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The cerebellum in neurodegeneration: more than just balance control

8 Sep, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the current issue of JNNP, Gellersen and colleagues have published the first meta-analysis designed to assess patterns of cerebellar atrophy across different neurodegenerative diseases. Typically, neurodegenerative diseases have been linked to impairment in cortical and basal ganglia structures, however increasing evidence suggests that degeneration in the cerebellum also plays a role in these complex diseases. Even though the cerebellum has been well defined as a crucial brain area for motor control and coordination, its extremely extended connectivity into non-motor areas (such as prefrontal and parietal cortices) supports its role in cognitive and neuropsychiatric processes.


In this study, the authors studied the patterns of regional cerebellar grey matter (GM) loss in seven neurodegenerative conditions: (i) Alzheimer’s disease (AD), (ii) Parkinson’s disease (PD), (iii) Huntington’s disease (HD), (iv) frontotemporal dementia (FTD), (v) amyotrophic lateral sclerosis (ALS), (vi) multiple system atrophy (MSA), and (vii) progressive supranuclear palsy (PSP). They carried out a systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After selecting 54 studies (a total number of n=1609 patients and n=1471 controls), the authors found consistent clusters of cerebellar atrophy in AD, ALS, FTD, MSA and PSP, but not in HD and PD. Importantly, the patterns of cerebellar GM atrophy were disease-specific (see figure 1), with some areas of overlap found in AD, ALS, FTD and PSP (Crus I/II), as well as between MSA and PSP (left lobules I–IV). Finally, GM atrophy co-located with cerebellar areas associated with motor (PSP, MSA) or cognitive dysfunction (FTD, ALS, PSP).


Figure 1. The pattern of cerebellar atrophy across neurodegenerative disease. (A) The cerebellum is a brain structure involved in motor, cognitive, behavioural, and limbic functions. (B) Structural atrophy in the cerebellum in AD, ALS, MSA and PSP.


The results presented in this JNNP article revealed that neurodegenerative diseases have unique patterns of cerebellar atrophy. These findings suggest that cerebellar GM changes are disease-specific and correspond to cortical or subcortical changes specific to the underlying pathology. Furthermore, these patterns were also related to cognitive, sensorimotor and affective symptoms in the respective disorder. Although it is well recognized that the cerebellum modulates diverse neuronal networks to regulate motor, cognitive, behavioural, and limbic circuits, the origin of the patterns of cerebellar atrophy is unknown. Further studies should address if these changes are due to Wallerian degeneration secondary to cortical or subcortical degeneration, or if they are primarily cerebellar in origin. In the meantime, the GM cerebellum atrophy in neurodegeneration can provide valuable diagnostic and pathological insights and therefore contribute to the understanding of this group of challenging human diseases.


Well worth the read!!





Cognitive profiling in bvFTD and ALS-bvFTD: is there a difference?

16 Aug, 17 | by Dr Thanuja Dharmadasa; JNNP web editor

In the August issue of JNNP, Saxon and colleagues analyse the cognitive characteristics of pure behavioural variant FTD (bvFTD) and compare this to the behavioural and cognitive symptoms that develop in a proportion of amyotrophic lateral sclerosis (ALS) patients (ALS-bvFTD).

The occurrence of cognitive impairment is now well recognised in ALS, and the clinical and genetic overlap between ALS and FTD has further exposed the relationship between these two disorders. Specifically, the recent discovery of a mutual mutation (a hexanucleotide repeat expansion) in the C9orf72 gene has unmasked the existence of a continuum from pure ALS (with no cognitive involvement) to pure FTD (with no motor involvement). As such, a proportion of patients have a crossed phenotype, with ~15% FTD patients developing ALS and 10-20% of ALS patients meeting the criteria for FTD (ALS-FTD). Although the majority of ALS-FTD cases develop behavioural variants of FTD, there are some suggestions that this is a distinct substrate from pure bvFTD. This is also supported by the consistent presence of TDP-43 (TAR DNA binding protein 43) pathology in the crossed ALS-FTD phenotype, in contrast to the pathologically heterogenous FTD cohort. Such potential differences hold important clinical implications for early diagnosis and management of these patients.

     The ALS-FTD spectrum of disease

In this study, the authors retrospectively explored a large cohort of bvFTD patients (n=185) and ALS-bvFTD patients (n=56), analysing group differences in cognitive, behavioural, and neuropsychiatric profiling. Overall, bvFTD patients were found to have a higher frequency of general behavioural change (eg social disinhibition and impulsivity), whilst specific domains of language impairment (sentence comprehension and agrammatism) were more frequently seen in ALS-FTD patients. A number of behavioural symptoms (such as apathy, affect, insight, repetitive behaviours) as well as all neuropsychiatric features were non-discriminatory, occurring at similar frequencies in both cohorts.

This JNNP article introduces the possibility of distinct cognitive profiles in ALS-bvFTD and pure bvFTD. Although less common, language impairment has previously been reported in the ALS and ALS-FTD literature, and the two language domains highlighted in this study were comparatively uncommon in the bvFTD group. Although the retrospective nature of this analysis confers possible methodological bias, the potential for this group distinction has relevant considerations, particularly to identify patients at risk of a crossed phenotype. As also suggested by the authors however, clarification of such differences is needed through further prospective analysis. The clinical clues provided in this interesting study pave the way for future analysis, which has the potential for significant clinical impact and more targeted patient management and treatment.

Anti-neurofascin-155 antibodies: dissecting peripheral nerve abnormalities in CIDP

20 Jun, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the June JNNP issue, Koike and colleagues have reported the morphological changes in sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who have autoantibodies against paranodal structures.

CIDP is an immune-mediated neuropathy that develops over 8 week, which manifests with progressive proximal and distal weakness and is associated with sensory disturbances. Clinically, CIDP encompasses a heterogeneous group of subtypes, including MADSAM, DADS, pure sensory CIDP, pure motor CIDP and more focal forms. In addition, treatment responses are varied, suggesting that the pathophysiological mechanisms involved in the disease are diverse. In recent years, the discovery of particular autoantibodies against nerve and glial structures has revolutionized the field.

In this study, the authors studied the morphological characteristics of sural nerve biopsies using light and electron microscopy techniques in 9 patients with CIDP how had anti-neurofascin-155 and 1 patient with anti-contactin-1 antibodies. The results were compared with 13 patients with CIDP who did not have autoantibodies. In the patients with anti-neurofascin-155 antibodies, the authors found a reduction in myelinated fibre density, without macrophage-mediated demyelination or onion bulbs. Segmental demyelination was also found in patients with large axonal degeneration. Moreover, electron microscopy of longitudinal sections showed detachment of the terminal myelin loop from the axonal membrane (figure 1), a finding that correlated with axonal degeneration.


Figure 1. CIDP with anti-neurofascin-155 antibodies. (A) Electron microscopy finding in longitudinal sections from patients with anti-neurofascin-155 antibodies. Large spaces were observed between the terminal loops and the axolemma (arrows). (B) Antibodies against NF155 disrupt paranodal morphology; NF155, neurofascin-155.










Myelinated peripheral nervous system fibres are divided into four compartments: (i) nodes, (ii) paranodes, (iii) juxtaparanodes and (iv) internodes. Each has a specific function in nerve physiology, essential for the safety of action potential propagation. Neurofascin-155 is expressed on the myelin side of the paranode and is attached to contactin-1 (axonal membrane), which is critical for axonal-Schwann cell interaction. The paranode compartment works as an isolator, which is crucial for saltatory conduction. From a pathological point of view, these autoantibodies produce detachment of myelin terminal loops, generating a leak in current and conduction failure, and secondary axonal degeneration. The morphological characterization of CIDP patients with anti-neurofascin-155 antibodies is a crucial step in the understanding of this complex disease and for future development of targeted treatments. Patients with such autoantibodies are known to display particular clinical features, such us sensory ataxia and tremor, and have a poor response to IVIg treatment. These peripheral neuropathies that compromise primarily the nodal and paranodal regions have recently been called “nodopathy”, a novel concept, that allows the classification of this unique group of patients. Further studies should be focused in development of optimal treatments to avoid axonal degeneration due to axo-glial disjunction.


As such, this is a very interesting study, which provides valuable insights into the pathophysiology of CIDP with autoantibodies against paranodal structures.







Corpus callosum dysfunction in ALS: more than just connecting two sides

2 Jun, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the May JNNP issue, Zhang and colleagues have published a study investigating the changes in structural and functional connectivity in patients with ALS.

ALS is one of the most complex neurodegenerative diseases, which affects the motor system. It is characterized by concomitant degeneration of the upper and lower motor neurons, producing progressive weakness and muscle atrophy. Even though it was initially conceived that just the motor cortex and anterior horn cells were affected, in recent years substantial evidence supports the compromise of extra-motor brain structures, such us the corpus callosum (CC).


In this study, the authors have explored interhemispheric connectivity in 38 patients with ALS and 35 controls using diffusion tensor imaging (DTI) and resting state functional MRI (rfMRI). Indices of interhemispheric structural and functional neural connectivity were compared between groups. The rfMRI revealed a reduction in homotopic connectivity in ALS patients, specifically between the precentral and postcentral gyrus, the paracentral lobule, the superior temporal gyrus, the middle cingulate gyrus, the putamen and the superior parietal lobule, suggesting an extensive dysfunction in interhemispheric functional connectivity. In addition, DTI analysis in ALS patients showed a reduction in structural connectivity through the CC, specifically affecting subregions II, III and V. Finally, the combination of structural and functional data suggest that the central motor cortical interhemispheric fibres were the most affected in ALS.


Abnormal interhemispheric homotopic connectivity in ALS


This interesting article extends and confirms previous results that suggest dysfunction in interhemispheric communication, proposing a preferential involvement of the CC in ALS. Previous DTI studies in ALS have shown a reduction on fractional anisotropy in the CC extending to the primary motor cortex. On the other hand, electrophysiological studies have also supported the compromise of the CC. Specifically, transcranial magnetic stimulation (TMS) has provided evidence of functional impairment of the CC, showing a reduction in the interhemispheric inhibition. Clinically, a typical feature of ALS is focal clinical onset and regional spreading of neuronal degeneration. These clinical features indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation, such as prions. Interestingly, TDP-43, the major pathological protein in ALS, forms insoluble fibrillar aggregates in vitro and theoretically can act as seeds to trigger the aggregation of native proteins. This cumulative evidence allows us to question the contribution of the CC in spreading of disease and its potential use as a therapeutic target in the future.








Prognostic factors in C9orf72 ALS: the battle of genders?

28 Mar, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


The C9orf72 hexanucleotide repeat expansion has been defined as the main genetic factor in amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (FTD) continuum. Clinically, the C9orf72-related ALS cases have several distinct features including an earlier age of onset, reduced survival, higher prevalence of bulbar onset and dementia, contributing to the broad clinical variability in this group of patients.

In the current issue of JNNP, Rooney and colleagues contribute to the understanding of the prognostic factors associated with the C9orf72 mutation. The authors investigated the prognostic impact of C9orf72 in European ALS patients and its interactions with demographic features such as age, gender, and site of onset. In summary, C9orf72 status and demographic/clinical data from 4925 ALS patients were analyzed using flexible parametric survival models that included the already known prognostic factors (age, diagnostic delay, and site of onset), gender and C9orf72 status. The meta-analysis of C9orf72 status estimated a survival hazard ratio (HR) of 1.36 (1.18 – 1.57). Models analysis demonstrated that males with spinal onset diseases were driving the reduced survival seen in patients with this mutation.


Spinal-onset disease in male patients drives the poor survival in a large population of C9orf72 ALS patients


This study is the largest combined analysis of the prognostic features of C9orf72 ALS. Regarding gender effect on survival, it is well known that the incidence and prevalence of ALS is higher in males (male: female ratio 3:2), with a greater likelihood of earlier disease onset and spinal onset. Moreover, it has been reported that male transgenic SOD1 mice have reduced survival in comparison with female littermates, suggesting differential motor neurone vulnerability determined by gender. Even though the exact mechanics of this difference is not well understood, a recent study suggests that mitochondrial dysfunction is expressed earlier in male compared to female mice, probably attributable to oestrogen levels. Without any doubt, the definition of prognostic factors associated with the C9orf72 mutation is not trivial given the advances in molecular biology and genetics, as well as their impact on the development of future targeted therapeutic strategies. This information is highly relevant for the design of future clinical trials, particularly in the C9orf72 ALS population.









Immunomodulatory therapy modulates progression in advanced multiple sclerosis

5 Mar, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the current issue of JNNP, Lizak and colleagues have published an interesting epidemiological study based on global multiple sclerosis (MS) database (MSBase), to evaluate prognostic factors in moderately advanced and advanced MS, specifically the impact of highly active immunomodulatory therapy. Using prospectively collected data from over 4000 patients with MS, the cohort was divided into three epochs between EDSS steps 3-6, 4-6 and 6-6.5 respectively. A multivariate survival model was used to examine the role of immunomodulatory therapy and clinical/demographic variables on progression to the outcome EDSS step 6/6.5. In summary, the disability trajectories showed large variability. The probability to reach the outcome was not associated with baseline variables, suggesting that previous disease activity before progress into advanced stages does not have a significant impact on later disease progression. However, higher relapsed rate was associated with disability. Additionally, highly active immunomodulatory therapy was associated with lower risk of reaching the outcome disability step. The authors conclude that disease progression in moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time with active immunomodulatory therapy are associated with decreased risk of accumulating further disability.


Highly active immunomodulatory therapy may delay disability in moderately advanced and advanced multiple sclerosis


In the last decade, we have seen significant advances in our understanding of MS, together with a rapid rate of progress in developing new effective disease modifying drugs. All these advances have reduced the levels of disability in comparison to patients who developed the condition decades ago. Although active immunomodulatory therapy has been proven to prevent relapses and reduce first disability progression, their effect in accumulative disability remains undefined. Moreover, the hypothesis of two possible MS pathophysiological phases, the first one dominated by an autoimmune inflammatory process and the second one driven by neurodegenerative mechanisms, which may be independent of each other, have suggested that the immunomodulatory therapy is not effective in advanced MS stages. However, the results of the study propose that highly active immunomodulatory therapy may delay disability in advanced MS, bringing hope to MS patients in this disease stage. Therefore, further randomized controlled trials are needed to evaluate the efficacy of these treatments during advanced disease stages. In the meantime, MS management needs to focus on optimizing clinical vigilance of progression and consider drug therapy modification in patients with incomplete responses.






Doxycycline: bringing hope for early sporadic Creutzfeldt-Jakob disease patients

31 Jan, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the current issue of JNNP, Varges and colleagues have published a randomized control trial (RCT) phase II comparing doxycycline versus placebo in early sporadic Creutzfeldt-Jakob disease (sCJD).

CJD is a fatal and heterogeneous neurodegenerative disease caused by the misfolding and aggregation of prions. Clinically, CJD is characterized by rapidly progressive cognitive impairment associated with motor dysfunction (e.g. ataxia and tremor), with an average survival time of 4 – 6 months. Even though tremendous advances have been achieved in the comprehension of this disease, clinical trials including a previous trial of doxycycline have not yet been successful.

In this study, the authors report results of an RCT as well as an observational study assessing the use of doxycycline in early stages of sCJD. In the RCT, seven patients in the treatment group were compared with five patients on placebo, with no significant differences in survival. In the observational study, 55 patients with sCJD who received compassionate treatment with doxycycline were compared with historical control subjects. The treatment group showed a significantly longer survival, a difference that was driven by the differential effect of the codon 129 genotype status (methionine/methionine). Subsequently, combined data from both studies in a random-effects meta-analysis showed a slight increase in survival time for the doxycycline treatment group (HR = 0.63 (95% CI 0.401 to 0.999)).


Prion disease and doxycycline. Doxycycline was reported as an antiprion agent in different experimental models. In this study the combined data from a RCT and an observational study of early sCJD patients treated with doxycycline showed a slight increase in survival time in the doxycycline treatment group.


This recent JNNP article shows us the many barriers to conducting clinical trials in CJD patients, including the small sample size, genetic heterogeneity, problems with patient recruitment during the early stages of the disease, together with difficulties in follow-up given the rapid neurological deterioration. Despite the possible methodological bias of this article, there are two clear lessons to highlight: i) early treatment in sCDJ should increase the likelihood of better survival outcome and ii) doxycycline may have a differential therapeutic effect related with the specific molecular subtypes of sCJD. Regarding the early diagnosis of sCDJ patients, the combination of clinical and paraclinical tools, together with the use of novel biomarker such us ultrasensitive seeding assays based on the amplification and detection of prions (e.g. RT-QuIC), may optimize the early diagnoses and the design of future clinical trials. Finally, as also suggested by the authors, a larger RCT of doxycycline use in early sCDJ should be tested.


This is an interesting study, which provides valuable insights into the challenges and future direction of clinical trials in CJD patients.





How can we diagnose Susac syndrome?

28 Nov, 16 | by Dr Jose Manuel Matamala, JNNP web editor.


In the current issue of JNNP, Kleffner and colleagues have published the first diagnostic criteria for diagnosing Susac syndrome based on clinical and paraclinical findings.

Susac syndrome is an uncommon disease characterized by the present of encephalopathy with or without focal neurological signs, branch retinal artery occlusion and neuro-sensorial hearing loss. Even though this clinical triad had been considered pathognomonic, only 13% of the patients presented at disease onset. The infrequent and clinically incomplete presentation of this syndrome usually leads to misdiagnosis, often diagnosed and treated as multiple sclerosis, therapy which may exacerbate Susac syndrome.

In this study, the interdisciplinary experts of the European Susac Consortium (EuSac) team have established a new diagnostic criteria for Susac syndrome based on a three steps process: (i) definition of a reference group of patients with Susac syndrome, (ii) selection of new diagnostic criteria based on the clinical and paraclinical findings (brain MRI, ophthalmological and vestibulocochlear tests) on the reference group and on the available literature cases and (iii) validation of the proposed criteria in a cohort of possible Susac syndrome (reported until 2012). After definition of the diagnostic criteria, more than 90% of Susac syndrome cases reported in the literature fulfilled the proposed criteria of probable or definitive, and 56% filled the criteria for definitive Susac syndrome. The authors conclude that these new criteria may help clinicians to make an earlier, accurate diagnosis of Susac syndrome, preventing the delay of treatment initiation.


The new diagnosis criteria for Susac syndrome. The new criteria are based on the presence of clinical and paraclinical evidence of involvement of the three main affected systems: (i) brain involvement (clinical findings + imaging), (ii) retinal involvement based on ophthalmological examination, and (iii) vestibulocochlear involvement (clinical findings + examination of inner ear function).

The new diagnosis criteria for Susac syndrome. The new criteria are based on the presence of clinical and paraclinical evidence of involvement of the three main affected systems: (i) brain involvement (clinical findings + imaging), (ii) retinal involvement based on ophthalmological examination, and (iii) vestibulocochlear involvement (clinical findings + examination of inner ear function).


The Susac syndrome was first described by John O. Susac in 1979 in two young women with the classic clinical triad. Since then exciting advances have been achieved regarding the clinical and paraclinical characterization of the syndrome and the pathophysiological mechanisms of the disease. Nowadays this syndrome is considered an autoimmune microangiopathy, affecting the precapillary arterioles of the brain, retina, and inner ear. Given the complexity of this syndrome, the creation of formal diagnostic criteria is relevant to improve the diagnostic process. These new criteria also emphasize the necessity of a multidisciplinary approach that includes the combined work of neurologists, neuroradiologists, ophthalmologists and otorhinolaryngologists. Although the primary pathogenic anti-antibody is yet to be discovered, precise immunosuppressive therapy results in significant clinical and radiological improvement, delaying disease progression and neurological disability. Further studies are needed to evaluate the use of these criteria prospectively. However in the meantime these criteria may aid the diagnostic process of patients with suspected Susac syndrome.


As such, this is a very interesting study, which provides valuable insights into the diagnosis of Susac syndrome.






Central autoimmune channelopathies: a link between Neurology and Psychiatry

31 Oct, 16 | by Dr Jose Manuel Matamala, JNNP web editor.


Since the recognition of antibodies against voltage – gated potassium channel (VGKC) and their pathogenic implication in central nervous system disorders (such as limbic encephalitis) in 2001, critical immunological and neurological advances have been achieved during the last 15 years. One of the main discoveries has been that these VGKC antibodies usually target proteins outside of the channel protein, which are part of the VGKC complex (e.g. contactin-associated protein 2). Moreover, each specific antibody is associated with distinct clinical phenotypes, which commonly overlap.

Clinically the primary neurological syndrome associated with VGKC antibodies is limbic encephalitis, classically presenting with severe memory impairment and secondary hippocampal atrophy. However, recently emerging psychiatric syndromes have been linked to this autoimmune condition.

In the current issue of JNNP, Prüss and Lennox have published a review describing novel psychiatric syndromes associated with VGKC complex antibodies. In the review, the authors described the recent highlights about the pattern of cognitive involvement and reversibility of memory dysfunction in limbic encephalitis, response to treatment with immunotherapy, immunology of VGKC complex antibodies and the relevance of the titre levels, and mood and psychotic disorders associated with VGKC complex antibodies.


Emerging psychiatric syndromes associated with VGKC complex antibodies. Psychiatric symptoms are frequently present in patients with limbic encephalitis secondary to VGKC complex antibodies. However, its role in psychiatric diseases is not well understood.

Emerging psychiatric syndromes associated with VGKC complex antibodies. Psychiatric symptoms are frequently present in patients with limbic encephalitis secondary to VGKC complex antibodies. However, its role in psychiatric diseases is not well understood.


Although, evidence regarding the pathogenic role of VGKC complex antibodies in psychiatric conditions is missing and many questions remain to be answered in this field, it is important that neurologists and psychiatrists combine their expertise to gain a better comprehension of this neuropsychiatric disorder. It is relevant for neurologists to be aware of psychiatric manifestations associated with autoimmune channelopathies and for psychiatrists to keep in mind that VGKC complex antibodies could be part of the differential diagnosis in patients with atypical psychiatric manifestations and autoimmune features.





Melatonin an effective alternative for migraine prevention

7 Oct, 16 | by Dr Jose Manuel Matamala, JNNP web editor.


In the current issue of JNNP, Gonçalves and colleagues have published a randomized control trial (RCT) comparing melatonin, amitriptyline and placebo for migraine prevention.

Migraine is a chronic neurological disease and has been ranked as the sixth disabling condition by World Health Organization (WHO). The goals of migraine prophylaxis are to reduce migraine attacks, limit the need for analgesic intake and improve the quality of life. However, despite the different pharmacological treatments available, only a small fraction of patients receive adequate preventive treatment, which amongst other reasons is related to unfavourable drug security profile.

In this study, after randomizing 196 patients into melatonin (3 mg), amitriptyline (25 mg) or placebo (randomization ratio 1:1:1) and following up for 12 weeks, the authors reported a significant reduction in the number of migraine headache days per month with melatonin or amitriptyline versus placebo. Even though melatonin and amitriptyline were equally effective for the primary endpoint, the number of patients with greater than 50% reduction in migraine headache days was significantly higher in the melatonin group. Moreover, the number of adverse effects was also significantly lower in this group compared with amitriptyline. These results support the efficacy and tolerability of melatonin as a prophylaxis therapy for migraine.

Melatonin a new therapeutic option for the treatment of migraine patients

Melatonin a new therapeutic option for the treatment of migraine patients


Melatonin is a hormone produced mainly in the pineal gland, and it plays an essential role as an endogenous synchronizer of internal circadian rhythms. Melatonin has demonstrated efficacy and safety in the treatment of nociceptive and neuropathic pain in several studies. Specifically in migraine, melatonin receptors have been described in the nuclei of the trigeminal nerve, suggesting that may decrease trigeminovascular nociception. Moreover, melatonin levels have been described to be reduced in migraine patients. Regarding the security profile, melatonin is remarkably well tolerated and it only has minor side effects such as daytime sleepiness, dizziness, and stomach pain. These features make melatonin a good candidate for migraine prophylaxis.


In short, this is an interesting article that has clear and immediate clinical application.





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