Georgios Koutsis

Cognitive impairment in different MS subtypes and clinically isolated syndromes

OBJECTIVE To investigate the pattern of cognitive impairment in patients with relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) multiple sclerosis, and patients with clinically isolated syndrome (CIS) suggestive of MS, relative to control participants in the Greek population. METHODS RR patients (N=75), SP patients (N=29), PP patients (N=23), CIS patients (N=33), and healthy control participants (N=43) were assessed by the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS The overall prevalence of cognitive dysfunction in our patients was 52.8% with CIS patients excluded and 47.5% with CIS patients included. All MS patients differed significantly from controls in all BRBN measures. Similar was the pattern of cognitive dysfunction in patients with CIS suggestive of MS, although verbal learning/memory capacity (as measured by the Selective Reminding Test) remained relatively spared. The comparisons between patient groups revealed some differences in the performance mainly in favor of CIS and RRMS patients. These differences largely disappeared after controlling for physical disability (EDSS). CONCLUSION All MS subtypes patients exhibit a pattern of cognitive impairment running across the studied cognitive domains. The pattern of cognitive dysfunction in patients with CIS is similar with relative sparing of verbal learning.

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

The polyglutamine diseases, including Huntingtons disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.

APOE ε4 is associated with impaired verbal learning in patients with MS

Objective: To investigate the effect of APOE ε4 on different cognitive domains in a population of Greek patients with multiple sclerosis (MS). Methods: A total of 125 patients with MS and 43 controls were included in this study and underwent neuropsychological assessment with Rao’s Brief Repeatable Battery. All patients with MS were genotyped for APOE. The effect of APOE ε4 on different cognitive domains was investigated. Results: Fifty-one percent of patients with MS were cognitively impaired. E4 carriers had a sixfold increase in the relative risk of impairment in verbal learning vs noncarriers (OR 6.28, 95% CI 1.74 to 22.69). This effect was domain-specific and was not observed in other cognitive domains assessed by the battery. Conclusion: We found an association of APOE ε4 with impaired verbal learning in patients with multiple sclerosis.

Clinical and subclinical autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy

Autonomic neuropathy, although common in Guillain–Barré syndrome, is considered rare in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and has not been systematically investigated in that disorder. The present study was aimed at determining the prevalence of autonomic dysfunction and investigating the integrity of autonomic nervous system (ANS) reflexes in CIDP. We studied 17 patients with idiopathic CIDP and 20 healthy controls. Six quantitative autonomic function tests (AFTs) were used: Valsalva ratio, 30/15 ratio, and inspiration–expiration difference for parasympathetic function; and tilt test, handgrip test, and sympathetic skin response for sympathetic function. Eleven patients had symptoms of autonomic dysfunction. AFTs were abnormal in 13 patients. Parasympathetic and sympathetic systems were affected with equal frequency. The tilt test was abnormal most frequently, followed by the 30/15 ratio. Three patients developed postural hypotension with loss of consciousness during the tilt test. Abnormality of AFTs did not correlate with the presence of dysautonomic symptoms; duration, severity, and clinical course of the disease; or with age or gender of patients. Our study suggests a higher frequency of clinical and subclinical involvement of the ANS in CIDP than previously estimated. Dysautonomic symptoms are frequent but are mild. However, upon prolonged passive standing, autonomic failure can lead to loss of consciousness. The subclinical involvement of the ANS affects mainly the sympathetic vasomotor and parasympathetic cardiovascular fibers. Muscle Nerve, 2005

Occipital neuralgia as an isolated symptom of C2 myelitis.

Occipital neuralgia has been attributed to lesions at a peripheral nerve or radicular level. On rare occasions, it has been associated with cervical cord lesions. We report a 55‐year‐old woman who presented with an isolated occipital neuralgia and was found on further investigation to have a restricted, isolated myelitis at C2 level. This represents the second reported case of occipital neuralgia due to C2 myelitis and should alert clinicians to considering cervical MRI in patients with occipital neuralgia.

C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population

An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes.

Late-onset Huntington's disease: Diagnostic and prognostic considerations

OBJECTIVE To address diagnostic and prognostic issues in patients with late-onset Huntingtons disease (HD). METHODS We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. RESULTS Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). CONCLUSIONS A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.

Association between asymptomatic median mononeuropathy and diabetic polyneuropathy severity in patients with diabetes mellitus

BACKGROUND Asymptomatic median mononeuropathy (AMM) and diabetic polyneuropathy (DPN) often coexist and can be difficult to distinguish electrophysiologically. Moreover, the potential association between AMM and DPN has not been extensively evaluated. OBJECTIVE We investigated the relation between AMM and DPN severity in consecutive diabetic patients. METHODS The non-dominant limb was studied electrophysiologically in 100 consecutive diabetic patients with no symptoms of carpal tunnel syndrome on the non-dominant side. AMM was diagnosed based on previously validated electrophysiological criteria. DPN severity was graded according to the Michigan diabetic neuropathy score. RESULTS AMM was discovered in 28% of the study population (Adjusted Wald 95% CI: 20%-37%). It was more common in women, displayed a tendency of being more common in patients over 50 years old and correlated with the severity of DPN and the number of abnormal nerves on nerve conduction studies. It was present in 18.1% of patients without evidence of DPN. No correlation was found with the duration and type of diabetes. In multivariate logistic regression models increasing severity of DPN was independently associated with the presence AMM (Wald test=10.557, df=3, p=0.014). Patients with DPN stage III and IV had a five-fold (OR=5.06, 95% CI=1.49-17.19) and a four-fold (OR=4.50, 95% CI=1.15-17.65) respectively increased likelihood to present with AMM in comparison to DPN stage I (reference group). CONCLUSIONS Our results confirmed the high incidence of AMM in diabetic patients. AMM was present in a significant number of patients in the absence of DPN and the likelihood of AMM detection increased with increasing severity of DPN.

Serum Leptin Levels in Treatment-Naive Patients with Clinically Isolated Syndrome or Relapsing-Remitting Multiple Sclerosis

Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P = .003) and female CIS patients (P = .001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner.

Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion.

Huntington’s disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes for mutations causing HDL2, SCA17, SCA1, SCA2, SCA3, SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.