The co-occurrence of multiple sclerosis and migraine headache: the serotoninergic link.

The occurrence of migraine headaches in patients with multiple sclerosis (MS) has been recognized for quite some time but the significance of this association to the pathogenesis of MS largely has been ignored. Several reports have documented that migraine headaches may occur during exacerbation of symptoms and may even herald the onset of relapse in MS. We present three MS patients in whom migraine headaches developed during a period of relapse. As migraine has been linked to changes in serotonin (5-HT) functions, the emergence of migraine headaches coincident with the onset of relapse implicates dysregulation of the 5-HT system in the pathophysiology of MS. This hypothesis is plausible considering the evidence that MS patients are serotonergically depleted and that 5-HT is involved in maintaining the integrity of the blood brain barrier, disruption of which is believed to occur in the initial stages of exacerbation of MS symptoms. Furthermore, this hypothesis may have potential therapeutic implications in the treatment of exacerbations of MS and possibly in the prevention of relapse in the disease.

The relationship of pineal calcification to cerebral atrophy on CT scan in multiple sclerosis.

Calcification is a known morphological feature of the pineal gland. The mechanisms underlying the development of pineal calcification (PC) are elusive although there is experimental evidence that calcification may be a marker of the past secretory activity of the gland and/or of degeneration. The increased incidence of PC with aging suggests that it may reflect cerebral degenerative changes as well. In a recent Editorial in this Journal it was proposed that the pineal gland is implicated in the pathogenesis of multiple sclerosis (MS). Cerebral atrophy, which can be demonstrated on CT scan, is a common feature of MS resulting from demyelination and gliosis. If PC is a marker of a cerebral degenerative process, then one would expect a higher incidence of calcification of the gland in patients with cerebral atrophy compared to those without cerebral atrophy. To test this hypothesis, we studied the incidence of PC on CT scan in a cohort of 48 MS patients, 21 of whom had cerebral atrophy. For the purpose of comparison, we also assessed the incidence of choroid plexus calcification (CPC) in relation to cerebral atrophy. PC was found in 42 patients (87.5%) and its incidence in patients with cerebral atrophy was significantly higher compared to the incidence in patients without cerebral atrophy (100% vs. 77.7%; p < .025). In contrast, CPC was unrelated to cerebral atrophy or to PC thus supporting the notion of a specific association between the pineal gland and the pathogenesis of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between melatonin secretion and serum cholesterol in patients with multiple sclerosis.

We have reported recently that nocturnal melatonin levels are reduced in a subgroup of patients with multiple sclerosis (MS). We have also noted in these patients a high incidence of hypercholesterolemia and propose that this may be linked to dysfunction of the pineal gland since pinealectomy in rats was reported to be associated with elevation of blood cholesterol levels. To test this hypothesis, we studied the relationship between nocturnal plasma melatonin levels and serum cholesterol levels in a cohort of 24 MS patients (4 men; 20 women; mean age: 40.2 years SD = 9.5) who were admitted to an inpatient neurologic clinic for acute exacerbation of symptoms. For the purpose of comparison we also evaluated in these patients the association between melatonin levels and serum triglyceride (TG) levels. As predicted, we found a significantly higher serum cholesterol level in 10 patients who had low nocturnal plasma melatonin levels (mean: 17.1 pg/ml +/- 5.9) compared to 14 patients in whom melatonin levels were in the normal range (mean: 42.9 pg/ml +/- 10.6) (mean cholesterol = 241.5 mg/dl +/- 50.8 vs. 183.7 mg/dl +/- 27.2; p < .001). In contrast, serum TG levels did not differ significantly between the groups. As serum cholesterol levels were statistically unrelated to TG levels, these findings suggest a specific association between pineal melatonin and cholesterol metabolism. If confirmed in future research, these findings suggest that the pineal gland may exert a cholesterol reducing effect and that melatonin could be used therapeutically in the treatment of hypercholesterolemia.

Relationship of nocturnal melatonin levels to duration and course of multiple sclerosis.

Multiple sclerosis (MS) is the most common of the demyelinating diseases of the CNS. The clinical course and prognosis of the disease are variable. Characteristically, the illness tends to progress in a series of relapses and remissions. Over the years there is a tendency for the patient to enter a phase of slow and steady deterioration of neurologic function. In about 10%-20% of patients, the course of the disease is not punctuated by a fluctuating course, but rather by an inexorable progression from the onset. The pineal gland has been implicated recently in the pathogenesis and clinical course of MS. Since MS is generally a chronic progressive disorder, we predicted an association between duration of illness and the activity of the pineal gland. To investigate this hypothesis further, we studied nocturnal plasma melatonin levels in relation to duration of illness in a cohort of 32 MS patients (4 men, 28 women; mean age: 41.1 years; SD = 11.1; mean duration of illness: 13.1 years; SD = 12.4) randomly selected from consecutive hospital admissions to a Neurology service for exacerbation of symptoms. For the purpose of comparison, we also studied in the sample serum prolactin levels. The cohort included 7 patients in whom the duration of illness since onset of first neurological symptoms was < or = 5 years (mean: 3.0 years +/- 1.1) and a cohort of 25 patients in whom the duration of illness was > 5 years (mean: 15.6 years +/- 12.7).(ABSTRACT TRUNCATED AT 250 WORDS)

Pineal calcification and its relationship to the fatigue of multiple sclerosis.

Fatigue is one of the most common clinical features of multiple sclerosis (MS) and is a frequent cause of disability. The pathogenesis of fatigue remains obscure. It may result from impaired propagation of action potentials in areas of demyelination. Other contributors may be mental depression, immobility, and physical disability. The fatigue of MS may be relieved by diverse pharmacological drugs such as amantadine and pemoline, but the mechanisms by which these agents act to ameliorate fatigue are unknown. Attention has been focused recently on the relationship between MS and the pineal gland and evidence has been presented to implicate the pineal gland and melatonin in the pathogenesis of the disease. To investigate this relationship further, we studied in 47 MS patients (mean age: 41.6 +/- 9.9 yrs; mean duration of illness: 13.6 +/- 12.6 yrs) the association between fatigue and incidence of pineal calcification (PC) on CT scan, which is thought to reflect past secretory activity of the gland. For comparison, we also evaluated the incidence of choroid plexus calcification (CPC) in these patients. The sample included 20 patients who experienced ongoing, debilitating fatigue during the course of the disease. 27 patients who did not complain of fatigue served as controls. The two groups were not distinguishable with respect to age, sex, age of onset, chronicity, course (relapsing-remitting vs. chronic progressive), and severity of the disease (ambulatory vs. immobile), as well as the incidence of affective illness.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic functions in the early stages of Parkinson's disease.

Disturbances of autonomic nervous functions are common in patients with Parkinson's disease (PD) and may develop as a result of pathological changes in centers of autonomic regulation such as the hypothalamus, brainstem, and sympathetic ganglia. We examined cardiovascular reflexes using bedside, noninvasive procedures in 20 unmedicated PD patients with early stages of the disease (stage 1 and 2 on the Hoehn and Yahr's scale). Sixteen patients (80%) exhibited some degree of autonomic nervous system dysfunction. These included predominantly cardiovascular functions mediated via the parasympathetic system. Our findings demonstrate: (a) a high prevalence of autonomic disturbances in early stage PD, and (b) that dysregulation of parasympathetic cardiovascular control mechanisms is a major feature of dysautonomia in early, unmedicated PD patients.

Multiple sclerosis: the role of the pineal gland in its timing of onset and risk of psychiatric illness.

The incidence of multiple sclerosis (MS) is age-dependent being rare prior to age 10, unusual prior to age 15, with a peak in the mid 20s. It has been suggested, therefore, that the clinical manifestation of MS is dependent upon having passed the pubertal period. Since pineal melatonin secretion declines from childhood to puberty and as melatonin is an immunomodulator, we have proposed that the dramatic decline in melatonin secretion just prior to the onset of the physical manifestations of puberty may disrupt immune responses resulting in either reactivation of the infective agent or in an increased susceptibility to post-pubertal infection. The fall in melatonin secretion during pre-puberty may also increase the susceptibility of these patients to affective disorder which is associated with lower melatonin secretion and the presence of a phase-advance of their biological rhythms. We predicted, therefore, a higher incidence of affective disorder in patients with pubertal or post-pubertal onset of MS compared to those in whom the disease manifested later. To test this hypothesis, we studied the incidence of affective disorder in relation to age of onset of first neurological symptoms in 31 MS patients, 6 of whom manifested symptoms of MS prior to age 18 (mean = 16.8 years). All patients with pubertal onset MS and only 48% of the control group had an affective disorder. The pubertal onset patients also had a significantly lower nocturnal melatonin levels and a lower incidence of pineal calcification on CT scan. These findings thus support the hypothesis implicating the pineal gland in the timing of onset of MS and in the risk for the development of affective disorder.

Multiple sclerosis: relationship between seasonal variations of relapse and age of onset.

The incidence of multiple sclerosis (MS) is age-dependent being rare prior to age 10, unusual prior to age 15, with a peak in the mid 20s. The manifestation of MS, therefore, appears to be dependent upon having passed through the pubertal period suggesting an endocrine influence on the timing of onset of the disease. Since pineal melatonin secretion progressively declines from childhood to puberty and as melatonin exerts an immunomodulating influence, we have proposed that the dramatic decline in melatonin secretion just prior to the onset of the clinical manifestations of puberty may lead to disruption of immune responses resulting in either reactivation of the infective agent or in an increased susceptibility to pubertal or post-pubertal infection. Melatonin secretion undergoes annual rhythms with a zenith in winter and declines to a nadir in the spring. Thus, the fall in melatonin secretion in the spring may account for epidemiological findings revealing a high incidence of relapse of MS in the spring. If the manifestations of MS are related to the fall in melatonin secretion in the post-pubertal period, then one would expect patients with a pubertal onset of the disease to have a higher incidence of relapses in spring than in winter. To test this hypothesis, we investigated in 51 patients the relationship between the seasonal occurrence of the last MS relapse with the age of onset of first manifestation of MS. While 9 of 22 patients (40.9%) who relapsed in spring (March-May) had the onset of MS prior to age 18, only 2 of 29 patients (6.9%) who relapsed in winter (November-February) experienced the onset of first symptoms prior to the age of 18 years (p < .005). These findings thus support the hypothesis implicating the pineal gland and melatonin secretion in the timing of onset of MS. Moreover, the findings may have clinical implications with respect to the prophylaxis of MS relapse in patients who experience seasonally-dependent exacerbation of symptoms.

Nocturnal melatonin secretion in suicidal patients with multiple sclerosis.

Multiple sclerosis (MS) is characterised by the occurrence of patchy CNS demyelinating lesions, leading to various degrees of motor, sensory, affective, and cognitive deficits. MS is associated also with an increased risk of suicide accounting for a substantial rate of death among these patients. Post-mortem studies in suicide victims with various psychiatric disorders demonstrate a decreased concentration of serotonin (5-HT) and its metabolites in the brain. Since 5-HT is a precursor in the synthesis of melatonin and as pineal melatonin content was found to be low in suicide victims, we predicted lower melatonin secretion in suicidal versus non-suicidal MS patients during an acute exacerbation of symptoms. To test this hypothesis, we investigated nocturnal plasma melatonin levels in a cohort of 28 relapsing patients who were admitted consecutively to an inpatient Neurology service, 6 of whom had a history of suicide attempts and were having suicidal ideation at the time of admission. While both cohorts of patients were not distinguishable on any of the demographic data including use of psychotrophic drugs on the day of admission to hospital, the mean melatonin level in the suicidal group was significantly lower than in the control group (19.0 pg/ml +/- 11.9 versus 45.5 pg/ml +/- 27.1; p < .05). These findings support the prediction of the study implicating the pineal gland in the pathogenesis of suicidality in MS and reinforce the concept that a biological rather than a reactive etiology underlies the development of psychiatric symptoms in MS.

Vitamin B12 and its relationship to age of onset of multiple sclerosis.

Attention has been focused recently on the association between vitamin B12 metabolism and the pathogenesis of multiple sclerosis (MS). Several recent reports have documented vitamin B12 deficiency in patients with MS. The etiology of this deficiency in MS is unknown. The majority of these patients do not have pernicious anemia and serum levels of the vitamin are unrelated to the course or chronicity of the disease. Moreover, vitamin B12 does not reverse the associated macrocytic anemia nor are the neurological deficits of MS improved following supplementation with vitamin B12. It has been suggested that vitamin B12 deficiency may render the patient more vulnerable to the putative viral and/or immunologic mechanisms widely suspected in MS. In the present communication, we report that serum vitamin B12 levels in MS patients are related to the age of onset of the disease. Specifically, we found in 45 MS patients that vitamin B12 levels were significantly lower in those who experienced the onset of first neurological symptoms prior to age 18 years (N = 10) compared to patients in whom the disease first manifested after age 18 (N = 35). In contrast, serum folate levels were unrelated to age of onset of the disease. As vitamin B12 levels were statistically unrelated to chronicity of illness, these findings suggest a specific association between the timing of onset of first neurological symptoms of MS and vitamin B12 metabolism. In addition, since vitamin B12 is required for the formation of myelin and for immune mechanisms, we propose that its deficiency in MS is of critical pathogenetic significance.

Late-onset schizophrenia: relationship to awareness of abnormal involuntary movements and tobacco addiction.

Although schizophrenia usually emerges at mid to late-adolescence, it has been estimated that almost 20% of schizophrenic patients develop their first symptoms in mid to late life (late-onset schizophrenia). The biological characteristics that distinguish patients with early onset from those with late-onset schizophrenia have not been well delineated. A subgroup of neuroleptic-treated schizophrenic patients develops tardive dyskinesia (TD) and the majority of these patients are unaware of their movements. To investigate whether early and late-onset schizophrenic patients with TD could be differentiated on the basis of awareness of involuntary movements, we compared the prevalence of awareness of these abnormal movements in patients with early (N = 40) and late-onset (N = 15) schizophrenia. We found a significantly higher prevalence of awareness of involuntary movements in patients with late-onset schizophrenia as compared to those with an earlier age of onset (86.6% vs. 25.0%, p < .0001). In a second study, we investigated whether early and late-onset schizophrenia could be differentiated on the basis of dopamine functions in the mesolimbic system. Since tobacco addiction is mediated via limbic dopaminergic functions, we investigated the prevalence of tobacco addiction in patients with early (N = 51) and late-onset (N = 13) schizophrenia. We found a significantly lower prevalence of tobacco addiction in patients with late-onset schizophrenia as compared to those with an earlier age of onset (15.4% vs. 54.9%; X2 = 6.49; p < .01). Our findings support the notion that distinct pathophysiological mechanisms underlie the development of early and late-onset schizophrenia.

Subjective awareness of abnormal involuntary movements in schizophrenia.

A wide majority of schizophrenic patients with Tardive dyskinesia, a neurological disorder produced by chronic neuroleptic therapy, lack awareness of their involuntary movements. This by contrast to patients with Parkinsonism who usually are aware of their abnormal movements. In the following communication we present a series of studies which are aimed at providing further insight into the issue of awareness of involuntary movements in schizophrenic patients with tardive dyskinesia. In addition, we investigated whether edentulosness, which may be a risk factor for orofacial dyskinesias in the elderly, is also a risk factor for neuroleptic-induced orofacial dyskinesias. We found that: (a) one's awareness of involuntary movements is related to some but not all muscle groups, (b) tardive dyskinesia may be associated with a significant distress, (c) lack of awareness may be a feature of frontal lobe dysfunction in schizophrenia, (d) patients who lack awareness of their involuntary movements have a higher prevalence of pineal calcification, and (e) edentulosness, which is related to deficits in the orofacial sensorimotor system, increases the risk for neuroleptic-induced orofacial dyskinesias.

Nocturnal melatonin secretion in multiple sclerosis patients with affective disorders.

The pineal gland has been implicated recently in the pathogenesis of multiple sclerosis (MS), a chronic demyelinating disease of CNS. Since nocturnal melatonin secretion is low in some groups of patients with mental depression, we predicted lower melatonin secretion in MS patients with history of affective illness compared to those without psychiatric disorders. To test this hypothesis, we studied single nocturnal plasma melatonin levels and the incidence of pineal calcification (PC) on CT scan in a cohort of 25 MS patients (4 men, 21 women; mean age = 39.4 years, SD = 9.3), 15 of whom had a history of coexisting psychiatric disorders with predominant affective symptomatology. Other factors that may be related to depression such as vitamin B12, folic acid, zinc, magnesium, and homocysteine, were also included in the analysis. Neither any of the metabolic factors surveyed nor the incidence of PC distinguished the psychiatric from the control group. However, the mean melatonin level in the psychiatric patients was significantly lower than in the control group. Since low melatonin secretion in patients with depression may be related to a phase-advance of the circadian oscillator regulating the offset of melatonin secretion, we propose that the depression of MS likewise may reflect the presence of dampened circadian oscillators. Furthermore, since exacerbation of motor symptoms in MS patients may be temporally related to worsening of depression, we propose that circadian phase lability may also underlie the relapsing-remitting course of the disease. Consequently, pharmacological agents such as lithium or bright light therapy, which have been shown to phase-delay circadian rhythms, might be effective in the treatment of affective symptoms in MS as well as preventing motor exacerbation and hastening a remission from an acute attack.

Nocturnal plasma melatonin and alpha-melanocyte stimulating hormone levels during exacerbation of multiple sclerosis.

The pineal gland has been implicated recently in the pathogenesis of multiple sclerosis (MS). To investigate this hypothesis further, we studied nocturnal plasma melatonin levels and the presence or absence of pineal calcification (PC) on CT scan in a cohort of 25 patients (5 men, 20 women; mean age: 41.1 years; SD = 11.1; range: 27-72) who were admitted to a hospital Neurology service for exacerbation of symptoms. Plasma alpha-melanocyte stimulating hormone (alpha-MSH) estimations were included in the study since there is evidence for a feedback inhibition between alpha-MSH and melatonin secretion. Abnormal melatonin levels were found in 13 patients (52.0%), 11 of whom had nocturnal levels which were below the daytime values (i.e., < 25 pg/ml). Although melatonin levels were unrelated to the patient's age and sex, there was a positive correlation with age of onset of symptoms (p < .0001) and an inverse correlation with the duration of illness (p < .05). PC was noted in 24 of 25 patients (96%) underscoring the pathogenetic relationship between MS and the pineal gland. Alpha-MSH levels were undetectable in 15 patients (60.0%), low in two patients (8.0%), normal in seven patients (28.0%), and elevated in one patient (4.0%). Collectively, abnormal alpha-MSH levels were found in over 70% of patients. These findings support the hypothesis that MS may be associated with pineal failure and suggest, furthermore, that alterations in the secretion of alpha-MSH also occur during exacerbation of symptoms. The relevance of these findings to the pathogenesis of MS are discussed.

Dysautonomia in Parkinson's disease: relationship to motor disability.

Disturbances of autonomic nervous system functions are common in patients with Parkinson's disease (PD) and may develop as a result of pathology in centers of autonomic regulation such as the hypothalamus, brainstem, and sympathetic ganglia. We examined the relationship between the degree of motor disability, as determined from the Hoehn and Yahr scale (1967), and the presence of pandysautonomia, as determined by the assessment of noninvasive cardiovascular reflexes, in 29 unmedicated PD patients (mean age: 72.0 years, SD = 8.9). In addition, we investigated the relationship of pandysautonomia to CT scan measures of cerebral atrophy and to the presence or absence of pineal calcification. Nine patients (31.0%) were found to have pandysautonomia with deficits in both sympathetic and parasympathetic cardiovascular functions. Pandysautonomia was statistically related only to the degree of motor disability (p < .01). These findings demonstrate a significant association between motor disability and objective impairment of central cardiovascular functions in PD.

Autonomic functions in the early stages of Parkinson's disease.

Disturbances of autonomic nervous functions are common in patients with Parkinson's disease (PD) and may develop as a result of pathological changes in centers of autonomic regulation such as the hypothalamus, brainstem, and sympathetic ganglia. We examined cardiovascular reflexes using bedside, noninvasive procedures in 20 unmedicated PD patients with early stages of the disease (stages 1 and 2 on the Hoehn and Yahr's scale). Sixteen patients (80%) exhibited some degree of autonomic nervous system dysfunction. These included predominantly cardiovascular functions mediated via the parasympathetic system. Our findings demonstrate: (a) a high prevalence of autonomic disturbances in early stage PD, and (b) that dysregulation of parasympathetic cardiovascular control mechanisms is a major feature of dysautonomia in early, unmedicated PD patients.

Risk factors for neuroleptic-induced movement disorders.

Chronic neuroleptic therapy may be associated with the development of diverse movement disorders including Tardive dyskinesia (TD), Parkinsonism, dystonia, and akathisia in a subset of schizophrenic patients. It is presently unknown why only a proportion of neuroleptic-treated patients develop these movement disorders. In the following communication, we present a series of studies which demonstrate that the development of these movement disorders may be facilitated by certain risk factors including disturbances in pineal melatonin functions, diabetes mellitus, cognitive deficits, suicidal behavior, and disturbances in the functions of the choroid plexus. Recognition of these biological factors may prove useful in: (a) further understanding of the pathophysiology of these disorders, and (b) identifying patients at risk for these movement disorders.

The pineal gland in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology. Clinical, neurochemical, and neuroradiological data implicate the pineal gland in the pathophysiology of MS. To investigate the relationship of MS to the pineal gland further, we surveyed the prevalence of pineal calcification (PC) on CT scan in a cohort of 29 MS patients (7 men, 22 women, mean age: 40.1 years, SD = 8.9) who were admitted consecutively to a neurological service for acute exacerbation of symptoms. For the purpose of comparison, we also surveyed the prevalence of choroid plexus calcification (CPC) in the sample. Twenty-one age and sex-matched neurological patients served as controls (5 men, 16 women, mean age: 37.0, SD = 9.2). PC was seen in 100% of MS patients, while 72.4% patients (N = 21) had CPC. In the control sample, PC was found in 42.8% (N = 9) and CPC in 28.5% (N = 6). Thus, the strikingly high prevalence of PC in MS provides indirect support for an association between MS and abnormalities of the pineal gland. Moreover, since pineal melatonin is involved in neuroimmunomodulation, we propose, for the first time, that abnormalities of pineal melatonin functions are implicated in the pathophysiology of the disease.