Globus pallidus internus activity during simultaneous bilateral microelectrode recordings in status dystonicus.

Limited data are available regarding the electrophysiology of status dystonicus (SD). We report simultaneous microelectrode recordings (MERs) from the globus pallidus internus (GPi) of a patient with SD who was treated with bilateral deep brain stimulation (DBS). Mean neuronal discharge rate was of 30.1 ± 10.9 Hz and 38.5 Hz ± 11.1 Hz for the right and left GPi, respectively. On the right side, neuronal electrical activity was completely abolished at the target point, whereas the mean burst index values showed a predominance of bursting and irregular activity along trajectories on both sides. Our data are in line with previous findings of pallidal irregular hypoactivity as a potential electrophysiological marker of dystonia and thus SD, but further electrophysiological studies are needed to confirm our results.

R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome.

TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.

Pallidal stimulation for acquired dystonia due to cerebral palsy: beyond 5 years.

BACKGROUND AND PURPOSE: There is increasing evidence that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is effective in patients with idiopathic or inherited generalized dystonia. There is comparatively less experience about the effects of GPi DBS on acquired dystonia, particularly dystonia due to cerebral palsy (DCP). Clinical and demographic outcome predictors for DBS in dystonia syndromes are also poorly defined. Our aim was to examine the efficacy and safety of GPi DBS for the treatment of generalized DCP. METHODS: Fifteen patients with DCP up to 6.2 years after DBS surgery were studied. Only mild limb spasticity or mild static brain magnetic resonance imaging abnormalities were acceptable for inclusion. Dystonia severity and disability were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), and health-related quality of life was assessed by the Short Form General Health Survey (SF-36) scale. The amount of energy delivered was calculated, and adverse events and side effects were collected. RESULTS: At last follow-up, BFMDRS motor score improved on average by 49.5%, and the disability score improved by 30%. Health-related quality of life improved in most patients. Age at implant, age at onset and disease duration did not correlate to outcome, whilst higher pre-operative dystonia severity and occurrence of spasticity were associated with poorer outcome. The patients received a stable amount of energy after the first 2 years post-implant and throughout all the observation period. There were few serious adverse events or side effects. CONCLUSIONS: The outcome was encouraging in the majority of DCP patients, with a stable outlook and a good safety profile.

Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13.

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.

EFNS guidelines on diagnosis and treatment of primary dystonias.

OBJECTIVES: to provide a revised version of earlier guidelines published in 2006. BACKGROUND: primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. DIAGNOSIS: primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. TREATMENT: botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.

The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disorder associated with brain iron accumulation. The brain MRI abnormality consists of T2 hypointensity in the globus pallidus with a small hyperintensity in its medial part, called the "eye-of-the-tiger" sign. We report on 2 patients affected by PKAN, in whom MRI examination did not demonstrate the "eye-of-the-tiger" sign in the early stages; the typical abnormalities were detected only in the following examinations. Case 1 is a 4-year-old boy first studied at age 2 years for psychomotor delay. The brain MRI was normal. In the following 2 years, the motor impairment progressed. The second brain MRI at age 4 years demonstrated the "eye-of-the-tiger" sign. Molecular analysis of the PANK2 gene revealed a missense mutation F228S in exon 2 in homozygosis. Case 2 is a 6-year-old boy first studied at age 2 years because of psychomotor delay. His brain MRI did not demonstrate abnormalities in the globus pallidus. In the following years spastic-dystonic tetraparesis became evident. A brain MRI at age 4 years demonstrated the "eye-of-the-tiger" sign. Molecular analysis of the PANK2 gene revealed a missense mutation in exon 5 (N501I). Our 2 cases demonstrate that the observation of a normal globus pallidus in the early stage of the disease does not exclude the diagnosis of classic PKAN.

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis.

Automatic imitation in youngsters with Gilles de la Tourette syndrome: A behavioral study.

It is widely known that humans have a tendency to imitate each other and that appropriate modulation of automatic imitative behaviors has a crucial function in social interactions. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterized by motor and phonic tics. Apart from tics, patients with GTS are often reported to show an abnormal tendency to automatically imitate others' behaviors (i.e., echophenomena), which may be related to a failure in top-down inhibition of imitative response tendencies. The aim of the current study is to explore the top-down inhibitory mechanisms on automatic imitative behaviors in youngsters with GTS. Error rates and reaction times from 32 participants with GTS and 32 controls were collected in response to an automatic imitation task assessing the influence of observed movements displayed in the first-person perspective on congruent and incongruent motor responses. Results showed that participants with GTS had higher error rates than controls, and their responses were faster than those of controls in incompatible stimuli. Our findings provide novel evidence of a key difference between youngsters with GTS and typically developing participants in the ability to effectively control the production of own motor responses to sensory inputs deriving from observed actions.

Impaired body movement representation in DYT1 mutation carriers.

OBJECTIVE: The only known genetic cause of early-onset primary torsion dystonia is the GAG deletion in the DYT1 gene. Due to the reduced penetrance, many mutation carriers remain clinically asymptomatic, despite the presence of subclinical abnormalities, mainly in the motor control circuitry. Our aim was to investigate whether the DYT1 mutation impairs the inner simulation of movements, a fundamental function for motor planning and execution, which relies upon cortical and subcortical systems, dysfunctional in dystonia. METHODS: DYT1 manifesting patients, DYT1 non-manifesting carriers and control subjects were asked to fixate body (hand, foot, face) or non-body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collected. RESULTS: DYT1 carriers, manifesting and non-manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects. CONCLUSIONS: The DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms. SIGNIFICANCE: These findings suggest that the cognitive representation of body movements may be altered subclinically in dystonia, thus contributing to the endophenotypic trait of disease.

Polymyography in the diagnosis of childhood onset movement disorders.

UNLABELLED: We report on the results of a clinical and polymyographic retrospective study of 61 paediatric patients with tremor, dystonia and/or myoclonus. Aim of the study was to verify the contribution of polymyography in the classification of these movement disorders and in their aetiological definition. METHODS: The movement disorders were clinically classified by two experts, based on clinical and videotape recordings evaluation; all patients underwent standardized polymyographic evaluation; aetiological diagnosis was performed according to diagnostic protocols for dystonia, myoclonus, tremor and psychogenic movement disorders. The polymyographic features were summarized in five different patterns (dystonia, subcortical myoclonus, myoclonic dystonia, tremor, normal) and compared with the clinical classification and with aetiological diagnosis. RESULTS: In more than 70% of the patients the polymyographic features were in accordance with the clinical classification; in 31% the polymyographic features allowed to identify a clinically unclassified movement disorder and in 19.6% disclosed a not clinically evident associated movement disorder. The polymyographic study did not contribute to the aetiological diagnosis, but was useful in supporting the clinical diagnosis of psychogenic movement disorder.

CT and MRI in maple syrup urine disease.

We describe a patient with a variant form of maple syrup urine disease who had unusual CT and MRI features that raised the suspicion of a metabolic disease. There were low density and abnormal signal in the white matter and pallida. Sponginess in these areas is the likely explanation for these findings.

Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria.

OBJECTIVE: To present clinical, neurophysiologic, and neuroradiologic findings in 13 patients with infantile neuroaxonal dystrophy (INAD), focusing on aspects that assist early diagnosis. BACKGROUND: Clinicopathologic diagnostic criteria for INAD were delineated by Aicardi and Castelein in 1979, but atypical cases are reported frequently and little is known of the diagnostic utility of MRI. METHODS: The authors reviewed the clinical, neurophysiologic, and MRI findings of 13 patients who met the diagnostic criteria for INAD. RESULTS: Symptoms onset was between 6 months and 2 years of age. In nine patients the clinical course was typical, with rapid motor and mental deterioration; in four patients progression was slower and the clinical picture was different. Electromyographic (EMG) signs of chronic denervation, fast rhythms on EEG and abnormal visual evoked potentials were observed in all patients during the disease course. Cerebellar atrophy with signal hyperintensity in the cerebellar cortex on T2-weighted images were the most characteristic MRI findings; hypointensity in the pallida and substantia nigra was also observed in two patients. alpha-N-acetyl-galactosaminidase activity on leukocytes was normal in the 10 patients tested. CONCLUSIONS: EMG and MRI abnormalities are the earliest and most suggestive signs of INAD, which has a clinical and radiologic spectrum that is broader than reported previously.

High prevalence of antiphospholipid antibodies in children with idiopathic cerebral ischemia.

BACKGROUND: The presence of circulating antiphospholipid antibodies (aPLs) is frequently associated with thromboembolic phenomena. OBJECTIVE: To investigate the prevalence of aPLs, detected as lupus anticoagulant (LA) or anticardiolipin antibody (aCL), in a group of unselected children with idiopathic cerebral ischemia. DESIGN: Prospective, case series. SETTING: A pediatric neurology department. PATIENTS: Thirteen children with cerebral ischemia (eight with stroke, three with transient ischemic attacks, and two with ocular ischemia). Age-matched apparently healthy children served as controls. MEASUREMENTS: LA and aCL determination was performed within 3 days after the occurrence of the ischemic event and was repeated after 3 to 6 months. To be defined as aPL-positive, patients had to have either a positive LA test or positive IgG and/or IgM aCL at moderate/high level in both determinations. MAIN RESULTS: Ten (76%) of the 13 patients were positive for either LA or aCL. No differences were found between aPL-positive and aPL-negative patients with respect to clinical manifestations or radiological features. Six (46%) of the 13 patients had a history of multiple ischemic events. CONCLUSIONS: Our results show a very high prevalence of aPLs in children with idiopathic cerebral ischemia. Because the presence of these antibodies has relevant therapeutic implications, their determination in children with cerebral ischemia is recommended.

Neuronal ceroid-lipofuscinosis: a clinical and morphological study of 19 patients.

We report on clinical, electrophysiological, neuroradiological, and morphological data from 19 patients with different types (late infantile, juvenile, and adult) of neuronal ceroid-lipofuscinosis (NCL), observed in the last 10 years at the Neurological Institute of Milan. Late Infantile NCL (LINCL) (8 patients, 4m/4f). Age at onset: 2-4 1/2 years. Seizures (6 patients) or decline of mental capacities (2 patients) were the presenting symptoms, followed by myoclonus and ataxia; visual loss and optic atrophy occurred in 6 patients within 3 years. All but 2 children became bedridden within 3 1/2 years. CT and MRI demonstrated different degrees of cerebral and cerebellar atrophy within 3 years from onset of the disease. Ultrastructural studies showed fingerprint profiles (FP) and osmiophilic bodies (OB) in circulating lymphocytes; curvilinear bodies (CB) and FP were detected in eccrine secretory cells. Juvenile NCL (JNCL) (7 patients, 4m/3f). Age at onset: 6-9 years. Visual loss with retinal degeneration was the presenting symptoms, accompanied in all but 2 patients by slight mental impairment. Seizures occurred within 2-4 years. CT and MRI detected cerebral or cerebellar atrophy in those patients (5 patients) with a clinical follow-up longer than 4 years. Electron microscopy showed FP on circulating lymphocytes, and both FP and CB on skin biopsy specimens. Adult NCL (ANCL) (4 patients, 3 m/1f). Age at onset: 12-50 years. Progressive myoclonus epilepsy (1 patient) or dementia with motor disturbances (3 patients) were the clinical phenotypes of the disease. MRI demonstrated cerebral and cerebellar atrophy within 6 years from onset. Electron microscopy disclosed FP in cytoplasmic vacuoles inside eccrine secretory cells.

Idiopathic dystonia with onset in childhood.

The natural history of early-onset idiopathic dystonia was studied in 30 patients. Worsening of motor symptoms was observed in the early stages, followed by spontaneous stabilization. Most of the patients retained functional independence. None showed mental deterioration, mood alteration or personality disturbance.

Hallervorden-Spatz disease: clinical and MRI study of 11 cases diagnosed in life.

The diagnosis of Hallervorden-Spatz disease (HSD) has usually been made post mortem, although the recent description of characteristic abnormalities in the globus pallidus has suggested the possibility of an in vivo diagnosis. We present the clinical histories, neurological features and MRI findings of 11 patients, diagnosed as having HSD. Generalized dystonia with predominance of oromandibular involvement, behavioural changes followed by dementia and retinal degeneration were present in all the patients. MRI pallidal abnormalities consisted of decreased signal intensity in T2-weighted images, compatible with iron deposits, and of a small area of hyperintensity in its internal segment ("eye of the tiger" sign). We propose that the combination of these neurological signs with these MRI findings could be considered as highly suggestive of a diagnosis of HSD in living patients.

Idiopathic dystonia: neuropharmacological study.

A total of 15 patients affected by idiopathic dystonia (7 with generalized and 8 with focal or segmental dystonia) were subjected to therapy with bromocriptine at low doses, pimozide and trihexyphenidyl. The symptoms were evaluated by giving a progressive score in relation to the intensity of the dystonic symptom to each of the body segments involved by the dystonia. Bromocriptine did not significantly modify the dystonia. Pimozide showed a slight nonsignificant improvement of the dystonic symptoms. Trihexyphenidyl was effective in the generalized dystonias, in agreement with previous reports in the literature. The variation in the pharmacological results could be due to the diversity of the dystonic syndromes, which comprise cases that are different in age at onset, site of dystonic symptoms, and evolution.

Hallervorden-Spatz disease: MR and pathologic findings.

PURPOSE: To compare the MR findings of eight cases with clinical diagnosis of Hallervorden-Spatz disease (HSD) with the pathologic findings of two other cases of HSD. MATERIALS AND METHODS: The eight imaged cases were studied with 0.5-T (seven cases) and/or 1.5-T (five cases) units. Six patients also had CT scans. The two other cases with proven HSD had detailed histologic evaluation. RESULTS: The 1.5-T findings showed abnormalities confined to the pallidum, which presented a diffuse low signal intensity in T2-weighted images, and an anteromedial area of high signal intensity (eye-of-the-tiger sign). In 0.5-T studies, low signal intensity was less evident and poorly detectable in spin echo, but gradient-echo images could enhance its demonstration; the area of high signal intensity was always well demonstrated. In three cases (three with 1.5 T, one with 0.5 T) a central spot of low signal intensity was seen in this area. The pathologic cases, in addition to neuroaxonal swellings and iron deposits, exhibited areas of "loose" tissue with vacuolization and lesser amounts of iron in the anteromedial part of the pallidum, in a location corresponding to the area of high signal intensity of the imaged cases. CONCLUSION: Comparison of MR findings with the pathologic studies demonstrates that the low signal intensity in T2-weighted images at 1.5 T corresponds to iron deposits in a dense tissue, and that the high signal intensity of the eye-of-the-tiger sign corresponds to an area of loose tissue with vacuolization. No correlation was found in the two pathologic cases for the central spot of low signal intensity.