Gavin I. Awerbuch

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 patients 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.

Mexiletine for Thalamic Pain Syndrome

The thalamic pain syndrome, a rare sequelae of cerebrovascular event, is a severe and disabling form of central pain which treatment remains a major clinical problem. We present our results of a preliminary open label study using mexiletine, an orally active antiarrhythmic agent, in the management of thalamic pain in 9 patients. Using a dose of 10 mg/kg/day over a 4-week period, mexiletine produced improvement in pain in 8 of the 9 patients. Mexiletine was generally well tolerated with only two patients experiencing transient nausea and dizziness. Our findings suggest that mexiletine may be a safe and effective agent in the management of thalamic pain and possibly other paroxysmal pain syndromes of central origin.

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

Disturbances of autonomic nervous functions are common in patients with Parkinsons 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 Yahrs 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.

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.

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.

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.

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.

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.

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.

Reversible Optic Neuritis Secondary to Paranasal Sinusitis

Three patients are described in whom optic neuritis was presumably caused by concurrent sinus infection. Aggressive treatment of the underlying sinus condition led to prompt visual improvement. Although underrecognized in clinical neurology, paranasal sinusitis is an uncommon but treatable cause of optic neuritis. Shortcomings of conventional radiological investigations and inappropriate use of corticosteroids may contribute to initial misdiagnosis.