Migraine with unilateral motor symptoms: a case-control study

Objective

To characterise the clinical features of non‐familial migraine with unilateral motor symptoms (MUMS) and compare these features with those of migraine without weakness.

Methods

24 patients with MUMS and 48 matched controls were identified from a tertiary care headache centre. Using a structured interview, the migraine symptoms of both groups were characterised. Results of previously administered Beck Depression Inventories (BDI), Minnesota Multiphasic Personality Inventories and psychiatric diagnoses were collected, when available, and compared between groups.

Results

9 patients had episodic migraine and 15 had chronic migraine. Patients with MUMS always had weakness involving the arm subjectively, and both arm and leg objectively. A give‐way character was always present. Only 17% of patients with MUMS reported facial weakness; 58% reported persistent interictal weakness; 92% reported sensory symptoms. A rostrocaudal march of sensory and motor symptoms was frequently reported. Weakness was ipsilateral to unilateral headache in two thirds of the patients. Compared with controls, patients with MUMS had had similar pain intensities, but were more likely to report other migrainous symptoms, including allodynia. 38% of patients with MUMS were told they had had a stroke, and 17% believed they had had a stroke despite normal brain imaging. Patients with MUMS reported fewer affective disorders and more adjustment disorders than controls, and had similar BDI scores.

Conclusions

A syndrome of severe migraine with accompanying give‐way weakness is common in tertiary care headache centres. It is accompanied by other neurological symptoms.Migraine has a variety of subtypes, some of which are associated with hemiplegia. Aura is highly variable and is thought to be generated from many areas of the cortex or brain stem. A recent epidemiological study estimated the prevalence of both familial and sporadic hemiplegic migraine in Denmark to be 0.01%.¹ By contrast, Couch et al² reported the rate of hemiplegic symptoms to be 10% in a large tertiary care headache practice. In all, 11 of 78 patients admitted to the Thomas Jefferson University Hospital (Philadelphia, Pennsylvania, USA) for the treatment of headache reported hemiplegic symptoms, and six had hemiparesis on admission.³Of 205 subjects in Fisher''s studies of patients with late‐life migraine accompaniments, 45 had motor weakness.^4,5 All cases were accompanied by visual symptoms, paraesthesias and speech disturbances. Of 22 cases of migraine and cluster headache with limb pain accompanying the headache, six also had recurrent weakness.⁶ Sensorimotor disturbances often accompany chronic pain syndromes. Complex regional pain syndrome is often associated with allodynia, weakness and dystonia.⁷ These symptoms, along with non‐dermatomal sensory loss, have been labelled “psychogenic pseudoneurological dysfunction” by some authors.⁷ Motor impairments correlate with allodynia in complex regional pain syndrome type I.⁸Our study was designed to confirm and further characterise previous observations on motor weakness accompanying migraine headache. We postulated that unilateral motor symptoms are common in patients with migraine in a tertiary care centre, and that their presence may be due to the activation of sensorimotor programme related to the pain and presence of allodynia.     

Plasmodium falciparum-Specific Cellular Immune Responses after Immunization with the RTS,S/AS02D Candidate Malaria Vaccine in Infants Living in an Area of High Endemicity in Mozambique

Results from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-γ), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4⁺ and CD8⁺ cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P = 0.053) and with higher CSP-specific IFN-γ-producing CD8⁺ T-cell responses (P = 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.Malaria remains one of the major world heath problems affecting between 200 and 400 million people annually and causing 2 to 3 million deaths, mostly children and pregnant women living in sub-Saharan Africa (37). Infections by Plasmodium falciparum, one of the four species of plasmodia that affect humans, cause 80 to 90% of the malaria cases and are responsible for 95% of all malaria-associated deaths (14). Since most of the worldwide malaria burden is due to P. falciparum, efforts for prevention and eradication of malaria have focused on this parasite, and a P. falciparum-customized malaria vaccine is one of most promising tools (12, 25, 26).The most abundant and immunogenic antigen on the surface of Plasmodium sporozoites is the circumsporozoite protein (CSP), which is a target for vaccine development (9, 10, 17, 27). In vaccines based on irradiated sporozoites and CSP in human and mouse models, antibodies to circulating sporozoites, followed by cell-mediated responses to the protein after invasion of hepatocytes, have been described as crucial for the generation of protective responses (7, 11, 13, 28, 29).RTS,S is a subunit malaria vaccine candidate based on the CSP of P. falciparum that has been under study for many years. The chimeric vaccine contains a portion of the NANP-repeats, all four NVDP-repeats, and the complete carboxyl-terminal region of CSP suggested to be targets for humoral and cellular immunity, along with the amino-terminal region of HbsAg (HBS) (16). The malaria vaccine candidate RTS,S (GlaxoSmithKline, Rixensart, Belgium) formulated with the adjuvant system AS01 or AS02 has proven to confer partial protective immunity against malaria infection in malaria-naive adults (20, 21, 41), as well as in adults and infants in areas where malaria is endemic (2-6). Clinical safety, immunogenicity, and efficacy trials in infants and children have shown RTS,S/AS02 to be safe and protective and to induce high antibody titers (2, 4, 6, 34).Although the induction of a CSP-specific humoral response after RTS,S vaccination has been well described, the generation of cellular immune responses has not yet been addressed in infants or young children immunized with the RTS,S vaccine candidate. In adults, protection conferred by the RTS,S vaccine has been associated with acquisition of strong antibody and cellular responses to the CSP fragment of RTS,S (20, 22). Malaria naive volunteers immunized with RTS,S/AS02 frequently develop strong proliferative and IFN-γ-producing T-cell responses to peptides representing T-cell epitopes (Th2R and Th3R) present in the vaccine (22). A correlation between protection against experimental challenge and the CSP-specific production of IFN-γ by CD4⁺ and CD8⁺ T cells has been described in a limited number of individuals (42).Current efforts are under way to proceed to phase III clinical trials with the RTS,S vaccine, despite no currently identified immune correlates of protection for vaccination with RTS,S in infants or young children. The present study was integrated into a phaseI/IIb clinical trial of the RTS,S/AS02D candidate vaccine in infants in a rural area of malaria endemicity in Mozambique (4). We sought here to examine the cellular responses in infants vaccinated with RTS,S/AS02D and further the development of assays for use in malaria vaccine trials in infants and young children, the population most vulnerable to severe malaria.     

Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence

There is considerable interest in herbal therapies for cancer prevention but often with little scientific evidence to support their use. In this study, we examined epidemiological data regarding effects of commonly used herbal supplements on risk for ovarian cancer and sought supporting biological evidence. 4.2% of 721 controls compared to 1.6% of 668 cases regularly used Ginkgo biloba for an estimated relative risk (and 95% confidence interval) of 0.41 (0.20,0.84) (p=0.01); and the effect was most apparent in women with non-mucinous types of ovarian cancer, RR=0.33 (0.15,0.74) (p=0.007). In vitro experiments with normal and ovarian cancer cells showed that Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in serous ovarian cancer cells, but little effect in mucinous (RMUG-L) cells. For the ginkgolides, the inhibitory effect appeared to be cell cycle blockage at G0/G1 to S phase. This combined epidemiological and biological data provide supportive evidence for further studies of the chemopreventive or therapeutic effects of Ginkgo and ginkgolides on ovarian cancer.     

Familial occurrence of systemic sclerosis, rheumatoid arthritis and other immunological disorders: report of two kindreds with study of HLA antigens and review of the literature

We report two Caucasian families with systemic sclerosis and other connective tissue and immunological disorders, including rheumatoid arthritis, discoid lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, asthma, Sj?gren's syndrome, Raynaud's phenomenon and thyroid disease. In one of these families, two sisters are affected with systemic sclerosis. Clinical, serological, and HLA haplotype results are reported, along with a review of the medical literature on familial occurrence of systemic sclerosis.     

Evaluation and Management of Outlet Obstruction in Women Without Anatomical Abnormalities on Physical Exam or Cystoscopy

Bladder outlet obstruction (BOO) in women can be either anatomic or functional. Anatomic causes for BOO are often readily apparent by history and physical exam. On the other hand, causes for functional obstruction, including dysfunctional voiding, primary bladder neck obstruction, and detrusor-external sphincter dyssynergia, are more difficult to establish. Because the appropriate treatment for functional obstruction drastically varies according to etiology, making an accurate diagnosis is paramount. Videourodynamics, interpreted in the context of individual clinical symptoms, remains the diagnostic gold standard in women with functional obstruction.     

Prevalence of the K76T mutation in the putative Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene and its relation to chloroquine resistance in Mozambique

K76T, a mutation in the Plasmodium falciparum chloroquine (CQ) resistance transporter protein, has been implicated in resistance to CQ. A modified 14-day in vivo test to estimate the CQ resistance level was done in southern Mozambique: 21 (42%) of 50 subjects who completed the follow-up were CQ susceptible. Use of msa2-restriction fragment length polymorphism (RFLP) genotyping to differentiate new from recrudescent infections made little difference in the estimated prevalence of resistance. The K76T mutation prevalence was estimated by RFLP-polymerase chain reaction and sequencing, and its relation to parasitological CQ resistance was explored on day 0 samples: 51 of 56 pretreatment samples presented the T76 codon, and it was present in 100% of children with parasitological resistance. T76 also was present in 18 of 23 subjects in whom the infection resolved after CQ treatment. These findings show a high prevalence of the K76T mutation among wild isolates but also suggest additional factors responsible for CQ resistance.     

Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial

Stopping antimalarial chemoprophylaxis can be followed by increased risk of malaria, suggesting that it interferes with the development of antimalarial immunity. We report analysis of extended follow-up until age 2 years of a randomised, placebo-controlled double-blind trial of intermittent preventive antimalarial treatment in infants. The rate of clinical malaria (events per person-year at risk, starting 1 month after final dose of intermittent treatment) was 0.28 in the sulfadoxine-pyrimethamine group and 0.43 in the placebo group (protective effect 36%, 95% CI 11-53). Intermittent treatment produced a sustained reduction in the risk of clinical malaria extending well beyond the duration of the pharmacological effects of the drugs, excluding a so-called rebound effect and suggesting that such treatment could facilitate development of immunity against Plasmodium falciparum.     

Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation

Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted.