Progressive myoclonic encephalopathy in X-linked hypogamma-globulinemia. Case report, review of the literature and its relationship with progressive encephalopathy in children with A.I.D.S

A 7-year-old boy suffering from X-linked hypogammaglobulinemia and progressive myoclonic encephalopathy is reported. The onset of neurological disturbances is at four years of age with ataxic gait and myoclonic jerks. The EEG shows a progressive slowing of background activity, bilateral diffuse and repetitive, pseudoperiodic, high amplitude slow waves, myoclonic jerks polygraphically documented. The CT-scan shows generalized cerebral atrophy, white matter hypodensity--principally in the frontal regions -, multiple nodular calcifications, also in the basal ganglia. Two years after the onset of neurological signs, the boy is completely bedridden, spastic, dement and blind; the myoclonic jerks persist. Finally the relationship is discussed with both the previously reported patients with the same affection, and with similar progressive encephalopathy in children suffering from A.I.D.S.     

Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases

OBJECTIVE: Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate. METHODS: Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats. RESULTS: Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients. INTERPRETATION: These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.     

Synaptic vesicle-associated glutamate decarboxylase: Identification and relationship to insulin-dependent diabetes mellitus

Glutamic acid decarboxylase (GAD) catalyzes the biosynthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). GAD has been suggested as an autoantigen in insulin-dependent diabetes mellitus and stiff-man syndrome. Recently, three forms of membrane-associated GAD (MGAD) have been characterized in porcine brain, but the subcellular localization and function of these proteins are unknown. We present evidence that GAD activity is associated with synaptic vesicles from porcine brain. These vesicles contain a 60 kDa protein recognized by serum from patients with insulin-dependent diabetes mellitus, probably MGADII, as shown by subcellular fractionation and immunoblotting. These results raise the possibility that the association of MGADII with synaptic vesicles may be crucial for its role as an autoantigen in insulin-dependent diabetes mellitus. © 1995 Wiley-Liss, Inc.     

Stiff-man syndrome: an immunopathy?]

The discovery of autoimmune processes in the stiff-man syndrome (SMS) not only raises questions concerning the syndrome itself, but may also lead to new insights into pathogenetic principles of neurological disorders. Autoantibodies against GAD, the GABA synthesising enzyme, may become a helpful (though not specific) diagnostic tool, and furthermore may serve as a plausible explanation for both the symptoms of the syndrome and the delayed development of type I diabetes mellitus. However, it remains unexplained why autoimmunity against such widespread inhibitory transmitter systems should induce a syndrome which by definition is confined to only a few symptoms, and for which the majority of neurological signs are regarded as exclusion criteria. It is therefore hypothesised that SMS is part of a broad spectrum of encephalomyelopathies with autoimmunity against GABAergic neurones in common, but with a heterotopic manifestation. Progressive encephalomyelitis with rigidity may be an extreme variant within this spectrum.     

Galloway–Mowat syndrome: An early-onset progressive encephalopathy with intractable epilepsy associated to renal impairment. Two novel cases and review of literature

Galloway–Mowat Syndrome (GMS) is an autosomal recessively inherited condition which manifests with severe encephalopathy, featuring microcephaly, developmental delay, and early-onset intractable epilepsy. Patients typically show also renal involvement from the onset. We report two siblings with GMS presenting with early-onset, intractable epilepsy and neurological deterioration, later followed by renal impairment. In both patients intractable epilepsy started during the first months of life and included a combination of spasms, focal and myoclonic/atonic seizures, along with psychomotor retardation and dysmorphic features. One of the patient died from fulminating renal failure at age 6 years. The other patient developed only isolated proteinuria from the age 3 years. Our cases differ from ‘classic’ GMS, as manifested the clinical and laboratory features of renal involvement only some years later the onset of epilepsy and neurological symptoms. Therefore, the diagnosis of GMS should be considered in infants with intractable epilepsy, encephalopathy, and multiple neurological deficits, also in absence of renal manifestations. The literature data about the electroclinical features of epilepsy in GMS are also reviewed.     

The immunological basis for treatment of stiff person syndrome

Antibodies against autoantigens involved in GABAergic neurotransmission are a shared feature of the different subtypes of stiff person syndrome (SPS). The autoantigens can be either presynaptic such as the smaller isoform of glutamic acid decarboxylase (GAD65), postsynaptic such as GABA-A receptor-associated protein and gephyrin, or located at the pre- and postsynaptic side such as amphiphysin. Most of these autoantigens are intracellular, and antibodies against GAD65 also occur in diabetes mellitus type 1 as well as other neurological diseases. Their pathogenic role has therefore been questioned. We here discuss the role of autoantibodies and T cells in SPS.     

Infantile spasms as an epileptic feature of DEND syndrome associated with an activating mutation in the potassium adenosine triphosphate (ATP) channel, Kir6.2

Activating mutations in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium (KATP) channel is a cause of neonatal diabetes associated with various neurological disorders that include developmental delay, epilepsy, and neonatal diabetes (known together as DEND syndrome). This article reports a girl who developed infantile spasms and early onset diabetes mellitus at the age of 3 months and revealed DEND syndrome with a heterozygous activating mutation in Kir6.2. Infantile spasms with hypsarrhythmia on the electroencephalogram were severe and refractory to steroids. Steroids combined with oral sulfonylurea, a drug that closes the ATP-sensitive potassium channel by an independent mechanism, allowed partial and transitory control of the epilepsy. However, the child still exhibited severe encephalopathy and died of aspiration pneumonia. The role of oral sulfonylurea as an anticonvulsant in DEND syndrome associated with Kir6.2 mutation is discussed.     

Hashimoto's thyroiditis and myoclonic encephalopathy. Pathogenic hypothesis

A 49 year old caucasian female with Hashimoto thyroiditis, developed during two years a neurological disorder with tonic-clonic and myoclonic seizures and confusional states. Some attacks were followed by a transient postictal aphasia. Some parallelism was noted between the clinical state and TSH levels. Neurological events disappeared with the normalisation of thyro?d functions. This association of Hashimoto thyroiditis and myoclonic encephalopathy has been rarely published. Pathogenesis could be double. Focal signs could be due to an auto-immune mechanism, perhaps through a vasculitis. A non-endocrine central action could explain diffuse signs: tonic-clonic seizures, myoclonus and confusional episodes.     

Valproate encephalopathy and hypocarnitinaemia in diabetic patients

Two patients with epilepsy and diabetes mellitus developed encephalopathy while on valproate monotherapy. Low plasma carnitine levels were found. Discontinuation of valproate was followed by clinical recovery and normalization of carnitine levels. Both valproate treatment and diabetes mellitus may contribute to secondary carnitine deficiency, with resultant encephalopathy. Thus, diabetic patients may be at increased risk of developing valproate encephalopathy associated with hypocarnitinaemia.     

GAD65 neurological autoimmunity

The glutamic acid decarboxylase 65‐kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff‐person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff‐limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy‐response. Muscle Nerve 56 : 15–27, 2017     

Cerebellar ataxia with glutamic acid decarboxylase autoantibodies

Degenerative cerebellar ataxia with autoantibodies against glutamic acid decarboxylase (GAD) is a rare disorder and may represent a subset of ataxias previously classified as idiopathic. The authors report a patient with progressive cerebellar ataxia, insulin-dependent diabetes mellitus, and GAD antibodies who responded to i.v. immunoglobulins.     

Early-onset progressive encephalophathy with migrant,continuous myoclonus

Three unusual cases of focal continuous myoclonus with onset during the first months of life, lasting from dozens of minutes to hours, are reported. During disease evolution, prolonged bilateral myoclonic seizures and generalized tonic-clonic seizures occur. Subsequently, a progressive encephalopathy with hypotonia and ataxia appears. A net worsening of the neurological condition is observed after the age of 4–5 years. Cortical atrophy is shown by CCT and MRI. Neurometabolic screening is not contributory. Repeated polygraphic recordings show continuous and segmental myoclonic jerks, localized in different muscles, at frequencies ranging between 0.5–1 c/s and 6–8 c/s. Moreover action myoclonus is recorded. During the first period of disease the EEG does not show any paroxysmal activity. As to the classification, this syndrome corresponds to an early onset progressive encephalopathy of unknown origin, similar in some aspects to Alper's disease. Another problem is the interpretation of the myoclonic phenomena. Some important aspects suggest a cortical origin of the diverse myoclonic phenomena observed in these cases.     

Rituximab treatment of stiff-person syndrome in a patient with thymoma,diabetes mellitus and autoimmune thyroiditis

Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by stiffness of the skeletal muscle with superimposed spasms and production of autoantibodies to glutamic acid decarboxylase (GAD) and amphiphysin. The disorder results from B cell-mediated clonal production of autoantibodies, requiring treatment with immunosuppressors; however, treatment results have been somewhat inconsistent. We report the results of rituximab treatment in a patient with SPS associated with a thymoma, diabetes mellitus, autoimmune thyroiditis and the presence of anti-GAD and anti-amphiphysin autoantibodies. The patient experienced a partial improvement following a thymectomy and the administration of prednisone, intravenous immunoglobulins and mycophenolate mofetil. Treatment with rituximab was followed by a complete sustained remission and the disappearance of serum anti-amphiphysin antibodies.     

Antigenic differences between neurological and diabetic patients with anti-glutamic acid decarboxylase antibodies

Antibodies to glutamic acid decarboxylase (GADAb) are found in Stiff-Person syndrome, type 1 diabetes, cerebellar ataxia and other neurological disorders (such as epilepsy and myoclonus) involving the GABAergic ways. GADAb are usually detected by immunohistochemistry (IHC), radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). This study analysed the serum of 14 patients with neurological disorders who were positive by IHC for GADAb. The performance of a commercial RIA was compared with in-house immunoblotting and ELISA methods using recombinant GAD65 (rGAD65). RIA was positive in 14 of 14, immunoblotting was positive in seven of 14 and ELISA in 12 of 14. There was no correlation between the RIA result and the ELISA optical densities. Using a sodium thiocyanate chaotrope system with ELISA to determine antibody affinity, we found no significant correlation between antibody affinity and the RIA result. A consensus should be defined concerning which assay could be used as the gold standard for detecting GADAb. The most intriguing finding was that GAD antibodies from uncomplicated diabetics do not appear to recognize GAD in frozen sections from the rat cerebellum, whereas GAD antibodies from neurologically compromised diabetics do. A working proposal is therefore that type 1 diabetic patients with unusual neurological symptoms should be tested for GADAb both by RIA and IHC.     

Epilepsia partialis continua in cat scratch disease.

Cat scratch disease (CSD) is a world-wide, diffuse, non-epidemic infection caused by the Gram-negative bacillus Bartonella henselae. The occurrence of encephalopathy represents an infrequent and atypical complication, whose manifestations include ischemic strokes, transverse myelitis and epileptic seizures. Status epilepticus has been described as the most frequent emergency in CSD encephalopathy. In this report, we describe a case of CSD complicated by an epilepsia partialis continua (EPC) manifested as rhythmic movements of the flexor muscles of the left hand. Although CSD is a benign, self-limited disease and a complete neurological recovery usually occurs, in the present case the EPC resulted in a partial epilepsy. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and back-averaged EEG data recorded during myoclonic activity document this CSD complication.     

The T-C(8356) mitochondrial DNA mutation in a Japanese family

A rare point mutation at nucleotide position 8356 in the transfer RNA gene in mitochondrial DNA was found in a Japanese family. Our proband had migraine and dementia associated with lactic acidosis in addition to myoclonic epilepsy with ataxia and ragged-red fibres in a muscle biopsy specimen consistent with the clinical characteristics of myoclonic epilepsy with ragged-red fibres (MERRF). His mother, who had the same point mutation, also had migraine but without myoclonus or ataxia. His aunt, who had the same point mutation and migraine, developed diabetes mellitus, encephalomyopathy and several stroke-like episodes associated with lactic acidosis (MELAS). This is the third family with the rare mutation seen in American and Italian families. The mutation may not be specific to Caucasians, and is probably closely related to the MERRF/MELAS overlap syndrome.     

Epilepsia partialis continua in type 1 diabetes: evolution into epileptic encephalopathy with continuous spike-waves during slow sleep

Hyperglycemic status may be rarely complicated by Epilepsia partialis continua (EPC) that usually responds to metabolic normalization. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) play a pivotal role in the autoimmune process that leads to clinical onset of type 1 diabetes mellitus (T1DM). GAD-Ab have been recently reported in association with rare forms of refractory epilepsy, with or without association to T1DM. Here we describe a young patient who developed EPC five months after T1DM onset; GAD-Ab were detected in his cerebrospinal fluid with evidence of oligoclonal bands. His epileptic disorder evolved over time into drug-resistant epilepsy with continuous spike-waves during slow sleep and severe behavioral impairment. The role of both metabolic imbalance and GAD autoimmunity is discussed.     

Vigabatrin caused rapidly progressive deterioration in two cases with early myoclonic encephalopathy associated with nonketotic hyperglycinemia

Vigabatrin, a structural analogue of gamma-aminobutyric acid (GABA), is used for the treatment of generalized and partial seizures in infants. The drug inhibits the GABA transaminase and elevates the GABA concentration in the brain. Here we present the vigabatrin experience in two patients with early myoclonic encephalopathy owing to nonketotic hyperglycinemia (glycine encephalopathy). Both patients had early infantile seizures characterized by fragmentary myoclonic jerks associated with burst-suppression pattern on electroencephalography. Nonketotic hyperglycinemia was diagnosed with elevated cerebrospinal fluid and plasma glycine levels. The seizures were initially thought to be infantile spasms, and vigabatrin (50 mg /kg/day) was started for the treatment of seizures. Rapidly progressive deterioration was noticed after a few days. Acute encephalopathy associated with sleepiness and respiratory failure developed. Vigabatrin produced acute encephalopathy, which regressed in a few days after vigabatrin was stopped in the first patient. However, in the second case, despite the discontinuation of vigabatrin, there was no recovery of general conditions. Our observations in two cases indicate the risk of using vigabatrin in patients with nonketotic hyperglycinemia. The elevated GABA concentration in the brain can enhance the encephalopathy, together with the elevated levels of glycine. (J Child Neurol 2006;21:82-84).     

Repetitive EEG recordings are necessary for the diagnosis of early myoclonic encephalopathy

Early myoclonic encephalopathy (EME) is a rare malignant epileptic syndrome. The erratic myoclonus with or without focal motor seizures, time of onset before 3 months of age, and suppression-burst (SB) pattern in EEG are accepted as the diagnostic criteria for EME. We report a 40-day-old infant with the diagnosis of non-ketotic hyperglycinemia (NKHG). The infant developed myoclonic and focal tonic seizures on the first day of life. His first sleep EEG recorded after onset of seizure was normal. Because of the diagnosis of NKHG and early developed myoclonic seizure, we thought the infant might be EME, and repeated sleep EEG on admission in which asymmetrical SB pattern was seen. We concluded that the absence of SB pattern in the first EEG recording does not exclude the diagnosis of EME, but repetition of EEG is necessary to demonstrate the presence of SB pattern to meet the diagnostic criteria for EME.