalograms (EEGs) of three deceased patients who developed SE in the hospital were reviewed. Their brains were formalin-fixed, and 17 brain regions were selected, embedded in paraffin, and sectioned. Alternate sections were stained with either hematoxylin and eosin and cresyl violet to determine the extent of neuronal loss and gliosis or glial fibrillary astrocytic protein to confirm the extent of astrocytic proliferation. RESULTS: The three patients died 11 to 27 days after the onset of focal motor SE; none had hypotension, hypoxemia, hypoglycemia, or significant hyperthermia. Two patients had no prior seizures and no underlying brain pathology. The third patient, who had leptomeningeal carcinomatosis, had one seizure 2 months before the onset of SE. The duration of SE was 8.8 hours to 3 days. EEGs showed unilateral temporal lobe sharp-wave discharges in one patient and independent temporal lobe sharp-wave discharges bilaterally in the other two patients. In addition to widespread neuronal loss and reactive gliosis in the hippocampus, amygdala, dorsomedial thalamic nucleus, and Purkinje cell layer of the cerebellum, we report for the first time periamygdaloid (piriform) and entorhinal cortical damage occurring acutely after SE in humans. CONCLUSIONS: In the absence of systemic complications or preexisting epilepsy, SE produces neuronal loss in a distribution similar to that from domoic acid-induced SE in humans and from kainic acid- and pilocarpine-induced SE in rats.     

Ultrastructural study of three cases of encephalopathy with hypsarrhythmia

Summary We report a morphological study of three cases of infantile hypsarrhythmia. The cerebral cortex lesions consisted of a diffuse neuropile microspongiosis, corresponding ultrastructurally to vacuolized and enlarged neuronal processes, particularly postsynaptic bags. The morphological aspects and the high cell fusion index in one case resemble those described in transmissible subacute spongiform encephalopathies.     

Extrapyramidal-pyramidal-parakinetische Syndrome bei progressiven Encephalopathien mit achromatischen Nervenzellschwellungen und Zellgliosen im höheren Lebensalter

Zusammenfassung An Hand von drei weiteren klinisch-neuropathologischen Beobachtungen wird über morphologisch relativ einheitliche und gut charakterisierbare Gewebsprozesse im höheren Lebensalter berichtet, welche sich klinisch maßgeblich durch extrapyramidal-corticospinal-parakinetische Mischsyndrome kennzeichnen. Gegenüber solchen Übereinstimmungen unterscheiden sich die alshirnorganische Endzustände perniciöser Involutionspsychosen und alscortico-dentato-nigrale Degeneration (Rebeiz et al., 1968) beschriebenen Krankheitsbilder hinsichtlich ihrer neurologisch-psychiatrischen Gesamtsyndromatik und ihres Verlaufes erheblich. Das gilt auch für eine ätiopathogenetisch alsparathyreoprive Encephalopathie geklärte Beobachtung von Lange u. Creutzfeldt (1923). Allen klinischen Beobachtungen und auch den hier beschriebenen, die sich teilweise an ein Jahrzehnt vorangehendes Krampfleiden anschlossen, lag ein neuropathologisches Gewebssyndrom zugrunde, das nach mancher Richtung jener besonderen Form der Creutzfeldt-Jakobschen Krankheit vergleichbar ist, bei welcher spongiöser Gewebszerfall vermißt wird. Es kennzeichnet sich durch achromatische Nervenzellschwellungen mit Kernverdrängung an die Peripherie, Nervenzellchromatolysen,-sklerosen,-verfettungen und Nervenzellausfälle in Verbindung mit diffusen, syncytialen oder knötchenartigen Gliazellproliferationen und Neuronophagien. Der ätiopathogenetisch unspezifische Syndromcharakter dieser Gewebsveränderungen, gewisse topistische Variabilitäten und gelegentlich hinzutretende axonale Systemdegenerationen erscheinen bemerkenswert. Differentialdiagnostische Abgrenzungen gegenüber atypischen amyotrophen Lateralsklerosen und gewissen Initialstadien von Morbus Pick werden erörtert.

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Extrapyramidal-pyramidal-parakinetic syndrome in progressive encephalopathies with achromatic neuronal swelling and cellular gliosis in advanced ageOn Differential diagnosis of Creutzfeldt-Jakob disease, pernicious involutive psychoses with cerebral terminal stage, cortico-dentato-nigral degenerations, and amyotrophic lateral sclerosis

Summary Relatively uniform and readily characterizable neuropathologic processes observed in three further clinical-pathological cases are reported; the clinical picture is dominated by extrapyramidal-corticospinal-parakinetic mixed syndromes. In contrast to such correspondencies, the diseases described asbrain-organic terminal conditions of pernicious involutional psychoses and ascorticodentatonigral degeneration (Rebeizet al., 1968) differ considerably with regard to their overall neurological and psychiatric symptomatology and their clinical course. This is true also of the observation etiopathologically elucidated by Lange and Creutzfeldt (1923) asparathyroprival encephalopathy. All of these observations, also those described here, some of which were preceded a decade earlier by epileptic convulsions, were manifestations of a neuropathological tissue syndrome, which is in some respects comparable with that particular form of the Creutzfeldt-Jakob disease in which spongy tissue disintegration is not found. It is characterized by achromatic swelling of the nerve cells with peripheral displacement of the nuclei, chromatolysis, sclerosis, lipidosis and loss of nerve cells in connection with diffuse, syncytial or nodular glial proliferation and neuronophagia. The etiopathologically unspecific, syndromic nature of these tissue alterations, a certain topical variability and the occasionally observed degeneration of axonal systems (motor neurone disease) seem noteworthy. The differential diagnostic exclusion of atypical amyotrophic lateral sclerosis and of certain initial stages of Pick's disease is discussed.

     

Juvenile form of spongy degeneration of the CNS

Summary Clinico—pathological report of two sporadic cases of spongy degeneration of the CNS of non-Jewish origin with onset of clinical symptoms at the age of 5 years and protracted course up to late adolescence. The morphological findings of this juvenile type of the disorder, including diffuse spongy vacuolation of both the white and grey matter of the neuraxis, with diffuse and severe demyelination and astroglial hyperplasia, were consistent with those of other protracted infantile cases. In addition to spongy degeneration, axonal dystrophy and hyperpigmentation of the pallido-nigral system and axonal spheroids in the spongy cerebellar white matter were present in both cases. The significance of axonal dystrophy in these protracted forms of spongy degeneration is discussed.

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Zusammenfassung Klinisch-morphologischer Bericht über zwei sporadische Fälle von spongiöser Dystrophie des ZNS nicht-jüdischer Abstammung mit Beginn der klinischen Symptomatik im 5. Lebensjahr und protrahiertem Verlauf mit Tod in 21. bzw. 17. Lebensjahr. Die Gehirnveränderungen dieses juvenilen Typs der Erkrankung umfaßten diffuse spongiöse Veränderungen der weißen und grauen Substanz des gesamten ZNS mit schwerer diffuser Entmarkung und diffuser Astrogliareaktion. Sie entsprachen damit weitgehend den Befunden bei protrahierten infantilen Fällen. Beide Fälle boten daneben neuroaxonale Dystrophie und Hyperpigmentation des Pallidum und der roten Nigrazone sowie Axonschollen im spongiösen Kleinhirnmark. Die Bedeutung der axonalen Dystrophie bei den protrahierten Formen der spongiösen Dystrophie wird erörtert.

     

Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES)

Purposes:   To describe the clinical spectrum and to evaluate the efficacy of different therapeutic agents in children with electrical status epilepticus in sleep (ESES).
Methods:   Clinical data of all patients with ESES (not including patients with Landau-Kleffner syndrome) in four pediatric neurology outpatient clinics were analyzed. Thirty patients with ESES had been treated between 1994 and 2007.
Results:   Eleven (37%) children had benign partial epilepsies of childhood, five (17%) had cerebral palsy, five (17%) had hydrocephalus, one (3%) had schizencephaly, one (3%) had prenatal parenchymal bleeding, and the etiology was unclear in seven (23%). The duration of ESES ranged between 2 and 60 months. The antiepileptic drugs that were found to be efficacious were: levetiracetam (41%), clobazam (31%), and sulthiame (17%). Valproic acid, lamotrigine, topiramate, and ethosuximide showed no efficacy. Steroids were efficacious in 65%; immunoglobulins were efficacious in 33%. High-dose diazepam was efficacious in 37%, but all the children had temporary response. Seventeen patients (57%) had cognitive deterioration, whereas the rest presented with regression in attention, speech, communication, and behavior. Fourteen children had permanent cognitive deficit. There was a significant correlation (p = 0.029) between the duration of ESES and residual intellectual deficit at follow-up.
Conclusions:   ESES reflects an evolution of benign partial epilepsy of childhood in more than one-third of the patients, whereas there is an underlying structural brain anomaly in another one-third. The most efficacious antiepileptic drugs (AEDs) are levetiracetam and clobazam. The duration of ESES correlated significantly with residual intellectual deficit at follow-up.     

Imaging of neuro-AIDS

The pathogenesis of the human immunodeficiency virus (HIV) infection of the central nervous system and the imaging presentation of patients with neurological complications from HIV/AIDS are discussed. Imaging findings are often nonspecific; however, correlations with patient's clinical signs and CD4 count allow a working diagnosis to be made.     

Peripheral nerve lesion in spongy degeneration of the central nervous system

Summary This report describes a peripheral nerve lesion found in a case of spongy degeneration of the central nervous system. The lesion consisted of abnormal cellular infiltrates in the peri- and endoneurium, axonal changes, and demyelination. Possible relation of the lesion to that of the central nervous system is discussed.Supported by grant NB-02255 from the National Institutes of Health, United States Public Health Service.     

The effects of methyl-mercury-dicyandiamide on the peripheral nerves and spinal cord of rats

Summary Rats have been poisoned with methyl-mercury-dicyandiamide at two different dose levels, 5 mg/kg body weight or 7.5 mg/kg daily for 8 consecutive days. The morphological changes in peripheral nerves and the central nervous system are largely restricted to primary sensory cells of spinal ganglia, and to a lesser extent to the granular cells of the cerebellum.There were clearly two grades of cell damage, either whole cell death or whole fibre death; there is no evidence to suggest that partial fibre death could occur, at least not at the two dose levels used.No definite indications were found for this neuropathy being a dying back process, for the nerve fibres appeared to degenerate contemporaneously along their whole extent.     

Unilateral hemispheric cerebral changes similar to Creutzfeldt-Jakob disease in a case of hemiconvulsion

Summary A 77-year-old man suffered intermittent hemiconvulsions of unknown etiology on the left side for a period of about 5 weeks. At the autopsy, there was marked neuronal loss, severe proliferation of astrocytes and spongiform changes in the right cerebral cortex. The cerebral white matter showed loosening with astroglial proliferation in areas on the same side. These neuropathological changes were slight or absent in the left cerebral hemisphere. Histopathological changes were similar to those seen in unilateral Creutzfeldt-Jakob disease (CJD). Although unilateral CJD can not be ruled out, these unilateral hemispheric changes might be induced by intermittent hemiconvulsions.     

Ultrastucture of the central nervous system after prolonged hypoxia

Summary Chronic hypoxia was induced in rats by subjecting them to a low oxygen atmosphere (10% O₂ and 90% N₂) up to 24 days. Electron microscopy revealed striking alterations in nerve cells of the central nervous system. During the first 4 days, moderate swelling was noted in the Golgi complex in the mitochondria of some neurons. From the 6th to 24th days, alterations of these organelles became more pronounced: Many neurons and their processes exhibited varying degrees of cytoplasmic swelling, and inclusion bodies resembling myelin-figures were found in the perikaryon. Bizarre forms of tubular profiles occurred within the axoplasm of many nerve fibers. The presynaptic terminals became greatly enlarged, containing either unusual multilamellar bodies or clumped vesicles. These results indicated that prolonged hypoxia causes profound changes in the central nervous tissue that do not occur in the acute state.This study was supported by the Dorothy R. Victor Memorial Fund, the Lusyd Wright Hitchcock Memorial Research Fund and the Buswell Foundation.