Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.

Athetotic and spastic cerebral palsy: anatomic characterization based on diffusion-tensor imaging.

PURPOSE: To evaluate the anatomy of deep gray and white matter structures in children with athetotic cerebral palsy (CP) and those with spastic CP by using diffusion-tensor (DT) imaging and to investigate whether these types of CP have unique anatomic correlates that can support their diagnosis and prognosis. MATERIALS AND METHODS: This study was approved by the institutional review board of each participating institution, and written informed consent was obtained from the parents of each patient. DT imaging was used to retrospectively evaluate 19 children with clinically diagnosed athetotic CP (mean age, 3.4 years ± 3.3 [standard deviation]), 26 children with spastic CP (mean age, 3.3 years ± 3.2), and 31 healthy control subjects (mean age, 3.2 years ± 3.0). Fractional anisotropy (FA) and mean diffusivity (MD) were measured with a region of interest (ROI) method. The ROIs were drawn on bilateral deep gray and white matter structures, including projection fibers, association fibers, and commissural fibers. Statistical analysis was performed by using the Kruskal-Wallis test with Bonferroni correction. P < .05 indicated a significant difference. RESULTS: FA values in the athetotic CP group were significantly lower than those in the control and spastic CP groups for multiple structures, including deep gray and white matter (P < .05 and P = .0001, respectively); these differences were also associated with increasing MD (P < .05 and P < .001, respectively). On the other hand, in the spastic CP group, the significantly decreased FA values, compared with those of the normal group, were limited to several white matter structures (P < .05 and P = .0001). CONCLUSION: In children with athetotic CP, the extent of change on DT images due to early brain damage tends to be more diffuse, including multiple brain structures, compared with the changes in children with spastic CP.

Dysnomia, ataxia, choreoathetosis, sensory impairment, and gait imbalance after lentiform nucleus stroke.

We describe a patient in whom dysnomia, ataxia, choreoathetosis, sensory impairment, and severe gait imbalance resulted from an isolated left lentiform nucleus-posterior limb of internal capsule lacunar stroke. Each of these deficits has been described as a consequence of unilateral basal ganglia or internal capsule infarction in prior reports, but the combination of these findings in one patient is unusual. Accurate localization of the lesion to the anterior circulation has potential therapeutic implications.

Severe long-standing dysimmune sensory neuronopathy responsive to etanercept.

Sensory neuronopathy in association with connective tissue disease is a disabling disorder for which there is no well-established therapy. Various immunosuppressive agents, plasmapheresis, and intravenous immunoglobulin have shown only anecdotal or modest beneficial effects. Tumor necrosis factor alpha is a proinflammatory cytokine that mediates TH1-cell inflammatory responses and is a plausible contributor to dorsal root ganglion injury in sensory neuronopathy. We describe a patient with severe painful and ataxic sensory neuronopathy in association with systemic lupus erythematosus, who showed marked and sustained improvement on etanercept, a tumor necrosis factor alpha inhibitor, despite a chronic and progressive course that was refractory to several immunomodulatory interventions. We review the therapeutic potential of tumor necrosis factor alpha blockade in immune-mediated neuropathies and the reported neurologic complications from its use, most notably central and peripheral demyelination.

Clinical profiles of children with cerebral palsy having lesions of the thalamus, putamen and/or peri-Rolandic area.

Neurological findings, motor symptoms, mental abnormality and dysarthria were examined in 28 children with lesions in the thalamus, putamen, and/or peri-Rolandic area. The thalamus and putamen were involved in eight, and only the thalamus in ten of the children. Most of these 18 children had mild disabilities; they did not have severe mental retardation and could walk alone, speak words, and grasp an object. Dominant flexion of the hips was observed in many of the children who could walk. Two-thirds of these children had athetotic involuntary movement and the remaining had gross or fine motor abnormalities although they had no involuntary movement. In most of these children, reaching patterns were abnormal and were affected by shoulder retraction. Their abnormal movements were thought to be inappropriate muscle activity brought about by voluntary movements. In the remaining ten children, the thalamus, putamen, and peri-Rolandic area were all involved. Many had severe disabilities such as severe mental retardation and the inability to sit, speak words, or grasp an object. All had athetotic involuntary movements. Three children had spasticity of the lower extremities. Five children with severe disabilities and no spasticity were thought to have apparent weakness with athetosis.

Idiopathic paroxysmal kinesigenic choreoathetosis: precipitation of attacks by vestibular stimulation.

A 24-year-old woman presented with a 3.5-year history of paroxysmal dystonia that was precipitated by sudden movement, especially when she started to walk. It was characterised by shrugging of shoulders, flexion of the neck and thoracic spine, and stiffness of the right leg followed by falls. Each attack lasted for less than 5min. Inadequate sleep and stress were exacerbating factors. There was no similar family history. Physical examination and investigations were normal. The following manoeuvres that caused vestibular stimulation precipitated attacks: turning her head from side to side while standing still, sitting still on a rotating chair and an ice-water caloric test. She had partial responses to phenytoin and levodopa, and a good response to haloperidol. Vestibular stimulation as a precipitating factor in paroxysmal kinesigenic choreoathetosis has not been reported previously.

Bielschowsky bodies (Lafora bodies of Bielschowsky type): report of a case associated with Rosenthal fibers in the brain stem.

Bielschowsky bodies are an uncommon type of polyglucosan body. Similar to Lafora bodies, they are characteristically identified within neuronal perikarya and neurites. However, they lack the diffuse distribution of Lafora bodies, and instead are typically restricted to the external pallidum, often in association with status marmoratus or atrophy of the putamen. Fewer numbers of Bielschowsky bodies have also been identified in other areas such as the substantia nigra, putamen and inner globus pallidus. We report an additional case with Bielschowsky bodies in an 18-year old female with cerebral palsy. This case demonstrated multifocal Bielschowsky bodies and abundant Rosenthal fibers in the midbrain and pons. To our knowledge the association of Bielschowsky bodies with this peculiar distribution of Rosenthal fibers has not previously been reported.

Familial paroxysmal kinesigenic choreoathetosis: an electrophysiologic and genotypic analysis.

PURPOSE: We report a pedigree of familial paroxysmal kinesigenic choreoathetosis (PKC) in which five of 18 members are affected. The pathophysiologic basis for PKC is still uncertain; reflex epilepsy versus dysfunction of basal ganglia. We examined (a) whether there were ictal discharges during the attacks, and (b) a linkage between PKC and possible DNA markers linked to several familial epileptic or movement disorders. METHODS: Video-monitoring EEG was performed in two patients with PKC during attacks elicited by movements of the lower extremities. Blood samples for DNA studies were obtained from 15 members of the pedigree. Fourteen polymorphic markers on chromosomes 1p, 2q, 6p, 10q, and 20q were genotyped, and two-point lod scores were calculated for each marker under a dominant model. RESULTS: No ictal discharges were found during the attacks in both patients. We could not obtain significant linkage of PKC with any marker examined. CONCLUSIONS: The video-monitoring EEG findings in our cases strongly suggested that the etiology of PKC should be considered distinct from that of reflex epilepsy. However, the patients in this pedigree had experienced generalized convulsions in their infancies; thus we could not deny the possibility of an epileptogenic basis for PKC. There was no strong evidence for a linkage of the gene for PKC with the candidate regions on 1p, 2q, 6p, 10q, or 20q.

Vacuolating leukoencephalopathy with subcortical cysts with late onset athetotic movements.

We reported a 10-year-old male with vacuolating leukoencephalopathy with subcortical cysts, who presented athetotic movements in the late stage. Magnetic resonance imaging demonstrated diffuse cerebellar white matter lesions, in addition to typical cerebral white matter abnormalities and characteristic subcortical cysts in the anterotemporal and parietal areas. Fluid-attenuated inversion recovery images are highly sensitive for the detection of subcortical cysts, which is essential for a diagnosis. This is most likely to be a severe form of vacuolating leukoencephalopathy with subcortical cysts, presenting with athetotic movements in the late stage.

Amygdalo-subicular degeneration in a young adult with status epilepticus and choreoathetoid movements of acute onset.

Selective amygdalo-subicular degeneration was observed in a 25-year-old woman with encephalopathy of unknown etiology. Following flu-like symptoms, the patient presented with confusion and generalized seizures. Subsequently, she developed persistent stupor with absence of the brainstem reflexes, refractory status epilepticus accompanied by hyperthermia, and exhibited choreoathetoid movements. Despite therapies her condition showed no improvement, and she died four months after the onset of disease. Postmortem examinations revealed no evidence suggestive of viral encephalitis, and instead distinctive bilateral lesions were seen in the subiculum (the subiculum proper and the prosubiculum) and the basolateral nuclear group of the amygdala. The hippocampus proper from CA1 to dentate fascia was unremarkable. The selective amygdalo-subicular degeneration, for which pathogenesis remained unknown, was inconsistent with her serious clinical condition. To our knowledge, similar pathology has not been described so far.

Volumetric quantification of brain development using MRI.

We devised a three-dimensional method for estimation of cerebral development and myelination which measures cerebral volume using MRI. Accuracy of the system was estimated using cadaver brains. The mean percentage error in the calculated volumes compared with the real volumes was 2.33%, range 0.00-5.33%. We applied the method to the volume of both cerebral hemispheres (CH), basal ganglia, thalamus and internal capsule (BT), and myelinated white matter (WM) in 44 neurologically normal individuals (4 months to 28 years of age), 13 patients with spastic motor disturbances (2-25 years of age), and 9 patients with athetotic motor disturbances (2-23 years of age). In the neurologically normal cases, the volumes of CH, BT and WM increased with age; the volume of MW more slowly than that of CH. In cases with spastic motor disturbances, the volumes of CH, BT and WM were between -1.4 and 3.5 SD, -1.0 and -3.5 SD, and 0.0 and -5.2 SD respectively, of those of neurologically-normal cases. On the other hand, 7 of the 9 cases with athetotic motor disturbances were within 2 SD of the volume of CH in neurologically normal cases. Our method for direct measurement of cerebral volume based on serial MRI should be useful for the accurate assessment of brain development and quantitative analysis of delayed myelination.

Familial dystonia and choreoathetosis in three generations associated with bilateral striatal necrosis.

Nine cases of dystonia and choreoathetosis (six females and three males) have developed in three generations of a single family. There has been one death. Neuropathologic examination disclosed bilateral striatal necrosis. In this family, the neurologic disorder has evolved gradually or in association with a febrile illness. There has been no neurologic recovery. The disease is worse in females, has been transmitted only through females, and shows incomplete penetrance and anticipation. The maternal inheritance pattern suggests either an autosomal dominant trait also affecting male reproductive ability or a defect involving the mitochondrial genome.