Head titubation and irritability as early symptoms of Joubert syndrome with a homozygous NPHP1 variant

BackgroundJoubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable.Case reportWe report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year.ConclusionIrritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.     

Alpha-pattern coma: 24 cases with 9 survivors

Alpha-pattern coma denotes the association of a comatose state with an electroencephalogram consisting predominately of alpha-frequency activity. Over the past three years we have studied 24 such cases: 14 following cardiopulmonary arrest, 6 following respiratory arrest, and 3 following brainstem infarction. Of the 9 patients who survived, only 1 had a significant neurological deficit. It was found that: (1) alpha-pattern coma can result from a variety of neurological insults; (2) a significant proportion of patients survive, often with little or no deficit; (3) clinical evidence of intact brainstem function implies a favorable outcome; (4) the electroencephalogram was similar in survivors and nonsurvivors and did not differentiate diffuse cerebral dysfunction from focal brainstem disease; and (5) neuropathological studies demonstrated diffuse cortical as well as brainstem changes.     

Bickerstaff brainstem encephalitis associated with Mycoplasma pneumoniae infection

Bickerstaff brainstem encephalitis is a clinical syndrome of ophthalmoplegia, cerebellar ataxia, and central nervous system signs and is associated with the presence of anti-GQ1b antibodies. There is a clinical continuum between Bickerstaff brainstem encephalitis and Miller Fisher syndrome. We describe the case of an 11-year-old boy with encephalopathy, external ophthalmoplegia, brainstem signs, and ataxia with raised titers of anti-GQ1b antibodies. He presented following a respiratory illness and had laboratory evidence of recent infection with Mycoplasma pneumoniae. M pneumoniae infection has been associated with both Bickerstaff brainstem encephalitis and Miller Fisher syndrome. This is only the second case in the literature of Bickerstaff brainstem encephalitis with raised titers of anti-GQ1b antibodies described in association with M pneumoniae infection. The patient responded to intravenous immunoglobulin administration.     

Prognostic significance of multimodality evoked response testing in high-risk newborns

Exposure to hypoxic-ischemic events in fetal or neonatal life may lead to permanent brain damage and subsequent neurodevelopmental deficits. Clinical and diagnostic tools have been somewhat helpful in identifying an at-risk group, particularly those patients sustaining significant neurologic sequelae. In this prospective study, the prognostic significance of multimodality evoked responses in high-risk newborns was examined. A group of 44 high-risk newborns, as well as 14 healthy newborns, were tested during the newborn period with auditory brainstem responses and somatosensory evoked responses; these tests were repeated at 2 and 6 months corrected age. A neonatal neurologic examination, the Einstein Neonatal Neurobehavioral Assessment Scale, was also conducted. At 1 year corrected age, both groups were assessed in a blind fashion by a pediatric neurologist and a psychologist to determine neurodevelopmental outcome. Results indicated that somatosensory evoked response abnormalities in particular predict an abnormal neurologic status at 1 year of age. Abnormalities that persisted or worsened correlated with severe neurologic impairment, whereas an abnormal somatosensory evoked response that improved or normalized in infancy was associated with mild to moderate neurologic sequelae. Increased brainstem conduction in the auditory brainstem responses was also associated with neurologic sequelae. Normal findings from auditory brainstem responses and somatosensory evoked responses predicted normal developmental scores in all areas, as well as a normal neurologic outcome at 1 year with negative predictive powers ranging from 85–100%. Evoked response testing appears to be an important adjunct to the neurologic investigation of high-risk newborns.     

Distribution of hypocretin (orexin) immunoreactivity in the feline pons and medulla

The distribution of hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) immunoreactivities in the cat brainstem was examined using immunohistochemical techniques. Hcrt-1- and hcrt-2-positive fibers with varicosities were detected in almost all brainstem regions. However, no hcrt-1- or hcrt-2-immunoreactive neuronal somata were observed in the cat brainstem. Both hcrt-1- and hcrt-2-labeled fibers exhibited different densities in distinct regions of the brainstem. In most brainstem regions, the intensity of hcrt-1 immunoreactivity was higher than that of hcrt-2 immunoreactivity. The highest densities of hcrt-1- and hcrt-2-positive fibers were found in the nucleus raphe dorsalis (RD), the laterodorsal tegmental nucleus (LDT) and the locus coeruleus (LC), suggesting an important role for these peptides in functions related to sleep-wake behavior.     

Computed tomographic correlates of auditory brainstem responses in alcoholics.

A previous study has shown a high incidence of abnormal auditory brainstem responses in alcoholics, particularly when cerebral and/or cerebellar atrophy was present in CT scans. To correlate the electrophysiological findings with definable morphological alterations, quantitative measurements of the brainstem structures in CT scans were made. To determine the relative size of the brainstem, the ratio between the sizes of the brainstem and its cisterns was obtained at the midbrain, upper and lower pons. When compared to the aged-matched control group, the alcoholics as a whole and the alcoholics with abnormal auditory brainstem responses had a decrease in the ratio at all three brainstem levels, but these ratios were not decreased in the alcoholics with the normal auditory brainstem responses. The present data indicate that abnormal brainstem responses in the alcoholics correlated with an increased size of the brainstem cisterns and possible brainstem atrophy.     

Intractable hiccup induced by brainstem lesion

Four patients with brainstem lesions presented with intractable hiccup and mild to moderate neurological signs. Two of the patients had been initially diagnosed as having a psychogenic cause for their hiccup. Magnetic resonance imaging (MRI) demonstrated brainstem infarction in one case, tuberculoma at the junction of the medulla oblongata and the cervical spinal cord in two, and a vermian tuberculoma compressing the brainstem in one. The brainstem infarct and one of the medullary tuberculoma were not detected on high resolution enhanced computed tomography. The 3 patients with CNS tuberculoma were free of hiccup 1-5 months after antituberculous chemotherapy. It is proposed that hiccup is not an abnormal reflex, but a myoclonus generated by repetitive activity of the "inspiratory solitary nucleus" due to release of higher nervous system inhibitory/-regulatory control. The neuroanatomical network and the mechanisms underlying the formation of intractable hiccup are outlined. The value of MRI in the initial diagnosis and follow-up of patients with intractable hiccup due to brainstem lesions is emphasised.     

Spatial Distribution of Brainstem Auditory Evoked Potentials and Their Alterations in Lesions of the VIIIth Nerve and Brainstem1

Abstract

Brainstem auditory evoked potentials (brainstem AEPs) were simultaneously recorded from 13 scalp and earlobe electrodes from normal subjects employing a noncephalic reference. The scalp distributions of the individual components (waves I-V) were presented as isopotential maps with the use of a topographic computer display system. Binaural clicks produced symmetrically distributed brainstem AEPs over the scalp. With monaural stimulation, the topography of the responses differed in locus of maximum amplitude for each of the components, suggesting that different generators are involved in the production of these components (for example, wave V is of maximal amplitude with the shortest peak latency over the contralateral frontal area). Wave I was the only component that reversed its polarity according to electrode locations. Other waves were positive over the scalp and earlobes in confonnity with the concept that they are volume conducted, far field potentials. Brainstem AEPs in subjects with lesions in the Vlllth nerve and brainstem have different distributions from those of normal subjects, that is, reversal of polarities of the components after wave I at the ipsilateral earlobe and generalized reduction of their amplitudes over the scalp and contralateral earlobe. Thus an accentuation as well as an attenuation should be carefully evaluated in the clinical assessment of brainstem AEP changes associated with brainstem lesions, for brainstem AEPs are commonly recorded from the vertex referenced to the ipsilateral earlobe. These alterations in the observed field distributions, including polarity reversals of brainstem AEPs, seem to reflect changes in the spatial properties of the generators associated with brainstern lesions, such as a reduction in the magnitude of currents with a possible deviation of the dipole axes assuming that the generator for a given component is approximated by an equivalent dipole layer source.

Brainstem auditory evoked potentials (brainstem AEPs) that can be recorded from the scalp of humans have been considered far field reflections of the potentials generated within the brainstem auditory pathways. In contrast to the long-latency AEPs, it was suggested that the position of the scalp electrode is not critical in determining the waveforms of brainstern AEPs because of the large distance of the electrode from the supposed generators. The concept of far field thus defined by Jewett and Williston (1971) has led many workers to record the potentials only from a single electrode at the vertex with the earlobe or mastoid ipsilateral to stimulation as a reference in clinical applications.

In our laboratory, however, simultaneous bilateral recordings with C₃ to A_l and C₄ to A₂ configurations have been employed. Brainstem AEPs obtained froin both sides were similar in morphology in normal subjects except for wave I, and in lesins of the VIIIth nerve and brainstem considerable asymmetries were recorded. These asymmetries of the brainstem AEPs were correlated with the site of the lesions (Hashimoto et al., 1978; Hashimoto et al., 1979a). Apart from the clinical implications of the asymmetric brainstem AEPs, we think that such profound differences seen at the different locations on the scalp are seemingly inconsistent with the definition of the volume conducted far field potentials.

To our knowledge, there have been few studies involving detailed mapping of the distribution of the potentials in humans (Picton et al., 1974; Streletz et al., 1977; Martin and Moore, 1977). In mapping studies, however, amplitudes and latencies of the brainstem AEP components were measured on separate recordings from various locations on the scalp, presenting the obvious problem of run-to-run variability.

The main objectives of the present study were (1) to map the scalp distribution of each component of brainstem AEPs in normal subjects and patients with VIIIth nerve and brainstem lesions on the basis of simultaneous recordings from multiple electrodes and (2) to relate the altered distributions to the lesions involving various levels of the brainstem. The scalp distributions of the components were presented as isopotential maps with the use of a topographic computer display system (Veno and Matsuoka, 1976).     

Changes of neurotransmitters in the brainstem of patients with respiratory-pattern disorders during childhood.

We examined neuropathologically and immunohistochemically the respiratory centers in the brainstem of two patients with Joubert syndrome (JS), three patients with congenital central hypoventilation syndrome (CCHS) and a patient with apneustic breathing (prolonged inspiratory pause) due to unknown etiology. Immunoreactivity (IR) of tryptophan hydroxylase (TPH) was decreased in the dorsal raphe nuclei of two patients with JS compared with age-matched controls, as well as in two patients with Dandy-Walker malformation. The two JS patients showed vermian defect and elongated cerebellar peduncles, and peculiar vascularities in the midline of the whole brainstem were also noted in one of these patients. These findings, as a whole, confirm that the midline structures of brainstem are disordered both structurally and functionally in JS, conceivably resulting in respiratory patterns and psychomotor deficits. IR of serotonin 1A receptor showed no significant changes in the medulla oblongata of these patients, however. In the parabrachial complex, IR of substance P was increased in two patients with CCHS, and one with apneustic breathing. IR of tyrosine hydroxylase was also increased in the latter. The brainstem of these patients showed reactive astrogliosis. These findings suggest preceding hypoxic episodes as well as an increased activity in the parabrachial complex which plays an important role in conducting the driving force to the medullary respiratory neurons from ascending sensory pathways.     

Audiometric abnormalities in children with Gaucher disease type 3

Exogenous enzyme replacement therapy achieves satisfactory biomedical correction in Gaucher type 1 disease and may halt or reverse neurological progression in type 3, while it does not appear to influence the outcome in type 2. In view of the therapeutic possibilities, early detection and monitoring of type 3 Gaucher disease, as well as evaluation of the effectiveness of enzyme therapy on neuronopathic involvement is necessary. The objective of this study was to evaluate the extent of brainstem disease in children with proven Gaucher type 3, by means of an audiological test battery. We studied 9 patients with Gaucher type 3 disease. The tests included baseline audiometric tests, as well as auditory brainstem evoked responses (ABR), acoustic reflexes and medial olivo-cochlear suppression by contralateral noise tests, that involve overlapping but not identical efferent and afferent pathways and brainstem structures. We found a constellation of abnormalities including bilaterally raised acoustic reflexes, poor medial olivo-cochlear suppression, and very poor brainstem evoked potentials. These abnormalities could be due to a single lesion in the dorsomedial brainstem, or to multiple lesions, and further study is needed to clarify this issue. Combined audiological tests may provide information on the severity of the neurological involvement and should therefore be part of a standard assessment for the diagnosis as well as for long term neurological monitoring of Gaucher type 3 patients.     

Etiology matters for neuroprognostication: A multimodal electrophysiological investigation in a case of Bickerstaff's brainstem encephalitis

We report the case of a 19-year-old patient with an acute-onset non-traumatic coma. Brain MRI scan was normal, CSF showed mild pleocytosis and moderately elevated protein, and continuous EEG-monitoring was compatible with spindle-coma. Cortical somatosensory evoked potentials (SSEPs) and middle-latency auditory evoked potentials (MLAEPs) were bilaterally absent, and brainstem auditory evoked potentials suggested a brainstem dysfunction. Serum anti-GQ1b and anti-GT1a IgG antibodies positivity suggested Bickerstaff's brainstem encephalitis (BBE). The clinical and functional outcomes were favorable and normal cortical SSEPs/MLAEPs reappeared in a few weeks. Based on this report, in cases of unexplained MRI-negative coma with neurophysiological evidence of brainstem dysfunction, BBE should be eliminated before considering withdrawal of life-sustaining therapy (WLST).     

Nuclear magnetic resonance imaging of the brainstem: evaluation of the normal structures and small lesions

Nuclear magnetic resonance (NMR) imaging of the brainstem region from 12 asymptomatic individuals were reviewed in addition to these of 12 patients with various symptoms of small brainstem lesions. Abnormalities consisted of 3 cases of multiple sclerosis, 1 case of neuro-Beh?et disease, 5 cases of infarction and hematoma and 3 cases of degenerative disease. NMR transverse imaging using inversion recovery sequence was able to locate many of the normal intra-axial brainstem nuclei, such as the periaqueductal gray matter, the red nucleus, the substantia nigra, the pontine nuclei, the pontine reticular nuclei, the facial nerve nucleus and so on in an about half of 12 asymptomatic individuals. The remarkable gray-white matter differentiation was obtained on NMR imaging using inversion recovery sequence and enabled the internal structures to be visualized within the brainstem. In addition, the midsagittal imaging provided an excellent demonstration of anatomical relationships of the brainstem and surrounding structures. In the diencephalic region, the mamillary body, the anterior commissure and the optic chiasma were also demonstrated on the midsagittal imaging. The lesions within the brainstem were vaguely shown on X-ray computed tomography in 6 of 12 patients but NMR imaging using inversion recovery or spin echo sequence provided more detailed data and revealed clear small lesions, such as the demyelinated plaques of multiple sclerosis and lacunar infarcts in 9 of 12 patients. Especially, in 2 of 3 multiple sclerosis patients, the plaques of the brainstem were definitely identified on NMR imaging only and the accurate localized lesion which was responsible for the facial myokymia or the Foville syndrome was identified.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunohistochemical localization of phospholipase D1 in rat central nervous system

Phospholipase D (PLD) is one of the intracellular signal transduction enzymes and plays an important role in a variety of cellular functions. We investigated the distribution of PLD isozyme, PLD1 in the rat brain and spinal cord using an immunological approach. Western blot analysis showed the presence of PLD1 protein in all tissues studied, with significantly higher levels in the brainstem and spinal cord, which was correlated with the results obtained from PLD activity assay. Prominent and specific signals of PLD1 were observed in many functionally diverse brain areas, including the olfactory bulb, medial septum-diagonal band complex, cerebral cortex, brainstem, cerebellum, and spinal cord. In the brainstem, the red nucleus, substantia nigra, interpeduncular nucleus, cranial motor nuclei (trigeminal motor, abducent, facial, and hypoglossal), sensory cranial nerve nuclei (spinal trigeminal, vestibular, and cochlear), as well as nuclei of the reticular formation, all showed intense immunoreactivity. Purkinje cells and deep cerebellar nuclei of the cerebellum were also labeled intensely. However, no significant labeling was found in the thalamus, epithalamus, and basal ganglia. Although many of the PLD1 immunoreactive cells were neurons, PLD1 was also expressed in glial cells such as presumed astrocytes and tanycytes. These findings suggest that PLD1 may play an important role in the central nervous system of the adult rat.     

Neonatal monosodium glutamate administration alters noradrenergic measures in the brainstem of the mouse

Mice treated neonatally with MSG (4 mg/g) were compared to saline-injected controls on a number of neurochemical parameters of brainstem noradrenergic activity. MSG treatment resulted in an attenuation of brainstem norepinephrine (NE) decline after α-methyl-p-tyrosine administration. Neonatal MSG administration did not result in alterations in the steady state levels of brainstem NE or MOPEG. The synthesis of NE was slightly increased in the pons-medulla of MSG-treated mice as indexed by pargyline-induced NE accumulation. NE release, however, appeared diminished as reflected by a significant (p < 0.05) decrease in the ratio of normetanephrine to NE found in the pons-medulla of MSG-treated mice given pargyline. The results suggest that MSG-induced damage to the arcuate nucleus produces selective alterations in brainstem NE systems. These alterations may reflect the toxic action of MSG on the opiomelanocortin neurons of the arcuate nucleus or other descending systems that are damaged by MSG. The loss of the descending opiomelanocortin input to the brainstem could result in these types of neurochemical consequences since the pharmacologie action of opiate drugs results in a selective enhancement of brainstem NE turnover in rodents.     

Is neurogenic hypertension related to vascular inflammation of the brainstem?

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1), were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat) compared to normotensive Wistar-Kyoto rats (WKY). Over expression of JAM-1 in NTS of WKY rats was pro-hypertensive and induced leukocyte adherence to the microvasculature. Since leukocyte adhesion causes cytokine release, we found expression of monocyte chemoattractant protein-1 (MCP-1) was higher in the NTS of SHR while inter-leukin-6 (IL-6) was lower compared to the WKY rat. Inflammation of the brainstem microvasculature may increase vascular resistance within the brainstem. High brainstem vascular resistance and its inflammation may release pathological paracrine signaling molecules affecting central neural cardiovascular activity conducive to neurogenic hypertension.     

Intraoperative Monitoring and Mapping of the Functional Integrity of the Brainstem

The risk of iatrogenic damage is very high in surgical interventions in or around the brainstem. However, surgical techniques and intraoperative neuromonitoring (ION) have evolved sufficiently to increase the likelihood of successful functional outcomes in many patients. We present a critical review of the methodologies available for intraoperative monitoring and mapping of the brainstem. There are three main groups of techniques that can be used to assess the functional integrity of the brainstem: 1) mapping, which provides rapid anatomical identification of neural structures using electrical stimulation with a hand-held probe, 2) monitoring, which provides real-time information about the functional integrity of the nervous tissue, and 3) techniques involving the examination of brainstem reflexes in the operating room, which allows for the evaluation of the reflex responses that are known to be crucial for most brainstem functions. These include the blink reflex, which is already in use, and other brainstem reflexes that are being explored, such as the masseter H-reflex. This is still under development but is likely to have important functional consequences. Today an abundant armory of ION methods is available for the monitoring and mapping of the functional integrity of the brainstem during surgery. ION methods are essential in surgery either in or around the brainstem; they facilitate the removal of lesions and contribute to notable improvements in the functional outcomes of patients.     

Clinical deterioration in Bickerstaff's brainstem encephalitis caused by overlapping Guillain-Barré syndrome

A 37-year-old man developed an acute encephalitic condition after respiratory infection. His condition rapidly deteriorated, and he experienced ophthalmoplegia, tetraplegia, loss of brainstem reflexes and deep tendon reflexes, and deep coma. Electrophysiological evaluations indicated involvement of the peripheral nerve as well as the brainstem. Follow-up studies found acute progression of peripheral nerve damage. Serum anti-GQ1b IgG antibody was present. The initial condition was diagnosed as Bickerstaff's brainstem encephalitis, and subsequent overlapping of Guillain-Barré syndrome probably was responsible for the clinical deterioration. When unusual worsening is observed in clinically suspected encephalitis, neurologists must take into account the possibility of associated Guillain-Barré syndrome and related disorders.     

Brainstem encephalitis: an unusual presentation of herpes simplex virus infection

Herpes simplex virus (HSV) encephalitis has a predilection for the temporal and frontal lobes but occasionally affects the brainstem. We describe a patient who developed HSV brainstem encephalitis that progressed to quadriplegia. Using MEDLINE, we conducted a comprehensive review of other published cases of HSV brainstem encephalitis. Twenty-four published cases of HSV brainstem encephalitis met our inclusion criteria. The mean age was 41.4 years (range 18–71). HSV-1 was the etiologic agent in 79% of reported HSV brainstem encephalitis cases, and HSV-2 accounted for 21% of cases. Infection was limited to the brainstem in 29% of cases and multi-focal, including the brainstem, in 71%. Common manifestations of HSV brainstem encephalitis included neuro-ophthalmologic findings (81%), cranial nerve deficits (69%), and fever (69%). Quadriplegia, as occurred in our patient, was an unusual finding (19%). The mortality rate of HSV brainstem encephalitis was 41%. Intravenous acyclovir showed a beneficial effect on mortality (75% vs. 22%, p = 0.06). HSV brainstem encephalitis is a distinct type of HSV encephalitis. With the increasing use of HSV-PCR, more cases of HSV brainstem encephalitis may be identified. A greater recognition of this syndrome will help better define its optimal treatment and prognosis.     

Hyperekplexia in a patient with a brainstem vascular anomaly

OBJECTIVES: To describe a patient with a clinical picture suggestive of idiopathic hyperekplexia (IH), who was later found to harbour a subtle brainstem vascular anomaly. PATIENT: A 35-year-old man, 4 years earlier, developed sudden jumping and falling in response to unexpected sensory stimuli. RESULTS: Neurological examination was normal. Electromyography showed an excessively large and non-habituating motor startle response. There were no mutations of the alpha1 subunit of the inhibitory glycine receptor which cause hereditary hyperekplexia. Although all these findings were consistent with a diagnosis of IH, a blink reflex study showed an enhanced recovery curve suggestive of a brainstem lesion. A detailed MRI study revealed a subtle vascular anomaly involving the lower brainstem. CONCLUSION: This is the first report of sporadic hyperekplexia related to a brainstem vascular anomaly. Subtle damage to the brainstem should always be excluded in patients with sporadic hyperekplexia, regardless of the coexistence of additional clear-cut neurological symptoms.     

Ocular and cervical vestibular evoked myogenic potentials in multiple sclerosis patients

ObjectiveVestibular evoked myogenic potentials (VEMPs) are thought to provide useful information about brainstem functions, as the neural pathways of both ocular and cervical VEMPs pass through the brainstem. The aim of this study was to investigate the clinical value of ocular and cervical VEMP tests in the evaluation of brainstem involvement in multiple sclerosis (MS) patients and to assess their relation with clinical and cranial MRI findings.MethodsOcular and cervical VEMPs were recorded in 62 MS patients and 35 age and sex matched healthy volunteers. The latencies, amplitude asymmetry ratios of both VEMP responses and abnormality ratios (prolonged latencies and absent responses) were compared between the MS patients and the control group and among the groups of MS patients.ResultsoVEMP mean n1 and p1 latencies and cVEMP mean p13 latency were significantly prolonged in MS patients. Although the abnormality ratios of both VEMPs were higher in patients with brainstem clinical or MRI lesions, the correlation was not statistically significant. Both ocular and cervical VEMP latencies were significantly correlated with expanded disability status scale.ConclusionsAlthough there is no significant correlation with clinical or MRI findings, MS patients show high frequency of abnormality in VEMP tests, especially in oVEMP tests.SignificanceVEMP tests may be useful as an adjunct test in the evaluation of brainstem dysfunction in MS patients.