Chronic Tension-type Headache with Vitamin D Deficiency: Casual or Causal Association?

Sanjay Prakash, DM; Nilima D. Shah, MD

Disclosures

Headache. 2009;49(8):1214-1222. 

In This Article

Discussion

The second edition of International Classification of Headache Disorders (ICHD-II) classifies TTH on the basis of frequency into 3 divisions: infrequent episodic tension-type headache (IETTH), frequent episodic tension-type headache (FETTH), and CTTH. CTTH is defined as occurrence of TTH on 15 or more days per month (on average) for more than 3 months.[5] All of the cases fulfilled the ICHD-II criteria of CTTH. None of these patients were suffering from analgesic rebound headache. In parallel, all the patients were diagnosed as suffering from vitamin D deficiency (osteomalacia). All patients had a low vitamin D level, raised PTH, and low or low normal calcium and phosphorus. Twenty-four-hour urinary excretion was not done because of the technical difficulties. Most experts have defined vitamin D deficiency as a serum 25-hydroxy vitamin D level of less than 20 ng per milliliter.[3] All of the patients had 25(OH) D level ≤10 ng. PTH is considered as the best marker of underlying histological osteomalacia.[6] EMG showed myopathic abnormalities in all the patients.

Vitamin D deficiency is associated with a number of diseases. However, its relation with headache has not been explored in the literature. Thys Jacobs has reported dramatic reduction in the frequency and duration of migraine headache in two post menopausal women with vitamin D and calcium supplementation.[7] Recently, Wheeler reported vitamin D deficiency in 40% of patients with migraine.[8] It is difficult to associate a causal relation of vitamin D deficiency with migraine as treatment and follow up is lacking (published in abstract form). Plotnikoff et al in their 150 patients with persistent nonspecific musculoskeletal pain reported a 35-year-old woman who had headache with musculoskeletal pain and undetectable 25-hydroxy vitamin D in serum.[9]

Rickets (in children) and osteomalacia (in adult) are the most common manifestations of vitamin D deficiency. Osteomalacia commonly presents with easy fatigability, muscle aches, bone pain, and muscle weakness.[3,4] Osteomalacia (vitamin D def.) is usually a under recognized condition. Nonspecific symptoms of osteomalacia are usually not volunteered by the patients. Five of the patients (case 2, 4, 6, 7, 8) presented with the complaint of headache. However, on direct questioning these patients admitted having features suggestive of osteomalacia. Two of these patients (cases 6 and 8) denied the presence of weakness. However, proximal muscle weakness was demonstrated during examinations. The presenting complaint in case 3 was suggestive of osteomalacia (confirmed by investigations). On direct questioning this patient admitted having headache that fulfilled the criteria of CTTH. Cases 1 and 5 initially presented with headache (CTTH) that poorly responded to conventional therapy of CTTH. Later on these 2 patients developed features suggestive of osteomalacia.

The clinical features suggestive of osteomalacia have a long clinical differential diagnosis. It is considered as a very rare disease for generalized pain syndrome.[10] However, various observation/studies in the recent past demonstrated that vitamin D deficiency may be one of the common causes for body pain. Plotnikoff et al in a cross-sectional study demonstrated deficiency of vitamin D in all observed patients (150 patients) presenting with persistent and nonspecific musculoskeletal pain. Five patients had immeasurable vitamin D level. In none of them was osteomalacia suspected despite extensive contact with the health care system.[9] Al Faraz et al studied the contribution of vitamin D level in 360 patients presenting with low back pain with no obvious cause. They noted abnormally low level of vitamin D in 83% patients. Clinical improvement in symptoms was noted in 95% with vitamin D supplementation.[11] Two other studies have demonstrated low vitamin D level in patients with generalized body pain in women.[12,13] Few other case series have demonstrated similar association of muscle pain with low vitamin D level.[14,15] These observations/studies demonstrate that high prevalence of vitamin D deficiency exists in the patients with musculoskeletal symptoms, although a few conflicting results are also reported in the literature.[16,17] Other causes of body pain were excluded by careful history, detailed neurological examinations, and appropriate investigations.

Headache and musculoskeletal pain rank among the most common complaints in the general population. The prevalence of TTH usually varies between 16% and 39% (may be up to 72%). However, the prevalence of CTTH is usually 3–4%.[18] The usual prevalence of chronic musculoskeletal pain is 23–36% (may be up to 55%).[19] Systematic studies on the inter-relation of headache and musculoskeletal pain are lacking in the literature. As the prevalence of both symptoms is very high in the general population, a few percent of the general population are expected to have both by pure coincidence. However, Hagen et al reported the prevalence of chronic headache 4 times greater in individual with chronic musculoskeletal symptoms than in those without.[20] It indicates that the association of headache with musculoskeletal symptoms is more than just a chance. The associations of headache with musculoskeletal symptoms increased with increasing frequency of headache episodes.[20] It may suggest both have a common cause or a common pathogenesis.

The very high prevalence of TTH, generalized muscle pain syndrome, and vitamin D deficiency in the general population may indicate that some inter-relation exist among these 3 facts. The study on prevalence of vitamin D inadequacy among patients with chronic pain is limited in the literature. A recent study demonstrates 26% prevalence of vitamin D inadequacy among patients with chronic pain.[21] However, the prevalence of vitamin D deficiency may be 80–100% in some special groups of patients with chronic skeletal muscle pain.[9,11] In a study of 360 patients with low back pain in Saudi Arabia, the prevalence was more than 80%. However, patients with mechanical source for low back pain were excluded from the study.[11] The high prevalence of vitamin D inadequacy in patients with generalized muscle pain does not indicate its relation with headache. However, such high prevalence of vitamin D inadequacy in patients with chronic pain further strengthens the view that an inter-relation probably exists among TTH, generalized muscle pain syndrome, and vitamin D deficiency.[9,11]

Another common comorbid condition in the patients with TTH (especially CTTH) and musculoskeletal pain is psychiatry disorders (depression, anxiety, etc).[22] Depression is known to produce increased muscle tension (hence secondarily increased TTH). However, psychiatry symptoms in isolation (not with headache or musculoskeletal symptoms) are known to be associated with decreased bone marrow density, decreased 25-hydroxy vitamin D, and increased PTH level.[23,24] These observations suggest that a subset of the patients of CTTH and/or musculoskeletal symptoms with psychiatry symptoms may be causally related to vitamin D deficiency.

Vitamin D level is known to be lower during winter.[25] Incidence of depression and musculoskeletal symptoms are more common in the winter, and it is supposed to be because of low vitamin D level. Response of depression to phototherapy reinforces this view.[26] However, the literature is silent regarding the effect of season on the incidence and prevalence of TTH/CTTH. Marrelli et al studied the seasonal and metrological factors in primary headaches (classic migraine, common migraine, tension headache, and mixed headache). The overall frequency of headaches (including tension headache) was maximum during winter and least in summer. The frequency of migraine was more in spring and autumn. The authors did not discuss the relative frequency of tension headache in relation to weather. However, a graph provided by them showed marked increase in the frequency of tension headache during winter.[27] It supports the view that a subset of the patients with TTH is causally related to vitamin D deficiency or at least an overlap of osteomalacia exists with TTH.

Antidepressants are the most widely used first-line prophylactic therapy for CTTH (and musculoskeletal pain). The mode of action of antidepressants in CTTH remains to be determined. The response of various antidepressants in the patients with CTTH is variable. The different response of antidepressant in the patients with CTTH suggests that multiple mechanisms are responsible for the pathogenesis of TTH. The effects on CTTH are probably independent from their antidepressant effects.[2] A few antidepressants (including tricyclic antidepressants, selective serotonin reuptake inhibitors, or selective serotonin/norepinephrine reuptake inhibitors) may produce analgesic effects through reduction of central sensitization in combination with a peripheral antinociceptive action.[28] There is a suggestion that vitamin D and PTH status may be improved indirectly by adequate antidepressants in patients with depression because of increased food intake and physical activity.[24] Chronic low back pain (where depression is a common comorbid state) probably at least partly responds to antidepressants because of improved vitamin D and PTH level. We suggest that a subset of the patients with CTTH who show response to antidepressants may be due to improved vitamin D and PTH status because of improved food intake and (outdoor) physical activity.

The prevalence of vitamin D deficiency is common even in healthy/asymptomatic individuals.[3,4] Therefore, the possibility of coincidence of vitamin D deficiency with any disease cannot be ruled out completely. The possibility of casual relation of vitamin D deficiency and headache remains open in the patients. However, no (or minimal) response to previously used drugs and almost complete response to vitamin D supplementation in a few weeks suggest that vitamin D deficiency was pivotal in generating the headache. The supplementation of vitamin D can be given in a daily, weekly, or monthly dosing schedule. However, daily therapy seems to be more effective than less frequent dosing.[29] Long-standing vitamin D deficiency results in hypocalcemia. All the patients had low or low normal serum calcium. Vitamin D should always be repleted in conjunction with calcium supplementation,[30] and we gave calcium in addition to vitamin D to all 8 patients.

As the patients received both vitamin D and calcium simultaneously, we cannot rule out the possibility of role of calcium in suppression of headache. Normocalcemia is usually observed within 1 week of institution of therapy.[30] However, response in headache was noted after a few weeks of initiation of therapy. It suggests that vitamin D was probably more vital (than calcium) in relieving the headaches.

Pathogenesis

It is difficult to speculate the mechanisms of TTH due to deficiency of vitamin D as current information of the pathophysiology of CTTH and mechanisms of muscle pain due to vitamin D deficiency is limited.

The pathophysiology of TTH is multifactorial. Both peripheral and central sensitizations play a role for initiation and maintenance of TTH. Peripheral mechanisms probably have a role in IETTH and FETTH, whereas central sensitization is predominantly responsible in chronic pain. Persistent peripheral sensitization in active myofascial trigger points (TrPs) leads to sensitization of second order nociceptive neurons in the spinal trigeminal nucleus and third order neurons in the thalamus. Second order neurons receive information from face and scalp, third order neurons from the whole body. Therefore, spontaneous body pain and abnormal pressure thresholds are reported at many extracephalic sites (upper limb, LL, paravertebral muscles, etc).[1,31]

The exact cause of musculoskeletal pain due to vitamin D deficiency is unknown. It is postulated that there is swollen deposition of collagen rich osteoid on the periosteal surface of the skeleton. This swelling puts outward pressure on the periosteal covering that is innervated with sensory pain fibers (nociceptors). This is the likely explanation of bone pain in the patients with osteomalacia.[4,25] However, the mechanisms of muscle weakness, muscle aches, and muscle tenderness in the patients with vitamin D deficiency have not been explored in the literature. The relation of muscular symptoms to the concomitant bone pathology is difficult to pinpoint.[32] There is some evidence that vitamin D deficiency and excess PTH may impair muscle functions. Calcium and phosphate levels do not seem to correlate with the existence or severity of the myopathy.[32] Vitamin D deficiency leads to type II muscle atrophy, which may create a mechanical stress on the remaining muscle. Recent studies have demonstrated that the pathogenesis of TrPs could result from injured or overloaded muscles.[31] Therefore, the possibility TrPs formation because of the osteomalacic myopathy (hence central sensitization and referred pain) remains open in the patients. However, almost complete cessation of symptoms after vitamin D therapy indicates that the muscle atrophy may not be the main mechanism for muscle aches and/or central sensitization (as atrophied muscle fibers are less likely to show regeneration). We speculate that persistent stimulation of nociceptors of periosteal covering (because of swollen osteoid) may sensitize the second and third order neurons (a proposed mechanism for pain and increased hypersensitivity in the patients with CTTH). This may be the main mechanism for headache and pain in the muscle.

As sensitization of second order neuron (from head and face) precedes the sensitization of third order neuron (extracephalic body part), headache may be more prominent or may precede the body pain (not bone tenderness, as it does not depend on sensitization). All cases (except case 3) support this view. With these mechanisms we expect suppression of the continuous irritation of nociceptors (ie, suppression of central sensitization or relief in headache and muscle pain) before the subsidence of bone tenderness and muscle weakness. All the 8 patients had improvement on headache and muscle pain much earlier than the improvement of bone tenderness and muscle weakness. This indirectly suggests that central sensitization (because of swollen osteoid) was probably the main mechanism for the development of headache and body pain.

Another possible mechanism of headache in the patients with vitamin D deficiency may be because of hypomagnesemia. Abnormal magnesium (Mg) metabolism is also implicated in the pathogenesis of TTH. Low Mg has been demonstrated in brain, blood, erythrocyte, monocyte, and platelet in the patients with TTH (and other headache). About 40–50% patients with TTH have low serum Mg. Almost similar percentage of the patients with TTH has demonstrated response to Mg therapy in various studies.[33] Absorption of dietary Mg through intestine depends on vitamin D [1, 25 (OH) D].[30] Therefore, vitamin D deficiency may cause TTH through limiting the absorption of Mg.

These case reports, association of various comorbid states of TTH/CTTH with vitamin D deficiency in isolated form, and speculation of possible pathogenesis of vitamin D deficiency with headache and body pain suggest that a subset of patients with TTH/CTTH may be causally related to vitamin D deficiency (ie, TTH with vitamin D deficiency). However, a possibility of new type of secondary headache or coexistence of TTH with secondary headache also exists as almost complete improvement of headache occurs only after vitamin D supplementation. Further investigations (especially on the epidemiology and pathogenesis) of TTH and vitamin D deficiency are warranted to establish the inter-relations of headache and vitamin D deficiency. We suggest that every patient with CTTH should be asked about or examined for muscle aches, weakness (especially proximal), and bone tenderness. We hope these case reports may serve as a catalyst for further investigations to clarify the issue.

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