Clinical variability of neuroacanthocytosis syndromes-a series of six patients with long follow-up.

OBJECTIVE: To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes. METHODS: We present a long-term video accompanied follow-up of six Caucasian patients with neuroacanthocytosis from several centers, three diagnosed with chorea-acanthocytosis (ChAc): 34-y.o.(no.1), 36-y.o.(no.2), 43-y.o.(no.3), two diagnosed with McLeod Syndrome (MLS): 52-y.o.(no.4), 61-y.o.(no.5) and one 63-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. Additionally we report pathological findings of the mother of two brothers with MLS reported in our series with acanthocytes on peripheral blood smear RESULTS: The patients had an unremarkable family history and were asymptomatic until adulthood. Patients no. 1,2,4,5,6 developed generalized chorea and patient no. 3 had predominant bradykinesia. Patients no. 1,2,3 had phonic and motor tics, additionally patients no. 1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In patients no. 2 and 3 dystonic supination of feet was observed, patient no. 3 subsequently developed bilateral foot drop. Patients no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no. 2,3,5,6 and myoclonic jerks in patient no. 1. Cognitive deterioration was reported in patients no. 1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients. CONCLUSION: We highlight the variability of clinical presentation of neuroacanthocytosis syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found. Based on our observations and data from the literature we propose several red flags that should raise the suspicion of an NA syndrome in a patient with a movement disorder: severe orofacial dyskinesia with tongue and lip-biting (typical of ChAc), feeding dystonia, psychiatric and cognitive disturbances, seizures, peripheral neuropathy, elevation of creatine kinase, elevation of transaminases, hepatosplenomegaly, cardiomyopathy and arrhythmias, and an X-linked pattern of inheritance (McLeod Syndrome, MLS).

Changing phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation--a 5 year follow up.

Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.

Incidence of mutations in the PARK2, PINK1, PARK7 genes in Polish early-onset Parkinson disease patients.

BACKGROUND AND PURPOSE: Parkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO-PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients. MATERIAL AND METHODS: The analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification. RESULTS: Mutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients' genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers. CONCLUSIONS: The frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations.

Hemiparkinsonism-hemiatrophy syndrome - report on two cases and review of the literature.

Hemiparkinsonism-hemiatrophy (HPHA) is a rare neurological syndrome. The main clinical features of HPHA consist of atrophy of one side of the body (face, trunk, limbs), ipsilateral hemiparkinsonism (bradykinesia, rigidity, tremor) and in many cases dystonia. There are no data on prevalence of HPHA as the condition is rare. The mean age of parkinsonism onset is earlier than in idiopathic Parkinson disease (43.7 years, range: 15-63). Changes in magnetic resonance imaging (MRI) (cortical, basal ganglia atrophy contralaterally to the side of clinical presentation) are described in 30% of patients. The pathogenesis of HPHA is unknown, but in many cases a history of prenatal injuries was reported. We present two male patients with HPHA - 45 and 55 years old, with left-sided parkinsonism, dystonia and hemiatrophy (to our knowledge, the first Polish cases). Both patients had no atrophic changes in MRI and levodopa treatment was ineffective. In the discussion the authors review current literature on HPHA.

Frontotemporal dementia and parkinsonism linked to chromosome 17--the first Polish family.

BACKGROUND: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder with various clinical phenotypes. We present the first Central-Eastern European family (Gdansk Family) with FTDP-17 because of a P301L mutation in microtubule-associated protein tau (MAPT). METHODS: We have studied a family consisting of 82 family members, 39 of whom were genetically evaluated. The proband and her affected brother underwent detailed clinical and neuropsychological examinations. RESULTS: P301L mutation in MAPT was identified in two affected and five asymptomatic family members. New features included hemispatial neglect and unilateral resting tremor not previously reported for P301L MAPT mutation. Low blood folic acid levels were also detected. CONCLUSIONS: Our report suggests that FTDP-17 affects patients worldwide, but because of its heterogenous clinical presentation remains underrecognized.

The clinical and neuroimaging studies in Holmes tremor.

AIM: Holmes tremor (HT) is a combination of rest, postural and action tremor. A parallel dysfunction of cerebello-thalamic and nigrostriatal pathways seems necessary to produce this kind of tremor. We present the clinical and neuroimaging study verifying that hypothesis. MATERIAL AND METHODS: A total of 10 patients: five male, five female, fulfilling consensus criteria were included. Demographic, clinical and neuroimaging data (MRI = 9; CT = 1, SPECT with the use of 123-I-FP CIT: DaTSCAN in six patients to assess the presynaptic dopaminergic nigrostriatal system involvement, indices of asymmetry for ligand uptake for each striatum were calculated) were analyzed. RESULTS: Hemorrhage was the most frequent etiology and thalamus - the most commonly involved structure. Contrary to the previous reports, the visual assessment did not reveal remarkable interhemispheric differences of DaTSCAN uptake. Quantitative measurements showed only minimal differences. CONCLUSIONS: It is open to debate whether nigrostriatal pathway damage is crucial for the phenomenology of HT. Alternative hypothesis is presented that HT represents the heterogeneous spectrum of tremors with similar phenomenology, but different pathophysiology.

Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging.

Thyroid dysfunctions may be accompanied by numerous neurological and psychiatric disorders. The most known is cognitive impairment and depression in hypothyroid patients, as well as an increased risk of cerebrovascular accidents. A separate, although a rare entity, is Hashimoto's encephalopathy. In hyperthyroidism there is an increased incidence of psychiatric disorders, including apathetic hyperthyroidism and hyperthyroid dementia. Functional imaging of cerebral blood flow and metabolism helped establish both global and/or regional decrease of both cerebral blood flow and metabolism in hypothyroidism, particularly in regions mediating attention, motor speed and visuospatial processing. Hypothyroid dementia may be mediated by neurocircuitry different from that in major depression. Less is known on flow/metabolism changes in hyperthyroidism. Global blood flow may be slightly increased, with regional deficits of blood flow, particular in hyperthyroid dementia. As presented above radionuclide functional imaging showed some metabolic patterns in thyroid dysfunctions, but still many issues remain unresolved. In particular little is known about the underlying pathology of cognitive impairment and depression in hypothyroidism, which may differ from ones in euthyroid patients. Also little is known about the reversibility of changes in cerebral blood flow following thyroid replacement therapy. In hyperthyroid patients functional imaging might contribute to elucidate the background of apathetic hyperthyroidism and potential different background of psychiatric complications.

Interleukin-10 (IL10) and tumor necrosis factor alpha (TNF) gene polymorphisms in Parkinson's disease patients.

Recent studies revealed that inflammatory processes might play an important role in the pathogenesis of Parkinson's disease (PD). We hypothesized that genetically determined differences in the immune response, especially in anti- and pro-inflammatory cytokines production might influence the risk for the development and/or onset of sporadic PD. In the present study, we investigated the genetic polymorphisms of the IL10 (-1082 and -519) and TNF (-308) genes in relation to the risk of PD, and their associations with age of PD onset in a group of 316 patients, divided into two subgroups: Group 1: patients with early onset PD (EOPD), i.e. before 50 years of age (102 patients), and group 2: patients with onset of PD after 50 years of age comprising 214 subjects. Control samples were obtained from 300 randomly selected healthy individuals from the same geographical region with no signs of Parkinsonism as evaluated by a neurologist. PCR-RFLP methods were used for genotyping. No statistically significant differences between PD patients and controls were found in the frequency of a single locus of IL10 promoter. We found TNF -308A allele significantly more frequent in EOPD patients compared to the controls (p=0.007). The overrepresentation of the A allele was reflected by a significant increase in AA homozygous individuals in EOPD patients compared to the controls (p=0.0021). The results from our study revealed that the TNF -308AA genotype might increase the risk of early onset of PD.

Botulinum toxin type A for upper limb spasticity following stroke: an open-label study with individualised, flexible injection regimens.

Current antispastic medications are unsatisfactory for spasticity treatment, but botulinum toxin type A (BTX-A) shows promise as a new therapeutic option. This open-label, prospective study aimed to assess the effectiveness of BTX-A in improving functional mobility in the early post-stroke population using an individualised, flexible range of doses and targeted muscle groups. Twenty-one stroke patients (13 male, 8 female) were enrolled and injected with BTX-A (Botox, Allergan, mean dose: 255 U; range: 185-300) according to individual spasticity patterns. Assessments were made at baseline and weeks 2, 4, 6, 10 and 16 post-treatment. Outcome measures comprised: Modified Ashworth Scale (MAS), finger flexion scale (Bhakta), MRC scale, Physician's Rating Scale (PRS), Nine Hole Peg Test (9HPT), Motor Assessment Scale, Clinical Global Impression (CGI), Global Assessment of Spasticity (GASS) and Visual Analogue Scale (VAS) for pain assessment. Statistically significant improvements in muscle tone as determined by the MAS were found in all areas (except arm) till week 16 (p<0.05). Finger positioning improved for the study duration, whilst muscle power increased only slightly in specific muscles. PRS revealed significant improvements to week 10 and slight improvement in 9HPT performance in selected patients was observed. Motor Assessment Scale results were statistically significant for arm, hand and advanced hand functions, although the overall functional benefit was mild. GASS and CGI results also showed improvement. Pain was present only in 11 patients and did not significantly improve following treatment. Individualised BTX-A injection regimens may be an effective, reversible and safe new treatment option for patients with spasticity. Nevertheless, functional improvement may be reached only in selected patients.

Functional improvement in cerebral palsy patients treated with botulinum toxin A injections - preliminary results.

Authors report the preliminary results of an open-label, prospective study to evaluate a functional benefit of botulinum toxin type A injections in diparetic cerebral palsy patients, using gross motor function measure (GMFM) score. In a group of 14 children (mean age 3.9 years, range 2-6) treated with Dysport 30 IU/kg, a statistically significant improvement (P < 0.05) was noticed in both simple measurements (Modified Ashworth Scale, Selective Motor Control, Passive Range of Movements, Physician Rating Scale and parental Clinical Global Impression) and complex functions (GMFM dimensions D and E) after 1 and 3 months. However, the simple measurement scores decreased (but not to the baseline) after 3 months; surprisingly, GMFM scores were still increasing (7.7% change after 3 months and 11.3% change after 6 months in nine patients). These results are in concordance with a few other data published to date. The study may support the concept of persistent functional gain in long-term treatment of spasticity caused by cerebral palsy with botulinum toxin type A.

A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke.

BACKGROUND/OBJECTIVES: Calf muscle hypertonicity following stroke may impair walking rehabilitation. The aim of this study was to assess botulinum toxin (Dysport) in post-stroke calf spasticity. METHODS: A prospective, multicentre, double-blind, placebo-controlled, dose-ranging study was performed to evaluate dysport at 500, 1,000 or 1,500 units in 234 stroke patients. They were assessed at 4-week intervals over 12 weeks. RESULTS: The primary outcome measure, 2-min walking distance and stepping rate increased significantly in each group (p < 0.05, paired test), but there was no significant difference between groups (including placebo). Following dysport treatment, there were small but significant (p = 0.0002-0.0188) improvements in calf spasticity, limb pain, and a reduction in the use of walking aids, compared to placebo. Investigators' and patients' assessments of overall benefit suggested an advantage for dysport over placebo, but this was not significant. Sixty-eight patients reported 130 adverse events, with similar numbers in each group. The few severe events recorded were not considered to be treatment-related. CONCLUSION: Dysport resulted in a significant reduction in muscle tone, limb pain and dependence on walking aids. The greatest benefits were in patients receiving dysport 1,500 units, but 1,000 units also had significant effects. Dysport 500 units resulted in some improvements. Since few adverse events were reported, this therapy is considered safe and may be a useful treatment in post-stroke rehabilitation of the leg. Possible reasons why functional improvements in gait parameters were not observed are also discussed.

Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure.

BACKGROUND/AIMS: Combined BT-A (botulinum toxin A) therapy and local application of nitrates can be more effective than BT-A alone for chronic anal fissure treatment, but so far the optimal dose of BT-A is not known. The aim of our study was to learn if BT-A doses higher than those used so far could change the outcome of fissure treatment. METHODOLOGY: We enrolled 14 consecutive patients suffering from idiopathic chronic anal fissure who did not respond to previous local treatment of nitric oxide donor and subsequent BT-A therapy (25 U of Botox). They were offered a local nitroglycerin treatment. In failure cases patients received the greater doses of BT-A (50 U of Botox). RESULTS: In all 11 patients with chronic anal fissure who applied nitroglycerin after BT-A injection, an effect on the internal anal sphincter relaxation was observed but fissure healing after topical nitroglycerin occurred only in 1 case. Of 13 patients with chronic anal fissure who received 50 U of BT-A no healing was reported in 6 cases. One male from this group received a greater dose (100 U of Botox) and then the fissure healed. CONCLUSIONS: The effect of topical nitrates on internal anal sphincter relaxation after botulinum toxin injection is not the last line for nonsurgical treatment of chronic anal fissure. Always we ought to consider using the next greater dose of BT-A before surgical treatment.

[Camptocormia, a rare form of motor system disorders in Parkinson's disease]. / Kamptokormia--rzadka postac zaburzen ruchowych w chorobie Parkinsona.

Camptocormia is characterized by pronounced forward flexion of the thoracolumbar spine, which increases while walking and disappears in recumbent position. The clinical spectrum of the described disorders with concomitant camptocormia is heterogenous. It was described for the first time in idiopathic Parkinson's disease in 1999. The pathophysiology of this phenomenon remains unclear but seems to be not related to antiparkinsonian treatment. The authors present the case of a 54 years old woman, with idiopathic Parkinson disease diagnosed 5 years ago. The rapid progression of the disease was associated with good response to Levodopa therapy, although the dose had to be increased up to 1400 mg/d (with peripheral decarboxylase and COMT inhibitor). After 5 years she developed painful spasms of paraspinal muscles which resulted in trunk flexion. The clinical picture resembled the described cases of camptocormia. There was no correlation between the appearance of camptocormia and the regime of levodopa administration (time or dosage). Therefore, one can conclude, that presumably camptocormia is not a form of dystonia of the trunk but, the result of till now unclear other factors (dysfunction in other non-dopaminergic nigrostriatal projections?).

Botulinum toxin type A in the treatment of spasticity in cerebral palsy: theoretical and practical foundations of effective therapy.

Spasticity is one of the constituent elements of upper motor neuron syndrome. For now, it is also the only symptom which is pharmacologically treatable. The pathophysiology of spasticity is very complex, and many aspects remain unclear. The great majority of commonly used oral drugs modulate the activity of receptors and/or neurotransmitters at different levels of the central nervous system. This is perhaps the main reason for the limited effectiveness of these drugs in many cases. Recently a new strategy - local injections of botulinum toxin type A (BTX-A) - has been introduced for the treatment of spasticity in cerebral palsy and post-stroke patients. BTX-A is a unique drug that acts at the final stage of the common pathway of pathological information mediated through the peripheral nerves to the muscles (at the motor end plates). Its mode of action is known as "chemical denervation", which serves to reduce increased muscle tone, improve the range of motions, positioning, function, and promote muscle growth in children. BTX-A was firstly used in post-stroke spasticity patients by Das and Park in 1989, but the best effects have been achieved in cerebral palsy. Accordingly, since 1997 this method has been approved in many European countries and Australia, and the principles governing this treatment strategy were published in the journal "Gait and Posture" in 2000. In the present paper, the author discusses the mechanism of spasticity, the logical approach to therapy, and many practical problems (injection modality, tolerability).

Cerebral blood flow SPECT may be helpful in establishing the diagnosis of progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND: We present 4 cases, which illustrate the usefulness of neuroimaging studies in atypical forms of Parkinsonism. Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are rare neurodegenerative progressive disorders of the central nervous system of unknown cause. The clinical accuracy in this diagnosis is not very high even in centres specialising in movement disorders. Functional imaging can be helpful in diagnosing PSP and CBD. MATERIAL AND METHODS: We present the results of cerebral blood flow (CBF) SPECT scanning in 2 patients with PSP and 2 patients with CBD. This was performed using a triple-head gammacamera and 99m Tc-HMPAO. RESULTS: In PSP patients a diffuse frontal perfusion deficit was seen, eventually with striatal and occipital hypoperfusion. CT/MRI was either normal or showed a diffuse cortical-subcortical atrophy. In CBD patients left fronto-parieto-temporal cortex and a striatal hypoperfusion were shown. CT scanning was normal in one case and showed an asymmetrical temporo-parietal atrophy in second one. CONCLUSIONS: The pattern of diffuse frontal perfusions deficit in PSP and asymmetrical, contralateral to symptoms of CBD, cortico-subcortical hypoperfusion may be helpful in establishing the correct diagnosis.

Cerebral blood flow changes in Parkinson?s disease associated with dementia.

Dementia is one of the main non-motor symptoms of Parkinson's disease (PD) and it is diagnosed in about 30% of cases. Its aetiology remains unclear and contributing factors are controversial. Dementia may be more common in old patients with severe motor symptoms and mild cognitive impairment. Clinico-pathological studies show the association between dementia in PD and the age-related group of dementias, such as AD and VaD. A valuable aid in the assessment of dementia in PD is cerebral blood flow (CBF) brain SPECT scanning. It shows three different patterns of rCBF reduction, including frontal lobe hypoperfusion, Alzheimer-like type of hypoperfusion and multiple, vascular defects. The heterogeneity of rCBF reduction may reflect the multifactorial pathophysiology of dementia in PD. It may result from concomitant AD pathology, cerebrovascular disease, destruction of nigro-striato-frontal projection or may be a distinct disease of different aetiology.