David R. Lynch

Paraneoplastic anti-N-methyl -D -aspartate receptor encephalitis associated with ovarian teratoma

To report the autoantigens of a new category of treatment‐responsive paraneoplastic encephalitis.

Anti–N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents

To report the clinical features of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old.

N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease

N-methyl-D-aspartate (NMDA) receptors are the major mediator of excitotoxicity. Although physiological activation of the NMDA receptor is necessary for cell survival, overactivation is a signal for cell death. Several pathways are activated through NMDA receptor stimulation, most of which can contribute to excitotoxicity. These include events leading to mitochondrial dysfunction, activation of calcium-dependent enzymes, and activation of mitogen-activated protein kinase pathways. Understanding the role of these mechanisms is important in developing agents that block excitotoxicity without inhibiting functions necessary for survival. NMDA receptor subtypes may be responsible for mediating separate pathways, and subtype-specific inhibition has shown promising results in some neurological models. This review examines the roles of NMDA receptor subtypes in excitotoxicity and neurological disorders.

Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by short episodes of involuntary movement attacks triggered by sudden voluntary movements. Although a genetic basis is suspected in idiopathic cases, the gene has not been discovered. Establishing strict diagnostic criteria will help genetic studies. Methods: The authors reviewed the clinical features of 121 affected individuals, who were referred for genetic study with a presumptive diagnosis of idiopathic PKD. Results: The majority (79%) of affected subjects had a distinctive homogeneous phenotype. The authors propose the following diagnostic criteria for idiopathic PKD based on this phenotype: identified trigger for the attacks (sudden movements), short duration of attacks (<1 minute), lack of loss of consciousness or pain during attacks, antiepileptic drug responsiveness, exclusion of other organic diseases, and age at onset between 1 and 20 years if there is no family history (age at onset may be applied less stringently in those with family history). In comparing familial and sporadic cases, sporadic cases were more frequently male, and infantile convulsions were more common in the familial kindreds. Females had a higher remission rate than males. An infantile-onset group with a different set of characteristics was identified. A clear kinesigenic trigger was not elicited in all cases, antiepileptic response was not universal, and some infants had attacks while asleep. Conclusions: The diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) can be made based on historical features. The correct diagnosis has implications for treatment and prognosis, and the diagnostic scheme may allow better focus in the search for the PKD gene(s).

ADCK3, an Ancestral Kinase, Is Mutated in a Form of Recessive Ataxia Associated with Coenzyme Q10 Deficiency

Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

A patient with encephalitis associated with NMDA receptor antibodies

Background A 34-year-old woman presented with headache, feverish sensation and anxiety, rapidly followed by homicidal ideation, aggressive agitation, seizures, hypoventilation, hyperthermia and prominent autonomic instability requiring intubation and sedation. She developed episodes of hypotension and bradycardia with periods of asystole lasting up to 15 seconds. Upon weaning off sedation, her eyes opened but she was unresponsive to stimuli. There was muscle rigidity, frequent facial grimacing, rhythmic abdominal contractions, kicking motions of the legs, and intermittent dystonic postures of the right arm.Investigations Routine laboratory testing, toxicology screening, studies for autoimmune and infectious etiologies, brain MRI scan, lumbar puncture, electroencephalogram, whole-body CT scan, abdominal ultrasound, paraneoplastic and voltage-gated potassium channel antibody serologies, analysis of N-methyl-D-aspartate receptor antibodies.Diagnosis Paraneoplastic encephalitis associated with immature teratoma of the ovary and N-methyl-D-aspartate receptor antibodies.Management Intensive care, mechanical ventilation, antiepileptics, laparotomy and left salpingo-oophorectomy, corticosteroids, plasma exchange, intravenous immunoglobulin, cyclophosphamide, physical therapy, and chemotherapy.

Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale

Measuring the severity of neurologic dysfunction in patients with inherited ataxias, including Friedreich ataxia (FA), is difficult because of the variable rate of progression, the variable age at onset and the variety of neural systems that may be affected. The authors discuss the problems related to rating scales in the ataxias, report a neurologic rating scale for FA, and demonstrate acceptable interrater reliability of the instrument.

Cerebellar ataxia and coenzyme Q10 deficiency

The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.

Secondary mechanisms in neuronal trauma

Secondary damage in central nervous system trauma results from toxic effects of a variety of modulators that magnify the initial traumatic damage. These modulators include the excitatory transmitter glutamate, the intracellular messenger calcium, and the intercellular messenger nitric oxide. Glutamate-induced toxicity, called excitotoxicity, occurs from excess glutamate release following trauma. Passage of calcium into the cell through a specific postsynaptic glutamate receptor ion channel, the N-methyl-D-aspartate (NMDA) receptor, is crucial in activating cellular pathways leading to excitotoxic damage. The NMDA receptor requires both glutamate and glycine for activation and is blocked by many drugs that act at either of these sites. It is also blocked by agents that selectively block the ion channel of this receptor. Blocking NMDA receptors at any of these sites decreases the cellular damage mediated by glutamate in neuronal trauma and improves physiological measures associated with traumatic damage. Other strategies to limit secondary damage include blockade of other calcium channels, of calcium-activated enzymes, and of processes that mediate the effects of calcium. Calcium-activated enzymes include nitric oxide synthase and phospholipases, which cause production of free radicals. In combination with NMDA receptor blockade, these sites represent promising areas for therapeutic intervention in secondary traumatic damage.

Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers

The molecular pharmacologic basis of epileptogenesis in cortical tubers in the tuberous sclerosis complex is unknown. Altered transcription of genes encoding glutamatergic and γ‐aminobutyric acid (GABA)‐ergic receptors and uptake sites may contribute to seizure initiation and may occur selectively in dysplastic neurons and giant cells. Arrays containing GABA A (GABAAR), GluR, NMDA receptor (NR) subunits, GAD65, the vesicular GABA transporter (VGAT), and the neuronal glutamate transporter (EAAC1) cDNAs were probed with amplified poly (A) mRNA from tubers or normal neocortex to identify changes in gene expression. Increased levels of EAAC1, and NR2B and 2D subunit mRNAs and diminished levels of GAD65, VGAT, GluR1, and GABAAR α1 and α2 were observed in tubers. Ligand‐binding experiments in frozen tuber homogenates demonstrated an increase in functional NR2B‐containing receptors. Arrays were then probed with poly (A) mRNA from single, microdissected dysplastic neurons, giant cells, or normal neurons (n = 30 each). Enhanced expression of GluR 3, 4, and 6 and NR2B and 2C subunit mRNAs was noted in the dysplastic neurons, whereas only the NR2D mRNA was upregulated in giant cells. GABAAR α1 and α2 mRNA levels were reduced in both dysplastic neurons and giant cells compared to control neurons. Differential expression of GluR, NR, and GABAAR mRNAs in tubers reflects cell‐specific changes in gene transcription that argue for a distinct molecular phenotype of dysplastic neurons and giant cells and suggests that dysplastic neurons and giant cells make differential contributions to epileptogenesis in the tuberous sclerosis complex. Ann Neurol 2001;49:67–78