Pointers and pitfalls in the neurologic examination.

The neurologic examination is reviewed with regard to efficiency, technical errors, and patient comfort. Misleading nomenclature causes errors in executing and interpreting many bedside tests. The examiner can insure success by accepting every patient nonjudgmentally and by maintaining a mind-set that expects to find abnormalities. Since the examiner cannot do every possible test on every patient, intelligent utilization of the history may shorten the examination yet make it more informative. To insure full patient cooperation, the examiner should make each step in the examination into a game or contest and, wherever possible, match functions, such as muscle-to-muscle strength testing, directly against the patient's.

Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study.

The stage of regional structural and biochemical development of the central nervous system appears as a critical factor determining the distribution of hypoxic-ischemic lesions during the perinatal period. We describe the brain lesions in 12 patients who suffered hypoxia-ischemia during the perinatal period. The gestational age ranged from 35 to 42 weeks and the age at death from 2 to 16 weeks. There is one patient alive at age 18 years and a second patient at age 1 year. The cerebral cortical damage is mainly restricted to areas of primary myelination and adjacent subcortical white matter. In addition, there is thalamic, basal ganglia, brainstem, and spinal cord damage. It is postulated that selective damage occurs in those areas which at the moment of the hypoxic-ischemic insult had achieved higher rates of oxygen-glucose utilization. This hypothesis is supported by studies utilizing positron emission tomography which indicates that glucose utilization in the normal human neonatal brain follows a phylogenetic order. Regions that achieved higher levels of glucose consumption are those that suffered the brunt of the damage in our term neonates.

Ischemic thalamic infarction in children: clinical presentation, etiology, and outcome.

Clinical features of thalamic strokes have not been well delineated in children. Six children with ischemic thalamic infarcts (3 M, 3 F; age range: 21 months to 14 1/2 years) are reported. Three patients had infarction in the thalamoperforate artery territory and all had a decreased level of consciousness and hemiparesis; two of them also had associated ocular motility abnormalities. One patient with left thalamotuberal artery stroke presented with aphasia. Two patients with thalamogeniculate artery infarcts had hemiparesis and involvement of the posterior cerebral artery. Etiologic factors in our patients were: infectious vasculitis, congenital heart disease, migraine, and unknown in 1 patient each and trauma in 2 patients. Follow-up information was available for 5, 4 of whom recovered completely. One patient was left with a neurologic deficit. We conclude that the prognosis of ischemic thalamic strokes in children is relatively good.

Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene.

We studied a female infant with clinical signs of Pelizaeus-Merzbacher disease (PMD), who has a familial mutation (C41-->T) in exon 2 of the proteolipid protein gene (PLP), and selected relatives. While the carrier mother and grandmother of the proposita currently are neurologically normal and show normal T2 magnetic resonance imaging (MRI) of the brain, the infant has a neurological picture, MRIs, and brain auditory evoked response (BAER) consistent with that diagnosis. The data here presented show that PMD can occur in females carrying a mutation in the PLP gene. Our experience with the MRIs of this patient, her mother and grandmother, and those of a previously reported family [Pratt et al.: Am J Med Genet 38:136-139, 1991] show that molecular genetic analysis and not MRI is the appropriate means for carrier detection.

Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant.

Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.

Single stage repair of the median cleft lip deformity in holoprosencephaly.

A single stage repair of the median cleft lip in holoprosencephaly is presented. The use of a superiorly-based pedicle from the nasal lobule/columellar remnant for columellar creation and a free skin graft from excess horizontal lip tissue for philtral reconstruction, in addition to medial rotation of the lateral lip segments, permits complete repair in one procedure. Such an approach offers the advantage of a reduction in number of procedures and anaesthetic exposure in the severely medically compromised holoprosencephalic patient.

Magnetic resonance brain images in schizophrenic and normal subjects: influence of diagnosis and education.

Evidence from computerized tomography (CT) suggests that schizophrenic patients may have smaller brains than normal subjects. Magnetic resonance imaging (MRI), which produces more clearly defined images than CT, was used to measure T1 and brain size of 24 schizophrenic and 24 normal subjects matched for age and sex but not for education. Two transverse images were obtained: slice 1 at the foramina of Monro and slice 2 at the widest part of the lateral ventricles. Adequate T1 instrumental reliability could not be demonstrated. Schizophrenic subjects had smaller right hemispheres (slice 1) and smaller frontal areas (slice 2) than normal subjects. However, when education was taken into account, only the left frontal area (slice 2) was smaller in schizophrenic than in normal subjects. Larger brain areas were associated with better cognitive test scores and fewer neurological signs. Cranial and body size were similar in both diagnostic groups.

X-linked recessive inheritance of ataxia and adult-onset dementia: clinical features and preliminary linkage analysis.

Three generations of a family exhibit a unique syndrome of X-linked ataxia, pyramidal tract signs, and adult-onset dementia. Initial signs, manifested by 2 to 3 years of age, are delayed walking and tremor. During their teens, the patients develop mild but progressive ataxia and pyramidal tract signs. Memory problems in the third decade initiate a progressive dementia, leading to death in the sixth decade. Laboratory investigations failed to disclose a biochemical basis for the syndrome. Preliminary molecular linkage studies have been conducted, and although the specific position of the responsible gene on the X chromosome has not yet been determined, the q26-qter region and much of the p arm are unlikely sites for this gene. The linkage studies are continuing.

Serotonergic involvement in the backward tumbling response of the parlor tumbler pigeon.

The parlor tumbler is a breed of domestic pigeon which displays a hereditary movement disorder resulting in backward somersaulting upon attempting to fly. A neurochemical abnormality has been suggested to underlie this behavior. The effect on tumbling of several drugs with serotonergic actions was studied. Increasing available serotonin with 5-hydroxytryptamine (50 mg/kg) plus fluoxetine (10 mg/kg) as well as using amitriptyline (10-20 mg/kg) significantly suppressed tumbling without sedation. This suggests that serotonin mechanisms may be involved in the tumbling response.

Megalencephaly: types, clinical syndromes, and management.

The differential diagnosis of megalencephaly poses a challenge to the clinician. The two major categories, metabolic and anatomic, include a number of conditions, many of them rare. This article provides a systematic approach to the patient with megalencephaly.

Infantile autism.

The authors define infantile autism, giving its time of manifestation, clinical development, differential diagnosis, management, and treatment. They hypothesize that the cause of autism probably will not be found in some consistent gross alteration in brain size or gross structure but that autistic children have some generalized deficit of neurologic function that is common to most or all cerebral neurons.

Usefulness of BAER studies in the early diagnosis of Pelizaeus-Merzbacher disease.

Brainstem auditory evoked responses (BAERs) were markedly abnormal in a 1-month-old infant with Pelizaeus-Merzbacher disease. Wave II occurred at a prolonged latency, and all of the following waves were absent bilaterally. BAER is useful for early diagnosis in this disease.

Evoked response studies in patients with adrenoleukodystrophy and heterozygous relatives.

Brain-stem auditory evoked responses (BAERs) and somatosensory evoked responses (SERs) were studied in three patients and seven female relatives in three families with adrenoleukodystrophy (ALD). All patients with ALD had abnormal BAERs and SERs, reflecting the central demyelination occurring in ALD. Four of the seven female family members had abnormalities of SERs with or without abnormalities of BAERs, similar to those seen in the patients. We suggest that these abnormalities demonstrate the morphological effects of the ALD gene in the CNS and reflect the physiological alteration in the heterozygous females in families with ALD.

Brain stem auditory, visual and somatosensory evoked potentials in leukodystrophies.

Brain stem auditory (BAERs), visual (VEPs) and somatosensory evoked responses (SEPs) were recorded in 12 patients with Pelizaeus-Merzbacher leukodystrophy (PMD), three with adrenoleukodystrophy (ALD) and three with metachromatic leukodystrophy (MLD). All the 3 evoked responses were abnormal in all patients except normal VEPs and SEPs in a patient with early ALD. In most patients wave I with and without wave II were the only components of the BAERs that remained, subsequent components (waves III-VII) were absent. VEPs were severely altered; either no identifiable response to flash or pattern reversal stimuli could be recorded or the major components were significantly delayed in latency. Short latency SEPs following median nerve stimulation usually showed a normally recorded Erb's potential (N10), but an absence or marked attenuation of cervical (N14) and early scalp components (N19 and P22) or the occurrence of the scalp components with a significant delay. Multimodality evoked responses provide more information regarding the functional integrity of several afferent systems in patients with white matter disorders.

Failure of clorazepate to cause malformations or fetal wastage in the rat.

Clorazepate dipotassium (Tranxene), an anticonvulsant benzodiazepine, was tested for teratogenicity by injecting ten pregnant Long-Evans rats with 32 mg/kg of body weight intramuscularly on days 8.5, 9.5, and 10.5 of gestation. Ten control rats similarly received sterile water injections. Sixty fetuses recovered after killing five of the mothers on day 20.5 of gestation were sectioned to ascertain external and visceral malformations. Comparison with 55 control fetuses showed no statistically significant differences in external, visceral, or skeletal malformations, nor in fetal mortality, fetal and placental weight, and crown-rump length. Five clorazepate-treated rat mothers were allowed to deliver their 45 offspring for a companion study of possible behavioral effects. None of these additional 45 clorazepate-treated rats showed external malformations. Thus clorazepate caused no gross malformations in the rat under the conditions of this study.

Delayed maze-learning in rats after prenatal exposure to clorazepate.

Five pregnant Long-Evans rats were given 32 mg/kg of body weight of clorazepate dipotassium (Tranxene) intramuscularly on gestational days 8.5, 9.5, and 10.5. Five control mothers received sterile water. The control group of offspring (n = 19) and the experimental group (n = 20) were compared by means of a timetable for neurologic development and for maze learning ability. Although the experimental group was significantly slower in stomach-lifting and walking, the neurologic battery as a whole did not disclose any consistent difference. At 21 days of age, the experimental rats weighed significantly more than the control rats. On trials 10 to 14, the control group ran the maze in less than half of the time of the experimental group. The study emphasizes the need to include tests of cerebral function in addition to developmental reflexes to screen for subtle effects of teratogens, which the simpler developmental tests may miss.

Brainstem auditory evoked responses in leukodystrophies.

Brainstem auditory evoked responses (BAERs) were recorded in seven patients with Pelizaeus-Merzbacher leukodystrophy (PMD), two with adrenoleukodystrophy (ALD), and one with metachromatic leukodystrophy (MLD). BAERs were altered in all patients, and the alterations were severe in 9 of the 10 patients. A patient with ALD who as yet had no neurologic symptoms showed only minimal abnormality of the BAERs, consisting of prolongation of the latency of wave V. In the remaining nine patients, only wave I generated in the extramedullary portion of the eighth nerve was recorded with or without a wave II. Subsequent components (III through VII) were absent. No abnormality of BAERs was observed in the 10 known carriers of PMD. The combination of BAERs and EEG is helpful in differentiating leukodystrophy from progressive gray matter diseases.

Peripheral motor and sensory neuropathy of early childhood, simulating Werdnig-Hoffmann disease.

A five-year-old girl developed neurogenic muscular atrophy during infancy. On the basis of clinical findings and a muscle biopsy study a diagnosis of infantile spinal muscular atrophy, benign type II, was entertained. As the disease progressed, involvement of sensory pathways was detected by electrophysiological studies. Examination of a sural nerve specimen suggested a chronic polyneuropathy rather than spinal muscular atrophy. These findings were confirmed at autopsy by demonstrating severe loss of myelinated axons in ventral and dorsal spinal roots, peripheral nerves and dorsal columns of the spinal cord. In addition, islands of astroglial fibers were found in ventral and dorsal spinal roots, regarded as a secondary reaction to the breakdown of myelinated axons. This unusual scarring process seems to result from nerve fiber loss during the perinatal period, since radicular glial scar tissue is not known to occur in the spinal muscular atrophies of later onset. Examination of the sensory nervous system in patients with Werdnig-Hoffmann disease appears mandatory to clarify the precise disease entity leading to infantile neurogenic muscular atrophy.