Michael A. Nigro

Hyperekplexia: a treatable neurogenetic disease

Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype-phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.

Hyperekplexia and sudden neonatal death

Fifteen patients with hyperekplexia were identified in 3 families; diagnostic clinical characteristics were defined which allowed for early recognition and treatment. During the first 24 hours of life, spontaneous apnea and sluggish feeding effort were observed. After the first 24 hours, surviving infants exhibited the hyperekplexic startle response to nose tapping. This startle response is characterized by sudden muscular rigidity, feeding-induced oropharyngeal incoordination, and poor air exchange often with apnea, persisting with repetitive nose tapping. Untreated infants experienced recurring apnea until 1 year of age. Three of 15 patients died unexpectedly during the neonatal period. Patients treated with clonazepam (0.1-0.2 mg/kg/day) had no serious apneic episodes and startle reflexes were diminished. The pathophysiologic mechanism for hyperekplexia remains obscure. Electroencephalographic studies were consistently normal. The response to and tolerance of benzodiazepines are striking in newborns and infants and suggest an aberrant central nervous system reflex as the etiology; therefore, hyperekplexia should be considered in the evaluation of neonates and infants with apnea, aspiration pneumonia, episodic muscular rigidity, hyperexcitability, and near-miss sudden infant death syndrome. The need for immediate monitoring of at-risk infants, observation for signs of hyperekplexia, and initiation of clonazepam in these patients are emphasized. Hyperekplexic startle response to nose tapping should be included in the routine examination of all newborns.

Electroencephalographic findings in Rett syndrome

Rett syndrome is a progressive neurologic condition, affecting only girls and characterized by acquired microcephaly, dementia, seizures, autistic behavior, spontaneous hyperventilation, spasticity, hyperreflexia and a peculiar characteristic stereotypic movement disorder. A review of 35 EEGs (obtained over 0-8.5 years of follow-up) in 9 such patients revealed a striking age-related change in the electroencephalographic pattern. Often initially normal, the EEG shows a variety of epileptiform abnormalities but intact background activity between 3 and 5 years. Between 5 and 10 years of age, the background activity exhibits some slowing, epileptiform abnormalities persist and paroxysmal high-amplitude theta activity occurs over extended periods, related to spontaneous hyperventilation. After 10 years, there is a general reduction in the epileptiform activity but further slowing of the background rhythms is usually observed. As all other laboratory tests are mostly normal in Rett syndrome, EEG promises to be a powerful tool in confirming the diagnosis in a compatible setting, in follow-up of these patients, and in objective evaluation of any future therapeutic interventional modalities in this serious and common condition.

Altered regional brain glucose metabolism in Duchenne muscular dystrophy: a pet study.

The basis for cognitive impairment in Duchenne muscular dystrophy (DMD) is not well understood but may be related to abnormal expression of dystrophin in brain. The aim of this study was to determine whether regional brain glucose metabolism is altered in children with DMD and whether such metabolic disturbances are localized to regions shown to be normally rich in dystrophin expression. Ten boys (mean age, 11.8 years) with DMD and 17 normal adults as a control group (mean age, 27.6 years) underwent 2‐deoxy‐2[18F]fluoro‐D‐glucose positron emission tomography (PET) and neuropsychological evaluation. The PET data were analyzed by statistical parametric mapping (SPM). The SPM analysis showed five clusters of decreased glucose metabolism in children with DMD, including the medial temporal structures and cerebellum bilaterally and the sensorimotor and lateral temporal cortex on the right side. At the voxel level, significant glucose hypometabolism was found in the right postcentral and middle temporal gyri, uncus, and VIIIB cerebellar lobule, as well as in the left hippocampal gyrus and cerebellar lobule. The neuropsychological profile of the DMD group revealed borderline nonverbal intellectual functioning, impaired manual dexterity bilaterally, borderline cognitive functioning, and internalizing behavioral difficulties. Our findings demonstrate region‐specific hypometabolism, as well as cognitive and behavioral deficits in DMD children. As the regions showing hypometabolism on PET include those normally rich in dystrophin expression, it will be important to determine whether the hypometabolic regions also show cytoarchitectural abnormalities related to the lack of dystrophin.

Botulinum toxin as a novel treatment for self-mutilation in Lesch-Nyhan syndrome.

Lesch–Nyhan syndrome (LNS) is an X‐linked recessive disorder resulting from a deficiency of the metabolic enzyme hypozanthine–guanine phosphoribosyltransferase (HPRT). This syndrome presents with abnormal metabolic and neurological manifestations including hyperuricemia, mental retardation*, spastic cerebral palsy (CP), dystonia, and self‐mutilation. The mechanism behind the severe self‐mutilating behavior exhibited by patients with LNS is unknown and remains one of the greatest obstacles in providing care to these patients. This report describes a 10‐year‐old male child with confirmed LNS who was treated for self‐mutilation of his hands, tongue, and lips with repeated botulinum toxin A (BTX‐A) injections into the bilateral masseters. Our findings suggest that treatment with BTX‐A affects both the central and peripheral nervous systems, resulting in reduced self‐abusive behavior in this patient.

The treatment of Friedreich's ataxia with amantadine hydrochloride

Amantadine hydrochloride (AH) was orally administered to 16 patients with Friedreichs ataxia. We evaluated patient response with the functional ataxia scoring scale and calculated a total disability score. The mean percent improvement of the total disability score was 29.5%; for ambulatory patients alone it was 45.5%. No significant side effects were encountered. AH appears to be a safe and effective symptomatic treatment of Friedreichs ataxia.

High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis

Autoimmune neurologic disease management has been significantly modified by the use of high-dose intravenous immunoglobulin (HDIVIG) during the past 15 years. Venous access, readily available IgG (until recently), and the relative lack of serious identifiable complications have prompted its use in myasthenia gravis. In adults, its effectiveness has been inconsistent, with variable acetylcholine receptor (AChR) antibody responses. Ten children were evaluated for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. The HDIVIG dosage was 2 gm/kg body weight, infused at variable rates of 2 gm/kg for 1 day, 0.66 gm/kg daily for 3 days, and 0.5 g/kg daily for 4 days; in one patient the total dose was 0.8 gm/kg to correct to the ideal body weight. All children but one tolerated HDIVIG without complications. Eight patients exhibited definite improvement in functional strength after HDIVIG, but a decreasing response to HDIVIG was evident after multiple monthly treatments, warranting the additional use of corticosteroids in two patients. A decrease in anti-AChR antibody levels was observed in the three patients tested, but this decrease was constant in one patient. No correlation was observed between clinical response and antibody titers. HDIVIG is safe and effective in most patients for short-term management of juvenile myasthenia gravis, in myasthenic crises, and in preparing patients for surgery but appears to be of limited long-term benefit.

Otocerebral anomalies associated with topical tretinoin use

Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports. We report a case of a patient with anomalies involving the ear and central nervous system with exposure to topical tretinoin during the first trimester. Though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age.

Progressive Dystonia in a Child With Chromosome 18p Deletion, Treated With Intrathecal Baclofen:

We report a case of dystonia with a partial deletion of the short arm (p) of chromosome 18 and androgen insensitivity Neurologic findings in the 18p syndrome are reported to include mental retardation, seizures, incoordination, tremor, and chorea. A 15-year-old girl with a denovo 18p deletion [karyotype 46, XY, del (18)(p11.1)] developed progressive asymmetric dystonia. She had oromotor apraxia and partial expressive aphasia since childhood, and she was able to partially communicate through elementary sign language. At the age of 15 years, she developed subacute and progressive choreic movements of the right arm, severe dystonic posturing of the left arm, and spastic dystonia in both legs. Her response to parenteral or oral benzodiazepines, oral trihexyphenidyl, benztropine mesylate, baclofen, and L-dopa were brief and inadequate. The response to intrathecal baclofen has been sustained over 18 months. In all likelihood, the 18p deletion syndrome affecting this patient is significant in the pathogenesis of her acquired dystonia. Chronic intrathecal baclofen therapy via pump has been effective in this case and should be considered as a treatment modality in carefully selected patients with dystonia. (J Child Neurol 1999;14:75-77).

Rett syndrome — a gray matter disease? Electrophysiologic evidence

Electrophysiologic dichotomy of abnormal EEGs, as reported by us previously, and normal evoked potentials, as reported in this communication, in patients with Rett syndrome, suggests a predominant gray matter pathophysiologic insult in this serious condition of unknown etiology.