Neuroprogressive disease of post-infectious origin: a review of a resurging subacute sclerosing panencephalitis (SSPE).

Subacute sclerosing panencephalitis (SSPE) is a progressive, essentially untreatable, disease of the nervous system. When first described in the 20th Century, it was characterized more for its neuropathological features than for its pathophysiology or cause. It was not until the 1960s that a clear relationship to the measles virus was established. It is now thought that this uncommon infectious encephalopathy is caused by a "slow," altered or persistent form of the wild measles virus which has harbored in the nervous system for years. Then a "breakout" occurs and the more lytic and virulent organisms produce the progressive and spreading inflammatory and destructive lesions which are confined to the nervous system. Epidemiological study of the disease confirms its relationship to measles. In the years since the development of national measles immunization programs, there has been a dramatic decline in the incidence of measles exanthem and until recently a corresponding decline in the incidence of SSPE. In recent years there has been a mild to moderate increase in cases of SSPE as reported to the USA/International SSPE Registry. As yet, there has not been a totally effective treatment. The purpose of this paper is to give an overall review on SSPE and its relationship to measles. This review will include a prospectus of its history, considerations as to its etiology, correlation of clinicopathological features, and thoughts on the past and present epidemiology and treatment.

Subacute sclerosing panencephalitis. Clinical aspects and prognosis. The Brazilian registry.

Subacute sclerosing panencephalitis (SSPE) is an inflammatory neurodegenerative disease related to the persistence of measles virus. Although its frequency is declining because of measles eradication, we still have some cases being diagnosed. With the aim to describe epidemiological aspects of SSPE in Brazil, we sent a protocol to Child Neurologists around the country, 48 patients were registered, 27 (56%) were from the southeast region, 34 (71%) were male and 35 (73%) white, 27 (56%) had measles, 9 (19%) had measles and were also immunized, 7 (14%) received only immunization, 1 patient had a probable neonatal form. Mean time between first symptoms and diagnosis was 12 months (22 started with myoclonus or tonic-clonic seizures, 7 (14%) with behavioral disturbances); 36 patients (75%) had EEG with pseudoperiodic complexes. Follow up performed in 28 (58%) patients showed: 12 died, 2 had complete remission and the others had variable neurological disability. Our data shows endemic regions in the country, a high incidence of post-immunization SSPE and a delay between first symptom and diagnosis.

Classification of the neuronal ceroid-lipofuscinoses: expansion of the atypical forms.

The neuronal ceroid-lipofuscinoses (NCL) are a group of different genetic diseases. The major types of NCL are expressed by six forms which represent different clinicopathologic and genetic forms. These are CLN-1, Infantile; CLN-2, Late Infantile; CLN-3, Juvenile; CLN-4, Adult-Recessive; CLN-5, Adult-Dominant; and CLN-6, Early Juvenile. The distinction between CLN-4 and CLN-5 is still disputatious. CLN-6 has been called CLN-5. A seventh classification of NCL represents from 12 to 20% of those afflicted. This group consists of an extensive array of atypical types of ceroid-lipofuscin accumulation in the secondary lysosomes of neurons and cells of other tissues (e.g., skin, conjunctiva, and lymphocytes) or by presumed clinical and genetic relationships. The authors have identified 15 atypical subtypes of NCL. These as a group are here described as a seventh form. Further biochemical, molecular, and genetic studies will identify more precisely the phenotypic and genotypic expression of these "minor" forms of NCL.

Translocation 10;18 in a patient with juvenile neuronal ceroid-lipofuscinosis (Batten disease).

We report the first observation of a chromosome abnormality in a patient with typical juvenile ceroid-lipofuscinosis (NCL), who was found to have an apparently balanced translocation between chromosomes 10 and 18 [t(10;18)(q22.1;q21.1)]. Since juvenile NCL was previously mapped to 16p12, this report raises the possibility of heterogeneity in this form of NCL.

Cellular distribution of lesions in Batten disease.

One of the characteristic manifestations of chronic neuronal lipofuscinosis (Batten disease) is a marked predisposition for epileptic seizures. The management of these seizures is very difficult. The present study was initiated to determine what mechanisms could account for the seizure disorder. Tissue was examined from a patient with a history of Batten disease that was histologically verified. Reduced silver and Golgi impregnations were done on the parietal cortex of the patient. There was no evidence of the marked dendritic abnormalities seen in classic epileptic foci. Instead there was marked swelling and dilatation of the axon hillock and initial segment. This finding suggested that inhibition of these pyramidal neurons was markedly attenuated due to disruption of initial segment inhibitory synapses. Studies are continuing to determine if the GABA decreases seen in Batten disease may in part be due to trophic sequences brought about by loss of these critical inhibitory synapses.

Free radicals, anticonvulsants, and the neuronal ceroid-lipofuscinoses.

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

Changing character of subacute sclerosing panencephalitis in the United States.

We analyzed National Registry data from 575 patients with subacute sclerosing panencephalitis (SSPE) in the United States to assess changes in patient characteristics and SSPE epidemiology. Racial proportions have changed in recent years with an increasing number of Hispanic patients reported in relation to a constant black:white ratio; however, the male:female ratio of approximately 2:1 has remained. The most striking feature of the data is the rapid decline in SSPE incidence. Corresponding to this decrease is an increase in the proportion of cases following measles vaccination. There also is a shorter incubation period for SSPE following vaccination than after measles infection.

The neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses are clinical disorders associated with the accumulation of autofluorescent waxy pigments within cells of several different tissues. Such syndromes always have neurological manifestations. Variations in clinical course, genetics, pathogenesis, and possibly treatment occur in each of the several forms listed under this category. Ten subtypes have now been recognized: (1) chronic, juvenile (Batten type); (2) acute, late infantile (Bielschowsky type); (3) subacute-chronic, adult (Kufs type); (4) acute, infantile (Santavuori-Haltia type); (5) congenital (Norman-Wood type); (6) acute, adult (Zeman-Dyken type); (7) acute-subacute childhood (Bielschowsky variant); (8) chronic, childhood with pervasiveness (Edathodu-Dyken type); (9) chronic, infantile with autism (Dyken type); and (10) chronic, juvenile with ataxia and spasticity (Dyken type). By far the most common of these are the first four disorders listed. It is proposed that this present classification of neuronal ceroid lipofuscinosis is more comprehensive than previous ones and fails to support the hypothesis that this disorder represents a unitary disease process, rather than different diseases with similar characteristics. At present, each of the neuronal ceroid lipofuscinosis types are of unknown etiology.

Reconsideration of the classification of the neuronal ceroid-lipofuscinoses.

Neuronal ceroid-lipofuscinoses (NCL) represent diseases of different types. Each variety of NCL may have its own clinical course, genetics, pathogenesis, and treatment. Four disorders are presently accepted as examples of NCL. These include the chronic juvenile or Batten type, the acute late infantile or Bielschowsky type, the chronic or subacute adult Kufs type, and the acute infantile or Santavuori-Haltia type. Seventy patients with clinical and pathological features of NCL have been studied over 20 years; 62 of these fit into one of the above categories, but 8 are atypical and present nosologic problems. Recognized as examples of atypical NCL are 1) chronic congenital or Norman-Wood type, 2) acute adult or Zeman-Dyken type, 3) acute childhood or Bielschowsky variant, 4) chronic childhood (Edathodu-Dyken) type, with pervasiveness, 5) chronic infantile (Dyken) type with autism, and 6) chronic juvenile (Dyken) type with ataxia. It is proposed that our present classification of NCL be based on differentiating clinical dynamics and characteristics, age-of-onset, and morphological and pathological criteria. Although genetic characteristics are now recognized, these are of autosomal recessive or autosomal dominant type. No differentiating biochemical differences have been established to aid in the nosology of these diseases.

Magnetic resonance imaging in neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders characterized by accumulation of lipofuscin and/or ceroid within the tissues of the body. These entities are manifest by visual, intellectual, and motor deterioration as well as recurrent seizures. Computed tomography has been shown to demonstrate changes of cerebral atrophy in more severely affected patients. Seven patients with neuronal ceroid lipofuscinosis were examined with both computed tomography and magnetic resonance imaging, and the results were correlated with the clinical severity of the disorder. Two less severely affected patients had normal results on computed tomography and magnetic resonance imaging studies. Varying degrees of cerebral atrophy were seen in the remaining five patients with both computed tomography and magnetic resonance imaging. Severity of atrophy correlated with the severity of disability in these patients. Abnormal white matter was seen in the two most severely affected patients only with magnetic resonance imaging. Although the findings in patients with neuronal ceroid lipofuscinosis were nonspecific, the increased sensitivity of magnetic resonance imaging for subtle white matter abnormalities over computed tomography may prove helpful in monitoring the progression of this rare disorder.

Magnetic resonance and CT imaging correlated with clinical status in SSPE.

Five patients afflicted with subacute sclerosing panencephalitis were studied with computed tomography and magnetic resonance imaging. Computed tomography documented changes of nonspecific cerebral atrophy and low attenuation in the subcortical white matter. Magnetic resonance imaging revealed bilateral, symmetric, and diffuse abnormal increased signal in the white matter of the cerebral hemispheres with normal posterior fossa structures in 4 of 5 patients. Magnetic resonance imaging was superior to computed tomography in demonstrating the total extent of abnormality and may be the imaging modality of choice for this childhood disease.

Studies on a case of HHH-syndrome (hyperammonemia, hyperornithinemia, homocitrullinuria).

A patient with the hyperornithinemia, hyperammonemia, homocitrullinuria syndrome is described. This patient represents the 12th documented case of this rare, presumably autosomal recessive condition. Increased levels of ammonia, ornithine and homocitrulline were demonstrated in blood and cerebrospinal fluid. The blood ammonia concentration could be lowered by supplementation of the diet with low doses of arginine. High doses of arginine precipitated seizures, although plasma levels of arginine and ornithine were not altered. The uptake of ornithine by the particulate fraction of the patient's fibroblasts was lower than that of controls, but still measurable. It is suggested that HHH patients have a partial impairment of the uptake of ornithine by mitochondria.

Infantile spasms: ictal phenomena.

Ictal phenomena were studied during three separate six-hour video/polygraphic recording sessions in 10 patients with infantile spasms; 1,079 spasms occurred. Frequency during wakefulness (7.7 spasms/hour) was greater than that during sleep (2.5 spasms/hour); 46.6% of spasms occurred in clusters. Spasms were composed of one or more of three phases: a myoclonic contraction, a tonic contraction, and/or an arrest of activity. The most common types were myoclonic-tonic (40.3%) and myoclonic alone (36.3%). When classified by postural motor phenomena, 41.6% were "flexor", 16.3% "extensor", 39.0% "mixed", and 3.1% "arrest" alone. Electrographic monitoring revealed that myoclonic contractions were associated with an initial paroxysmal event. Tonic contractions and arrests were usually associated with suppression of electroencephalographic activity with or without rhythmic activity. Knowledge of these clinical and electrographic features is important for diagnosis and evaluation of proposed treatments.

Subacute sclerosing panencephalitis. Current status.

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disease of childhood that is due to a persistent measles infection. Owing to a nationwide immunization program in the United States, the incidence has decreased considerable, coexistent with the decline in natural measles infection. The disease, now fully understood, still represents a great international problem. Clinical presentation, etiology, pathogenesis, prevention, and treatment are updated in this article.

Short term effects of valproate on infantile spasms.

Although valproic acid (VPA) is used to treat infantile spasms, VPA's efficacy in infantile spasms has not been determined in a controlled study. This study evaluated the effect of VPA on infantile spasms in patients who had not responded to adrenocorticotropin (ACTH) and corticosteroid therapy. The hypotheses were tested using a double-blind, randomized controlled crossover design. Twenty-one patients were randomly assigned to either the baseline-valproate-placebo treatment or the baseline-placebo-valproate treatment groups. Based on a repeated measures analysis of variance test, the valproate group had lower total mean spasm frequency levels than the placebo group. However, this difference did not remain after the crossover; the difference was due to the initial administration of valproate and placebo. When the spasm index was analyzed, the valproate treatment was found to have lower mean spasm index scores than the baseline treatments (p less than 0.03). No short-term toxic effects were observed in any patient. We conclude that short-term VPA therapy has a beneficial effect even on chronic infantile spasm patients who have failed to respond to ACTH/corticosteroid therapy.