Headaches In Multiple Sclerosis

  1. Prevalence of primary headaches in people with Multiple Sclerosis
    Cephalalgia 2004 Nov;24(11):980-4

  2. Headache and Inflammatory Disorders of the Central Nervous System
    Neurol Sci 2004 Oct;25 Suppl 3:S148-53

  3. Interferon-ß but not Glatiramer Acetate therapy aggravates headaches in MS
    Neurology 2002 Aug 27;59(4):636-9

  4. Acetaminophen, Aspirin and Caffeine alleviate Migraine Headache Pain
    Arch Neurol 1998;55:210-217February 1998

  5. Mirtazapine is effective in the prophylactic treatment of chronic Tension-Type Headache
    Neurology 2004;62:1706-1711

  6. The association of BrainStem lesions with Migraine-like Headache: an imaging study of Multiple Sclerosis
    Headache 2005 Jun;45(6):670-7

  7. Assessment of MRI abnormalities of the BrainStem from patients with Migraine and Multiple Sclerosis
    J Neurol Sci 2006 May 15;244(1-2):137-41

  8. Brain Gray Matter changes in Migraine patients with T2-visible lesions: a 3-T MRI study
    Stroke 2006 Jul;37(7):1765-70


Prevalence Of Primary Headaches In People With Multiple Sclerosis

D'Amico D, La Mantia L, Rigamonti A, Usai S, Mascoli N, Milanese C, Bussone G
Cephalalgia 2004 Nov;24(11):980-4
C. Besta National Neurological Institute, Milan, Italy
PMID# 15482362

The aim was to investigate the lifetime prevalence of Headache and primary Headache (diagnoses according to International Headache Society criteria) in Multiple Sclerosis (MS).

The relationships between Headache and clinical features of MS and MS therapy were also investigated. We studied 137 patients with Clinically Definite MS; 88 reported Headache, 21 of whom developed Headache after the initiation of Interferon.

The prevalence of all Headaches in the remaining 116 patients was 57.7%. Migraine was found in 25.0%, tension-type Headache in 31.9%, and cluster Headache in one patient.

A significant correlation (P = 0.007, Fisher's exact test) between Migraine and Relapsing/Remitting MS was found. Primary Headaches are common in MS patients.

Further studies are needed to clarify the mechanisms underlying this association, particularly the association between Migraine and Relapsing-/Remitting MS, and the role of Interferon in the development of new Headache.


Headache And Inflammatory Disorders Of The Central Nervous System

La Mantia L, Erbetta A
Neurol Sci 2004 Oct;25 Suppl 3:S148-53
National Neurological Institute C. Besta, MS Centre, Via Celoria 11, I-20133 Milan, Italy
PMID# 15549526

The subcommittee of the International Headache Society for Headache classification (ICHD-II) has recently recognized that secondary Headaches may occur in patients affected by inflammatory diseases (ID) of the Central Nervous System (CNS).

Classifying them among the Headaches attributed to Non-Vascular IntraCranial Disorders.

The aim of the study was to verify the association between Headache and inflammatory non-infectious diseases of the CNS, by a review of the literature data on the topic, integrated by personal cases and data.

Secondary Headaches may occur in four main disorders: NeuroSarcoidosis (sec 7.3.1), Aseptic (non-infectious) Meningitis (7.3.2), other non-infectious ID (7.3.3) and Lymphocytic Hypophysitis (7.3.4).

Headache and/or primary Headaches are frequently reported in patients with NeuroSarcoidosis (30%), Behcet's Syndrome (BS) (55%) and acute Disseminated Encephalomyelitis (45-58%).

Recent data show a high incidence of Headache also in Multiple Sclerosis (MS) (58%) (not mentioned in ICHD-II).

The association between Headache and Inflammatory Dysimmune Diseases of the CNS, in particular BS and MS, might suggest a pathogenetic relationship.


Interferon-ß But Not Glatiramer Acetate Therapy Aggravates Headaches In MS

Pollmann W, Erasmus LP, Feneberg W, Bergh FT, Straube A
Neurology 2002 Aug 27;59(4):636-9
Marianne-Strauss-Klinik, Berg, Germany
PMID# 12196668

Type and frequency of Headaches during ImmunoModulatory Therapy in MS were determined in 167 consecutive patients.

In a prospective group of 65 patients beginning Interferon-ß therapy, Headache frequency and duration increased in 18% of all and in 35% of patients with pre-existing Headache by more than 50% during the first 6 months.

In two retrospective groups, increased Headache frequency was reported by 34% of 53 patients on Interferon-ß, but by only 6% of 49 patients during at least 6 months of Glatiramer Acetate therapy.


Acetaminophen, Aspirin & Caffeine Alleviate Migraine Headache Pain

Three Double-blind, Randomized, Placebo-Controlled Trials:
Arch Neurol 1998;55:210-217February 1998
Richard B. Lipton, MD; Walter F. Stewart, PhD, MPH; Robert E. Ryan, Jr, MD; Joel Saper, MD; Stephen Silberstein, MD; Fred Sheftell, MD

To assess the effectiveness of the nonprescription combination of Acetaminophen, Aspirin, and Caffeine in alleviating Migraine Headache pain.

Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies.

Private practice, referral centers, and general community.

Migraineurs with moderate or severe Headache pain who met International Headache Society diagnostic criteria for Migraine with Aura or without Aura.

The most severely disabled segment of Migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set.

Two tablets of the nonprescription combination of Acetaminophen, Aspirin, and Caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute Migraine attack.

Main Outcome Measures
Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none.

Significantly greater reductions in Migraine Headache pain intensity 1 to 6 hours after dose were seen in patients taking the Acetaminophen, Aspirin, and Caffeine combination than in those taking placebo in each of the 3 studies.

Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients (P< .001; 95% confidence interval [CI], 55%-63% for drug, 29%-37% for placebo).

At 6 hours after dose, 79% vs 52%, respectively, had pain reduced to mild or none (P< .001; 95% CI, 75%-82% vs 48%-56%).

In addition, by 6 hours after dose, 50.8% of the drug-treated patients were pain free compared with 23.5% of the placebo-treated patients (P< .001; 95% CI, 47%-55% for drug, 20%-27% for placebo).

Other Migraine Headache characteristics, such as Nausea, Photophobia, Phonophobia, and Functional Disability, were significantly improved 2 to 6 hours after treatment with the Acetaminophen, Aspirin, and Caffeine combination compared with placebo (P<.01).

The nonprescription combination of Acetaminophen, Aspirin, and Caffeine was highly effective for the treatment of Migraine Headache pain.

As well as for alleviating the Nausea, Photophobia, Phonophobia, and Functional Disability associated with Migraine attacks.

This drug combination also has an excellent safety profile and is well tolerated.


Mirtazapine Is Effective In The Prophylactic Treatment Of Chronic Tension-Type Headache

Bentsen L, Jensen R
Neurology 2004;62:1706-1711

PMID# 15546281

The Tricyclic AntiDepressant Amitriptyline is the only drug with prophylactic efficacy for chronic Tension-Type Headache.

However, Amitriptyline is only moderately effective, with Headache reduction of approximately 30%, and treatment is often hampered by side effects.

Mirtazapine is a relatively new so-called NorAdrenergic and specific Serotonergic AntiDepressant, which is more specific and therefore generally better tolerated.

To evaluate the efficacy of Mirtazapine.

Twenty-four nondepressed patients with chronic Tension-Type Headache were included in a randomized, double-blind, placebo-controlled, crossover trial.

All patients had tried numerous other treatments. Mirtazapine 15 to 30 mg/day or placebo was each given for 8 weeks separated by a 2-week wash-out period.

Twenty-two patients completed the study. The primary efficacy variable, area-under-the-Headache curve (AUC; duration x intensity), was lower during treatment with Mirtazapine (843) than during treatment with placebo (1275) (P= .01).

Mirtazapine also reduced the secondary efficacy variables Headache frequency (P= .005), Headache duration (P= .03), and Headache intensity (P= .03) and was well tolerated.

Mirtazapine reduced AUC by 34% more than placebo in difficult-to-treat patients.

This finding is clinically relevant and may stimulate the development of prophylactic treatments with increased efficacy and fewer side effects for Tension-Type Headache and other types of chronic pain.


The Association Of BrainStem Lesions With Migraine-Like Headache: An Imaging Study Of Multiple Sclerosis

Gee JR, Chang J, Dublin AB, Vijayan N
Headache 2005 Jun;45(6):670-7
University of California-Davis, Headache and Neurology Clinic, Davis, CA, USA
PMID# 15953299

To determine if the prevalence of Migraine-like Headache in patients with Multiple Sclerosis (MS) is associated with plaques in the BrainStem or in other locations.

There is increasing evidence to suggest that PeriAqueductal Gray Matter (PAG) plays a role in the pathophysiology of Migraine Headache. There are a few clinical case studies and some experimental evidence in support of this observation.

The study population of patients with DeMyelinating Disease was identified by accessing the Department of Radiology Magnetic Resonance Imaging (MRI) database accumulated between the years of December 1992 and June 2002.

A total of 4369 MRI scan reports were available for review from that time period. Out of this, 1533 studies were reported to have possible DeMyelinating lesions.

Medical records of these patients were reviewed to confirm the diagnosis of MS and also to document the Headache complaints, if any. Two hundred and seventy-seven patients were identified with definite MS.

A questionnaire was mailed to these patients to obtain additional details regarding MS and Headache. The questionnaire response rate was 61% (169 of 277).

This data were added to the information previously obtained from the medical records. The MRI films of each patient were examined, documenting location of the plaque, rather than the actual number.

MRI and clinical data were kept separate until the final analysis. The International Headache Society criteria were used to classify Headache types.

There were 207 female and 70 male patients available for analysis.

Sixty-six percent (182 of 277) of patients were diagnosed with Relapsing/Remitting MS, 17% (47 of 277) with Primary/Progressive MS, and 17% (48 of 277) with Secondary/Progressive MS.

Overall, 55.6% (154 of 277) of patients had a complaint of Headache.

Of these patients, 61.7% (95 of 154) met criteria for Migraine-like Headache, 25.3% (39 of 154) met criteria for Tension-type Headache, and 13% (20 of 154) had features of Migraine and Tension-type Headache.

MS patients with a plaque within the MidBrain/PeriAqueductal Gray Matter areas had a four-fold increase in Migraine-like Headaches (odds ratio 3.91, 95% confidence interval 2.01 to 7.32; P < .0001).

A 2.5-fold increase in Tension-type Headaches (odds ratio 2.58, 95% confidence interval 1.13 to 5.85; P= .02).

And, a 2.7-fold increase in combination of Migraine and Tension-type Headaches (odds ratio 2.77, 95% confidence interval 0.98 to 7.82; P= .05) when compared to MS patients without a MidBrain/PeriAqueductal Gray Matter lesion.

Although not statistically significant, MS patients with three or more lesion locations were found to be approximately two times more likely to have Migraine-like Headaches.

Compared to MS patients with 0 to 2 locations (3 to 5: odds ratio 2.47, 95% confidence interval 0.90 to 6.84; 6 to 8 locations: 1.82, 0.64 to 5.17; > or =9 locations: 2.41, 0.63 to 9.13).

A linear trend was also observed between numbers of lesion locations and Migraine-like Headaches (P= .02).

The results of this study indicate that the presence of a MidBrain plaque in patients with MS is associated with an increased likelihood of Headache with Migraine characteristics.

(Headache 2005;45:670-677).


Assessment Of MRI Abnormalities Of The BrainStem From Patients With Migraine And Multiple Sclerosis

Tortorella P, Rocca MA, Colombo B, Annovazzi P, Comi G, Filippi M
J Neurol Sci 2006 May 15;244(1-2):137-41
NeuroImaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Milan, Italy
PMID# 16530789

In patients with Migraine, functional changes have been described in the Red Nucleus (RN), Substantia Nigra (SN) and PeriAqueductal Gray Matter (PAG).

To evaluate whether and at which frequency these structures are involved by MRI-detectable structural abnormalities in Migraineurs and to investigate the pathogenic role of these abnormalities by assessing their frequency and extent in patients with Multiple Sclerosis (MS) and Migraine.

On Brain dual-echo scans obtained from 58 Migraineurs (40 without and 18 with Aura), 37 MS patients with Migraine without aura and 42 MS patients without Migraine.

The presence of HyperIntense lesions involving the BrainStem structures was recorded.

A test of heterogeneity between groups was used to compare the presence of lesions among patient groups.

Lesions of RN, SN and PAG were found in all patient groups, with frequency from 57.5% to 86.5%.

Significant between-group differences for all these regions were found. No difference was found between Migraine patients with and without Aura.

Compared with MS patients without Migraine, MS patients with Migraine had more significant involvement of the SN (p=0.02) and RN (p < 0.0001).

Compared with Migraine patients, MS patients with Migraine had more significant involvement of the SN and PAG (p ranging from 0.009 to 0.02).

T2-visible lesions in the BrainStem are frequent in patients with Migraine, but do not seem to be associated with the presence of Aura.

DeMyelinating lesions in the RN, SN and PAG might be among the factors responsible for the presence of Migraine in patients with MS.


Brain Gray Matter changes in Migraine patients with T2-visible lesions: a 3-T MRI study

Rocca MA, Ceccarelli A, Falini A, Colombo B, Tortorella P, Bernasconi L, Comi G, Scotti G, Filippi M
Stroke 2006 Jul;37(7):1765-70
NeuroImaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Milan, Italy
PMID# 16728687

Background And Purpose
In Migraine patients, functional imaging studies have shown changes in several Brain Gray Matter (GM) regions. However, 1.5-T MRI has failed to detect any structural abnormality of these regions.

We used a 3-T MRI scanner and Voxel-Based Morphometry (VBM) to assess whether GM density abnormalities can be seen in patients with Migraine with T2-visible abnormalities and to grade their extent.

In 16 Migraine patients with T2-visible abnormalities and 15 matched controls, we acquired a T2-weighted and a high-resolution T1-weighted sequence.

Lesion loads were measured on T2-weighted images.

An optimized version of VBM analysis was used to assess regional differences in GM densities on T1-weighted scans of patients versus controls.

Statistical parametric maps were thresholded at P<0.001, uncorrected for multiple comparisons.

Compared with controls, Migraine patients had areas of reduced GM density, mainly located in the Frontal and Temporal Lobes.

Conversely, patients showed increased periacqueductal GM (PAG) density.

Compared with patients without aura, Migraine patients with aura had increased density of the PAG and of the Dorsolateral Pons.

In Migraine patients, reduced GM density was strongly related to age, disease duration, and T2-visible lesion load (r ranging from -0.84 to -0.73).

Structural GM abnormalities can be detected in Migraine patients with Brain T2-visible lesions using VBM and a high-field MRI scanner.

Such GM changes comprise areas with reduced and increased density and are likely related to the pathological substrates associated with this disease.

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