Parry-Romberg syndrome: Physical,clinical, and imaging features

Progressive hemifacial atrophy also known as Parry-Romberg syndrome is an acquired, slowly progressive disorder, occurring more in women, primarily affecting one side of the face, mainly characterized by unilateral atrophy, and loss of skin and subcutaneous tissues of face, muscles, and bones. Ocular and neurologic involvements are common. The possible etiology is unclear without any known cure. We report a rare case of Parry-Romberg syndrome with classical features. The clinical features, radiological imaging findings, differential diagnosis, and available treatment options are discussed in this report.Parry-Romberg syndrome (PRS), also named as progressive hemifacial atrophy is an acquired, sporadic neurocutaneous disorder that is mainly characterized by unilateral self-limited atrophy and loss of skin and subcutaneous tissue of the face.1-5 It was first reported by Parry, and then elaborated as a syndrome by Romberg.6,7 It is a slowly progressive disorder, occurring more in women, primarily affecting one side of the face, including skin, subcutaneous tissue, muscles, cartilage, and bones.1-4,6 The onset of this syndrome generally occurs in the first and second decades of life with skin changes resembling scleroderma, which is usually accompanied by this neurological effects of PRS, including seizures, migraine, trigeminal neuralgia and darkening of skin; partial seizures are the most common neurologic complication.2-4,8 Ocular involvement is common, and the most frequent manifestation is enophthalmos.2-5,9 Its origin is unclear without any known cure. Several possible causes have been postulated (encephalitis, trauma, scleroderma, vasculitis, migraine, infections, genetic and hereditary factors, autoimmunity, and so forth) but a multifactorial pathogenesis may be the first etiology.1-5,9 Possible neuroimaging findings of PRS in CT and MR imaging are; atrophy of skin and subcutaneous tissue of face, intracranial calcifications, cerebral atrophy, deep and subcortical white matter lesions, encephalomalacia, hydrocephalus, meningeal, and leptomeningeal enhancement, aneurysms, cortical thickening and dysgenesis, infarctions in the corpus callosum, and so forth.1,5,10 We describe a rare case of PRS with classical features, associated with alopecia, hyperpigmentation around the left globe and eyebrows, and unilateral asymmetric loss of subcutaneous fat in left lower leg. Our objective in presenting this particular case is to highlight the classical neurologic, skin and ocular findings of PRS with addition of subcutaneous fat loss in long extremities.     

Profile of cognitive impairment in dementia associated with Parkinson's disease compared with Alzheimer's disease

Objective

To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).

Methods

Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).

Results

Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.

Conclusion

The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%¹ and a cumulative prevalence close to 80%.² In PD, dementia is associated with rapid motor³ and functional decline,⁴ and increased mortality.⁵Cortical Lewy body pathology correlates best with dementia in PD^6,7,8,9; subcortical pathology¹⁰ and AD‐type pathology¹¹ have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,¹² subsequently involving neocortical areas, including the posterior association cortices.¹³ In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.¹⁴ In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.¹⁵Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.^16,17 AD is characterised by memory loss emerging in the early stages of the disease,¹⁸ primarily involving learning and encoding deficits¹⁹ which are associated with medial temporal lobe pathology.^20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention²⁴ and working memory,^25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual^28,29,30 and visuoconstructional tasks are also frequent.³¹ Memory impairment is often present^26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,³⁵ indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently^36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.³²Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,³³ such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.^38,39     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Acute cervical cord infarction in anterior spinal artery territory with acute swelling mimicking myelitis

Acute infarction of the cervical segment of the spinal cord is extremely uncommon. Patients may present with signs and symptoms mimicking that of acute myelitis. On imaging, both conditions may present as a hyperintense area on T-2 weighted MRI. History of sudden onset is essential in establishing the diagnosis. We report a case of cervical spinal cord infarction in a 40-year-old man who was diagnosed with acute transverse myelitis, and was treated with high dose intravenous corticosteroids followed by 5 sessions of plasma exchange. An MRI of the spine revealed abnormal high T2 signal intensity extending from the C2 to C7 level involving the anterior two-thirds of the cord with more central involvement. The findings were consistent with anterior spinal artery territory cervical cord infarction.Infarction of the spinal cord is rare.1,2 Presentation in the cervical region is unusual, especially at a young age. It mostly occurs in the territory of the anterior spinal artery.1 Infarction of the cervical cord may present with pain, paralysis, dissociated sensory loss, and autonomic deficits.1,2 The posterior columns are relatively spared.3,4 Acute myelitis, on the other hand, may lead to damage of the functional areas at the affected segment of the cord.5,6 Like infarction, patients may present with pain, weakness or paralysis, sensory, and autonomic deficits.3,4,6 The disease may be idiopathic or attributed to other CNS, or systemic etiologies.7 Magnetic resonance imaging is essential for the diagnosis of both entities, and may reveal an area of hyperintensity on T-2 weighted imaging, suggesting infarction, or inflammation.1,8,9 Therefore, both conditions may have similar appearance, and accurate diagnosis can be challenging. We report a case of cervical spinal cord infarction (SCI) in a 40-year-old man who presented with a sudden onset of neck and back pain and paralysis. In addition, a literature review on SCI is presented. Our objective in presenting this particular case is to highlight the rare occurrence of acute medullary swelling in the first few hours following cord infarction simulating acute myelitis.     

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

Background

Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.^1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles^{4,5,6,7,8,9,10,11,12,13,14,15,16} (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33} We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.³⁴     

Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis

Background

To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).

Methods

Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).

Results

A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B₂, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.

Conclusion

A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.¹ Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.² Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,³ including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,⁴ fat,⁴ fish⁵ and milk,^6,7 and inversely associated with intake of lycopene,⁸ dietary fibre,⁴ bread and pasta.⁹ Two other studies, however, failed to establish the relationship with milk.^10,11 Several of these studies included only small samples of patients (<25),^5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.^{5,6,7,9,10,11} Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis^{5,6,7,8,9,10,11} or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.^{5,6,7,9,10,11}One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.⁴ This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.¹² In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors.     

Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding

Background

Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at‐risk condition for Alzheimer''s disease (AD).

Patients and methods

We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI.

Results

The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding.

Conclusion

These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.Episodic memory, which enables humans to consciously recollect personally experienced past events, is based on at least two fundamental mnemonic operations: memory formation and retrieval. Event related functional MRI (fMRI) provides a unique opportunity to study the neural correlates of these processes and their subcomponents, such as successful and failed encoding.¹Studies in young healthy subjects have shown that successful declarative memory formation, measured as the difference in brain activity during encoding between subsequently remembered and forgotten items, is accompanied by increases in activity in medial temporal and inferior prefrontal areas.^{2,3,4,5,6,7,8,9,10} Structures within the medial temporal lobe (MTL) region, especially hippocampal formation,^7,11 are believed to be essential in establishing new memories.Patients with mild cognitive impairment (MCI)¹² are characterised by significant memory impairment, which is not severe enough to interfere with usual activities of daily living.¹³ The majority of patients with MCI go on to develop Alzheimer''s disease (AD).Patients with AD, in comparison with older controls, show consistently decreased MTL activation during encoding of new materials.^14,15,16,17 Fewer fMRI studies have investigated MTL encoding activation in patients with MCI,^15,16,18 showing inconsistent results. A recent fMRI study showed decreased MTL activation during a memory encoding task.¹⁵ However, another study¹⁶ found that only a subgroup of subjects with “isolated memory decline” demonstrated decreased hippocampal activation during encoding, whereas still another study¹⁹ reported increased MTL activation in cognitively intact individuals genetically at risk for AD. The variability in these fMRI results may be because the groups differed in the degree of impairment and underlying neural pathology.The degree of activation detected by fMRI within MTL regions during encoding strongly correlates with subjects'' subsequent ability to remember the items encoded.^2,8 Decreased MTL activation in patients with MCI and AD has been associated with relatively poor performance on post scan memory testing.^14,15,17 In contrast, subjects who were genetically at risk for AD, but could successfully perform the fMRI encoding task, showed increased MTL activation. It has been hypothesised that increased MTL activation during successful encoding may represent a compensatory response that allows for relatively normal memory function in the face of developing pathological change¹⁹ There is first evidence that elderly subjects with MCI and with a relatively preserved performance in the fMRI memory task show such a compensatory increased hippocampal response in comparison with healthy subjects, while patients with AD who exhibited poorer performance in the task had lower hippocampal activation.²⁰To further examine this question, it is not sufficient to compare general encoding related activation between patients with MCI and healthy subjects as this comparison would be confounded by task performance. Therefore, we used an event related fMRI paradigm, where subjects are instructed to remember visually presented words. According to task performance in subsequent recognition memory tests, all learned items can then be separated into those that are later remembered (subsequent hits) and those that are later forgotten (subsequent misses), individually for each subject. By comparing brain activation between healthy subjects and patients with MCI only for subsequent hits, brain regions can be identified that differ between groups during successful encoding into episodic memory. It has been shown previously that the degree of neural activity increases with the demands of the cognitive task and that the magnitude and spatial extent of brain activation increases with cognitive effort.^21,22,23 We hypothesise that successful memory encoding, which should be more demanding for patients with MCI than for healthy elderly subjects, would result in increased MTL activation in patients with MCI.     

Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study

Background

Among elderly people without dementia, the apolipoprotein E ε4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex.

Methods

In a community‐dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70–74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT).

Results

Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes.

Conclusions

Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.Age and the apolipoprotein E ε4 allele (APOE4) are the most important known risk factors for sporadic Alzheimer''s disease. The disease is thought to have a long presymptomatic phase,¹ which suggests that APOE4 starts exerting its detrimental effects in the preclinical phase. Most studies on elderly people without dementia have found that the APOE4 allele is associated with various cognitive deficits,^{2,3,4,5,6,7,8,9,10,11,12,13,14} particularly in memory.^2,3,4,5,6,7 A recent meta‐analysis of more than 20 000 people concluded that this allele was associated with poorer performance on tests of global cognitive functioning, episodic memory and executive functioning.¹⁵The association of APOE4 with Alzheimer''s disease varies with sex.^{16,17,18,19,20} The meta‐analysis by Farrer et al²⁰ found that APOE4 homozygosity affords a high risk of Alzheimer''s disease for both men and women, but that a single copy of the allele confers a greater risk on women than on men. A similar sex difference related to APOE4 has been found in the degree of hippocampal atrophy in a cohort with mild cognitive impairment.²¹ We may therefore expect to find an effect related to sex of the APOE4 allele in cognitive tests in elderly people without dementia. Two studies^3,22 that have reported an influence of sex on this relationship found a stronger effect of APOE4 in women.^3,22In this study, we investigated whether sex influences the relationship between APOE alleles and episodic memory in community‐dwelling elderly people. We selected episodic memory because memory deficit is a hallmark of Alzheimer''s disease. Tests of episodic memory have been found to be particularly effective in identifying people at risk.^23,24 We compared the influence of sex in our cohort with that found on the risk of Alzheimer''s disease. We studied a relatively large group of 2181 people from western Norway.     

Psychiatric disorders in preclinical Huntington's disease

Background

Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.

Objectives

To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.

Methods

Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.

Results

Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.

Conclusions

Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,^1,2,3 irritability,^4,5,6 apathy^1,3,6 and psychosis.^4,7,8 Both major depression^1,2,4,9 and more subtle mood disturbances¹⁰ have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,^9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.^2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,^9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),² whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.^10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.^4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.^10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,^4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.^3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.¹⁶ The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset.     

Intravenous immunoglobulin treatment in painful sensory neuropathy without sensory ataxia associated with Sjögren's syndrome

Patients having neuropathy associated with Sjögren''s syndrome may present with pain and superficial sensory involvement in the absence of sensory ataxia. Treatment for this form of associated neuropathy has not been established. The case of a patient with painful sensory neuropathy associated with Sjögren''s syndrome, whose symptoms, particularly pain, responded well to intravenous immunoglobulin both at onset and in a relapse, is reported. Other patients with painful sensory neuropathy associated with Sjögren''s syndrome may also be candidates for intravenous Ig treatment.Ataxic sensory neuropathy associated with Sjögren''s syndrome is well recognised.^1,2,3 Pathologically, the underlying lesion is a sensory ganglionopathy affecting predominantly large neurones and their axons.^2,4 Intravenous immunoglobulin (Ig) treatment is reported to be effective in sensory ataxic neuropathy occurring in people with Sjögren''s syndrome.^5,6,7,8 Recently, another type of neuropathy associated with Sjögren''s syndrome was reported to affect small sensory axons in patients presenting with pain and superficial sensory involvement as opposed to sensory ataxia.^1,4,9,10,11 The treatment for this type of neuropathy remains uncertain. We describe a patient with painful sensory neuropathy associated with Sjögren''s syndrome, in whom intravenous Ig treatment dramatically reduced painful symptoms.     

Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study

Background

Amyotrophic lateral sclerosis (ALS) is defined as a disease of the motor neurones, although several studies indicate involvement of the sensory nervous system.

Aim

To evaluate the sensory nerve conduction studies (NCS) in 88 patients with ALS as part of a European multicentre study.

Methods

Seven European clinical neurophysiologists examined consecutive series of ALS patients. The examinations were peer reviewed, and the diagnosis of ALS was confirmed clinically.

Results

20 (22.7%) patients with ALS had sensory NCS abnormalities in at least one nerve. Of those, 11 (12.5% of all patients) obtained an additional peer review diagnosis of electrophysiological polyneuropathy. There was no difference between the subgroups of patients with normal versus abnormal sensory NCS findings with respect to age, duration and region of onset.

Conclusion

The findings support previous reports of sensory involvement in ALS, and raise the question of whether patients with ALS with sensory nerve abnormalities represent a variant of ALS. ALS associated with generalised sensory system abnormalities may be consistent with degeneration of motor neurones and dorsal root ganglion cells.Sporadic amyotrophic lateral sclerosis (ALS) is defined as a progressive degeneration of upper motor neurones (UMNs) and lower motor neurones (LMNs). Normal electrophysiological studies on sensory nerves are generally required for the diagnosis of ALS.¹ Nevertheless, several neurological, clinical neurophysiological and neuropathological studies have suggested that ALS is a more generalised neurodegenerative disorder.^{2,3,4,5,6,7,8,9,10,11,12,13,14,15,16}The aim of this study was to determine the incidence of patients with ALS with electrophysiological sensory nerve abnormalities and to examine the possible differences between patients with ALS with normal versus abnormal sensory nerve conduction studies (NCS). The study was carried out on the basis of electrodiagnostic examinations of 88 patients with ALS included in the European multicentre project ESTEEM (European Standardised Telematic tool to Evaluate Electrodiagnostic Methods).¹⁷     

Pre-training Catechin gavage prevents memory impairment induced by intracerebroventricular streptozotocin in rats

Objective:

To evaluate the effects of Catechin (CAT) on memory acquisition and retrieval in the animal model of sporadic alzheimer’s disease (sAD) induced by intracerebroventricular (icv) injection of streptozotocin (STZ) in passive avoidance memory test.

Methods:

Thirty adult rats were divided into 5 experimental groups (n=6). Animals were treated by icv saline/STZ (3 mg/kg) injection at day one and 3 after cannulation. The STZ+CAT group received 40 mg/kg CAT by daily gavages for 10 days, after icv STZ treatment and before training. The step-through latency (STL) and time spent in the dark compartment (TDC) were evaluated to examine the memory acquisition and retrieval. All tests were performed in Qom University of Medical Sciences, Qom, Iran, from April to December 2013.

Results:

The STZ treatment significantly decreased STL and increased the number of entries to the dark compartment on the training day. It also increased TDC, on day one and 7 after training. Pre-training gavage of CAT reversed the STL significantly (p=0.027). The CAT treatment also decreased the TDC in both early and late retrieval, in respect to STZ group.

Conclusion:

This data suggests that CAT as an antioxidant could improve both memory acquisition and retrieval in the animal model of sAD.According to reports in 2012, there are more than 35 million people living with dementia worldwide.1 Alzheimer’s disease (AD), which is characterized by amyloid (Aβ) plaque accumulation, is the most common forms of dementia, and results in memory loss and cognitive impairment.2 The pathological features of AD include Aβ peptide misfolding that form neurotic plaques on the neurons and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein.3 There are many reports indicating elevated oxidative stress in the brain of patients with mild cognitive impairment or AD.4 Oxidative stress may be the first feature in the brain of AD patients,5,6 which appears even before Aβ deposition.7,8 Transgenic mice bearing a mutant amyloid precursor protein (APP) similarly showed oxidative stress before Aβ deposition.9 The Aβ plaque formation is suggested to be an effort by the cell to protect itself against oxidative stress.10 The Aβ metabolism increases reactive oxygen species (ROS) and decreases adenosine triphosphate production in mitochondria.11 The secretion, oligomerization, and aggregation of Aβ is the result of its ROS sequestering activity and leads to destruction of cellular integrity.12 Other consequences of cellular oxidative damage include cell cycle aberration and tau hyperphosphorylation, leading to the formation of neurofibrillary tangles.13Polyphenolic flavonoids are neuroprotective against oxidative stress14 and possess potent radical scavenging15 and anti-inflammatory activities.16 Catechin (CAT) protects cultured mesencephalic neurons against 6-hydroxydopamine treatment,17 and also prevents primary hippocampal neurons from Aβ toxicity.18 Epicatechin gallate and epigallocatechin gallate was found to increase the activity of oxygen radical species-metabolizing enzymes, superoxide dismutase and catalase, in mouse striatum.19 The CAT is also capable of inhibiting lipid peroxidation induced by iron ascorbate in brain mitochondrial membranes.20 Evidence suggests that damages caused by Aβ can be undermined by antioxidants such as vitamin E21 or polyphenols.22 There are reports that CAT is more effective than vitamin E and C for the destruction of free radicals.15 So these antioxidants could be the major candidates for the prevention and treatment of AD. In this study, we evaluated the effects of CAT as a potent antioxidant on memory acquisition in the animal model of sporadic AD (sAD) induced by intracerebroventricular (icv) injection of streptozotocin (STZ) in passive avoidance memory test.     

Movement disorders in patients taking anticonvulsants

Background

A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Although it has been suggested that the risk of parkinsonism is 10‐fold higher in those taking valproate as compared with other AEDs, there have been no large, systematic trials assessing this.

Aim

To establish more precisely the prevalence of and risk factors for developing parkinsonism associated with valproate use,and to assess the occurrence of movement disorders with the newer AEDs.

Methods

Patients with epilepsy were recruited from the Toronto Western Hospital Epilepsy Clinic (University of Toronto, Toronto, Ontario, Canada). Each patient was examined by a movement disorder specialist who was blinded to the treatment status of the patient.

Results

201 patients were included. Postural tremor was the most common movement disorder (45%), followed by parkinsonism (4.5%). The odds of having parkinsonism were 5 times higher with valproate than with other AEDs. No single factor predicted the presence of parkinsonism; however, many (5/9) of the patients concurrently used other drugs or had comorbidities that could have caused or exacerbated parkinsonism. None of the newer AEDs were clearly associated with the presence of movement disorders; however, the numbers were too small to make a formal analysis.

Conclusion

Although the risk of parkinsonism with valproate is higher than with other AEDs, it is lower than originally reported. The cases available were not enough to accurately comment on the prevalence of movement disorders with the newer AEDs.A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Among the common movement disorders associated with AEDs, cerebellar ataxia is the most commonly reported, followed by asterixis and myoclonus, although a variety of others, including chorea, orofacial dyskinesias, tremor, tics and dystonia, can occur.^1,2,3,4,5 Most of the AEDs have been implicated at one time or another, with the most common offenders being phenytoin and carbamazepine, followed by valproate and phenobarbital.⁶ Despite its utility, valproate commonly exerts side effects on the central nervous system (CNS). The most common is dose‐related tremor, occurring in as many as one quarter of chronically treated patients.^7,8,9,10,11 Less often asterixis, chorea, sensorineural hearing loss and encephalopathy have been reported.^3,12,13 Although there have been case reports of parkinsonism induced by AEDs such as phenytoin^14,15 and carbazamepine,¹⁶ the most common drug associated with parkinsonism by far is valproate.⁶ Several case reports of valproate‐induced parkinsonism, often accompanied by cognitive disturbances have been published.^{11,17,18,19,20,21} A report of a multiple system atrophy‐like syndrome is also available.²² Both syndromes are said to resolve when the drug is withdrawn.^11,17,22 However, most studies have reported isolated cases and the few series looking at the prevalence of valproate‐induced parkinsonism have been based on small sample sizes.^18,21 Moreover, there have been no recent systematic studies dealing with the prevalence of movement disorders related to new AEDs such as topiramate, vigabatrin, lamotrigine and gabapentin among others.The primary purpose of this study was to establish more precisely the prevalence of and risk factors for developing valproate‐induced parkinsonism. The secondary aim was to attempt to delineate the profile of new AEDs with regard to involuntary movement abnormalities. To avoid biases that may have influenced previous reports, we evaluated patients with epilepsy for the presence of movement disorders, blinded to the knowledge of which AEDs they were taking.     

Trunk performance after stroke: an eye catching predictor of functional outcome

Background and aim

Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.

Methods

A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.

Results

The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R² = 0.52, p<.0001) and static sitting balance subscale score (partial R² = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.

Conclusions

This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,¹ it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).^2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.⁴ Trunk performance has also been identified as an important independent predictor of ADL after stroke.^5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.^5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.^5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,^5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients^7,8 and trunk assessment of Fujiwara et al.⁹ A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.^5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.⁹ All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,⁸ no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.¹⁴ The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.^14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.¹² To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.¹⁶ Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke.     

Post-surgical changes in brain metabolism detected by magnetic resonance spectroscopy in normal pressure hydrocephalus: results of a pilot study

Background

Adult normal pressure hydrocephalus (NPH) is one of the few potentially treatable causes of dementia. Some morphological and functional abnormalities attributed to hydrocephalus improve following treatment.

Objectives

We focused on analysis of changes in cerebral metabolites using proton magnetic resonance spectroscopy (¹H‐MRS) after NPH treatment, and its clinical and cognitive correlation.

Methods

¹H‐MRS, neuropsychological and clinical status examinations were performed before and 6 months after shunting in 12 adults with idiopathic NPH. We obtained N‐acetyl‐aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) values.

Results

After surgery, NAA/Cr was significantly increased. Moreover, NAA/Cr values were related to cognitive deterioration.

Conclusion

MRS could be a marker of neuronal dysfunction in NPH.Normal pressure hydrocephalus (NPH) is a potentially treatable cause of dementia,^1,2 characterised by progressive cognitive dysfunction, gait disturbance and urinary incontinence associated with ventricular enlargement and abnormalities in CSF dynamics. In these patients, some morphological and functional abnormalities attributed to hydrocephalus improve after treatment.^3,4,5 Proton magnetic resonance spectroscopy (¹H‐MRS) allows non‐invasive in vivo measurement of brain metabolites. Findings from MRS studies reveal that ¹H‐MRS is a potentially non‐invasive technique with sufficient sensitivity to detect subtle changes in neuronal function in neurodegenerative diseases, allowing investigation of neuronal injury or dysfunction^6,7 and the assessment of treatment efficacy.^8,9,101H‐MRS studies in patients with hydrocephalus are scarce.^{6,7,11,12,13,14,15} Changes in cerebral metabolites after treatment with hydrocephalus using this technique have been analysed in only two studies, which concentrated exclusively on the results of lactate metabolites.^11,12The aim of our study was to describe changes in other major metabolites, using ¹H‐MRS, before and after treatment in idiopathic NPH patients, and to obtain preliminary data on their clinical and cognitive correlation, which could serve as the basis for larger studies with control subjects.     

Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Background

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).

Methods

Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.

Results

In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p<0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength–duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p<0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.

Conclusions

Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurones in the spinal cord, brainstem and motor cortex.^1,2 The consequences of this neurodegeneration are motor deficits in the limbs, bulbar and respiratory muscles.³ Although the mechanisms of neuronal dysfunction, and ultimately the development of symptoms in ALS, remain unknown, glutamate excitotoxicity,^4,5,6 increased levels of inducible nitric oxide synthase levels⁴ and, in cases of inherited ALS, oxidative stress secondary to mutations in the superoxide dismutase‐1 gene, have been proposed.^7,8,9,10Increased fatigability, defined as an inability to sustain a predictable maximal force during voluntary contraction, is a common symptom of ALS.^11,12,13 The mechanisms underlying fatigue in ALS are complex, and contributions from both the central and peripheral nervous systems have been reported.^11,12 Central fatigue refers to a reduced excitatory drive to motor neurones, secondary to central nervous system dysfunction, resulting in incomplete motor unit recruitment and submaximal motor unit discharge rates. In contrast, peripheral fatigue typically refers to impaired muscle activation, caused by dysfunction at or below the anterior horn cell.^13,14 Perhaps somewhat counterintuitively, fatigue in ALS appears to be independent of muscle strength and disease severity.^15,16 Regardless of the underlying mechanism, fatigue in ALS severely impacts on the patient''s quality of life.^15,16The ability to sustain a motor output may be assessed by measuring changes in axonal membrane threshold following a voluntary contraction. Specifically, in peripheral nerves, voluntary contraction activates the axonal membrane Na⁺/K⁺ pump,¹⁷ which attempts to return the resting membrane potential to baseline after contraction has ceased,^18,19,20,21 resulting in activity dependent hyperpolarisation. The magnitude of activity dependent hyperpolarisation is determined by the impulse load²² and, in neurological diseases where the safety margin for impulse conduction has been reduced as occurs for instance in demyelinating neuropathy, may be sufficient to induce conduction failure.^23,24,25 In an attempt to further delineate the mechanisms underlying fatigability and weakness in ALS, the present study measured activity dependent changes in axonal excitability induced by voluntary contraction.     

Functional and magnetic resonance imaging correlates of corpus callosum in normal pressure hydrocephalus before and after shunting

Background

Normal pressure hydrocephalus (NPH) is associated with corpus callosum abnormalities.

Objectives

To study the clinical and neuropsychological effect of callosal thinning in 18 patients with idiopathic NPH and to investigate the postsurgical callosal changes in 14 patients.

Methods

Global corpus callosum size and seven callosal subdivisions were measured. Neuropsychological assessment included an extensive battery assessing memory, psychomotor speed, visuospatial and frontal lobe functioning.

Results

After surgery, patients showed improvements in memory, visuospatial and frontal lobe functions, and psychomotor speed. Two frontal corpus callosum areas, the genu and the rostral body, were the regions most related to the clinical and neuropsychological dysfunction. After surgery, total corpus callosum and four of the seven subdivisions presented a significant increase in size, which was related to poorer neuropsychological and clinical outcome.

Conclusion

The postsurgical corpus callosum increase might be the result of decompression, re‐expansion and increase of interstitial fluid, although it may also be caused by differences in shape due to cerebral reorganisation.Ventricular dilatation and corpus callosum abnormalities are the anatomical changes most often reported in association with normal pressure hydrocephalus (NPH). Callosal abnormalities include changes in the morphology and the magnetic resonance imaging (MRI) signal. The most consistent findings are stretching, uniform and focal thinning, and upward elevation.^1,2,3,4 Callosal damage has been primarily attributed to lateral ventricle dilatation¹ and to the impingement of the corpus callosum against the falx.²Two studies indicated a partial or complete recovery of different callosal parameters after shunt surgery.^4,5 However, in these studies, only five and eight patients with different types of hydrocephalus were analysed postsurgically. Other studies have reported corpus callosum abnormalities after surgery in 3–17% of cases, including signal changes,^6,7,8,9,10 a transient scalloping deformity⁶ and increased thickness.^7,8 Although the nature of the postsurgical changes in the corpus callosum remains unclear, several causes have been suggested, including callosal compression against the falx, decompression and overdrainage.^6,7,8,9To our knowledge, no morphological MRI quantitative studies of corpus callosum in NPH have been performed to date, nor has the possible involvement of the corpus callosum in the neuropsychological deterioration in NPH been investigated in depth. As damage to the corpus callosum can affect cognition,¹¹ the aim of this study was to investigate the contribution of corpus callosum thinning to the neuropsychological deficits in NPH and to determine the postsurgical callosal changes and their relationship with cognitive outcome.     

Association between human leukocyte antigen-DR and demylinating Guillain-Barré syndrome

Objective:

To find an association between human leukocyte antigen (HLA) class II DRB1, DRB3, DRB4, and DRB5 alleles frequencies in a sample of Iraqi patients with Guillain-Barré syndrome (GBS) and compare with a healthy control group.

Methods:

We performed a cross-sectional study consisting of 30 Iraqi Arab patients with GBS attending the Neurological Department in the Neuroscience Hospital, Baghdad, Iraq between September 2012 and June 2013. The control group comprised 42 apparently healthy volunteers. Human leukocyte antigen genotyping for HLA DRB1, DRB3, DRB4, and DRB5 was performed using the polymerase chain reaction-sequence-specific primers method. The allele frequencies were compared across both groups. Major histocompatibility complex (MHC)-class II HLA-DR genotyping and serotyping were performed by software analysis.

Results:

We found increased frequencies of HLA genotype DRB1*03:01 (p=0.0009), DRB1*07:01 (p=0.0015), and DRB4*01:01 (p<0.0001) in patients with GBS compared with healthy controls. The HLA DR6 was increased in the control group (p<0.0001).

Conclusions:

Our results suggest an association between HLA-DRB1*03:01, DRB1*07:01, DRB4*01:01, and HLA DR3, DR7 and a susceptibility to GBS.Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy that is autoimmune in nature, and manifests as a rapidly evolving reflexic motor paralysis with or without sensory disturbance and autonomic system involvement.1 Guillain-Barré syndrome is subdivided into the most common type, which is the acute inflammatory demyelinating polyneuropathy (AIDP), and an axonal variant, which is subdivided into 2 subtypes: acute motor axonal neuropathy (AMAN), and an acute motor sensory axonal neuropathy (AMSAN).2-4 There is an additional rare third type, which is Miller Fischer syndrome that accounts for only 5% of cases. The GBS prevalence is between 0.6-4/100.000 /year,5 with age range from 2 months to 95 years.6 Most patients are between 15-50 years.7,8 The autoimmune nature of the disease is triggered by a nonself-antigen (infectious agent, vaccine) that attacks gangliosides in the axonal membrane by a molecular mimicry mechanism in axonal GBS, but in AIDP, the specific antigen or antibodies are still uncertain.8,9 There is evidence that both cellular and humeral mediated immunity participates in the immune mechanism. The most common infectious agents that participate in the molecular mimicry autoimmune response are Campylobacter jejuni,10,11 cytomegalovirus,12 Epstein barr virus,13 and Mycoplasma pneumoniae.14Much of the research has focused on finding the high risk predisposition of certain people with an infection to develop GBS evidenced by a twin study, linkage disease, genetic, familial, and HLA study.15,16 The HLA antigen system is the name of the loci of genes that encode for the major histocompatibility complex (MHC) in humans. These genes reside on chromosome 6, and encode cell-surface antigen-presenting proteins, along with many other functions. The HLAs corresponding to MHC class I (A, B, and C) present peptides from inside, while HLAs corresponding to MHC class II (DP, DM, DOA, DOB, DQ, and DR) present antigens from outside of the cell to T-lymphocytes. The HLAs corresponding to MHC class III encode components of the complement system.17 In GBS, there is macrophage activation with circulating activated T-lymphocytes evidenced by augmented expression of histocompatibility antigens (HLA-DR), suggesting that there is an association between GBS and HLA alleles.15,16 The HLA typing in GBS was investigated in several studies worldwide suggesting various associations.15,16,18 The aim of the current study is to investigate any association between GBS and HLA-DR.     

Head trauma in primary cranial dystonias: a multicentre case-control study

Background

The relationship between prior trauma and primary adult‐onset dystonia is not well understood. Previous uncontrolled observations and exploratory case–control studies have yielded contradictory results.

Objective

To analyse the association between cranial dystonia and prior head trauma.

Methods

An ad hoc multicentre case–control study was performed using a semistructured interview to collect detailed information on the history of head trauma before disease onset in five Italian tertiary referral centres for movement disorders. The presence of a history of head trauma and of post‐traumatic sequelae (loss of consciousness, bone fractures, scalp/facial wounds) before disease onset was recorded from 177 patients with primary adult‐onset cranial dystonia and from 217 controls with primary hemifacial spasm matched by age strata and sex. Differences between groups were assessed by Mann–Whitney U test and Fisher''s exact test, and the relationship between prior head trauma and case/control status was analysed by multivariate logistic regression models.

Results

No association was found between vault/maxillofacial trauma and cranial dystonia. Most reported traumas occurred several years before disease onset. None of the main post‐traumatic sequelae altered the chance of developing cranial dystonia compared with patients with primary hemifacial spasm, nor did head trauma modify the age at onset of cranial dystonia.

Conclusions

These results do not support prior head trauma as a possible environmental factor modifying the risk of developing late‐onset cranial dystonia. The lack of association may have pathogenetic and medical–forensic implications.Cranial dystonia is an adult‐onset dystonia most commonly affecting the orbicularis oculi and oromandibular muscles.^1,2,3 Like other forms of primary adult‐onset dystonia, cranial dystonias are thought to be multifactorial in origin, with a possible contribution of both genetic and environmental factors.⁴Head trauma leading to structural lesions in the caudate, lentiform nuclei, thalami or midbrain is one of the possible causes of secondary dystonia.^5,6,7,8 A few uncontrolled studies have also suggested an association between cranial dystonia and head trauma in the absence of overt brain lesions.^9,10 Two possible pathogenic mechanisms have been proposed to explain the link between traumatic head injury and cranial dystonia.^9,10,11 The first is discrete brain damage in “sensitive” areas such as the basal ganglia. The second mechanism is that of a peripheral maxillofacial trauma inducing topographically related dystonia^12,13 through maladaptive plastic reorganisation of cortical and subcortical circuits.^{9,10,12,13,14} Two exploratory case–control studies nevertheless found no significant association with cranial dystonia.^15,16 Because these studies assessed a large number of variables owing to multiple testing, they were more liable to a higher risk of false positive results than ad hoc hypothesis‐testing studies. In addition, prior studies^15,16 only partly explored the relationship between dystonia and clinical features of the trauma (loss of consciousness, scalp or facial wounds, cranial or maxillofacial bone fractures), the topographical distribution of the trauma (vault or maxillofacial localisation) and the time elapsed from the trauma to the development of dystonia.To discuss these shortcomings and establish the relationship between previous head trauma and primary late‐onset cranial dystonia, we conducted an ad hoc multicentre case–control study, collecting detailed information on the history of head trauma antecedent to the onset of dystonia.