Given the high frequency of patients with various thyroid pathologies that show neurological signs we conducted this study that had as purpose the study of neurological manifestations in patients with thyroid disorders, referring to the frequency, clinical aspect and therapeutic response of the neurological determinations in the thyroid pathology.
2. GENERAL OBJECTIVES
To achieve that purpose, the conducted clinical trial based on neurological.
Manifestations in patients with various thyroid disorders we had the following objectives:
The evaluation of the frequency of neurological manifestations in thyroid disorders.
The identification of some specific clinical pictures in various thyroid disorders.
Revealing the difficulties of diagnosis regarding the nervous system disorders produced by thyroid pathologies.
3. MATERIAL AND METHOD
The study group included 820 patients with thyroid pathologies. We examined neurologically 820 patients with thyroid diseases, admitted in the neurology and endocrinology wards from the Emergency Hospital “St. Andrew” Galati or that were under medical observation in the specialized clinic of the hospital in the neurology and endocrinology sections. The study was conducted over a period of 5 years.
3.1. Clinical and laboratory characteristics of the study group regarding terms of neurology and endocrinology.
Patients from the study group were examined clinically and paraclinically every 3 months.
Out of all the examined cases with thyroid pathology, 616 cases had presented neurological symptoms. The prevalence of neurological manifestations in patients with thyroid pathologies was of 75.12% (Fig. 1).
3.2.1. Study type
The research followed the recommended methodology for realizing the clinical and epidemiological studies.
3.2.2. Choosing the subjects
The patients that were included in the study group were recruited among the hospitalized patients with thyroid disorders that were admitted in the neurology and endocrinology wards of the Emergency Hospital Galati or that were present in the sections of neurology and endocrinology from the Specialized Clinic of the hospital.
Clinical examination was correlated with laboratory tests. Laboratory data (recommended, most of the time pursued and partially performed) was recorded in the observations charts of the departments and offices mentioned.
3.2.3. Data gathering
Laboratory data was collected from the observation charts of the above mentioned
Sections and also from the sheets of neurological and endocrinological medical supervision.
The clinical trial was conducted with the consent of the investigated patients and had the approval of the Bioethics Commission of the Emergency Hospital Galati.
For the clinical diagnosis of hyperthyroidism we used the Newcastle index.
In the clinical evaluation of hypothyroidism we followed the Billewicz index.
For the endocrinological laboratory diagnosis there were used: hormone dosages: T3, T4, FT4, TSH, prolactin, corthysol, testosterone; basal metabolism; thyroid ultrasound, thyroid scintigraphy – substance used being 99 mTcO4, in dosages of 2 mCi; fine needle thyroid puncture biopsy – ABC; sella turcica radiography, brainCT, brain MRI, biochemical usual dosages in blood and urine: cholesterol, Hb, Ht, number of white cells with leukocyte formula, liver tests, CPK, TGO, TGP, total proteins, bilirubin, alkaline phosphatase; immunoassay: immunoelectrophoresis, lupus cells, C-reactive protein, serum complement, circulating immune complexes, lues tests, antithyroglobulin antibodies, antiperoxidase antibodies; bone scintigraphy, EKG.
For studying the neurological damage, there were used: electromyography data, VCM, VCS, oculus fundus examination; EEG including mapping and spectral map; Brain and mediastinum CT, using contrast substances iopamiro and omnipaque; brain MRI – using the same device previously described, using gadolinium as well; nerve biopsy with optical microscopy evaluation; muscle biopsy with optical microscopy evaluation; pathological examination of neurosurgical excision parts ; pulmonary, mediastinal, bone X-ray; Doppler- ECD, TCD; CSF study; biochemical blood and urine usual dosages, mentioned above; bone scintigraphy with same equipment mentioned before;
3.2.4. Processing and statistical data analysis
The processing and data analysis were conducted using a suitable software. We calculated central tendency indicators (mean and standard deviation), structure indicators and frequency indicators (prevalence).
Of the total patients in the study:
– 291 cases – 47.24% – were patients with hypothyroidism;
– 106 cases – 17.20% – were patients with hyperthyroidism;
– 160 cases – 25.97% – were patients with euthyroid goiter;
– 26 cases – 4.22% – were patients with thyroiditis;
– 23 cases – 3.73% – were patients with thyroid tumors;
– 10 cases – 1.62% – were patients with iodine IDD deficiency (Fig 2.);
The structure of the study group – by gender:
We noticed the particularly high frequency of cases in women, 94.48%, compared to males, 5.52%, (p<0.001), both in number of cases of thyroid diseases as well as in number of thyroid pathologies with neurological damage.
Main morbid associations in patients from the study group included:
– Diabetes type I and II;
– Primary hypertension;
– Various forms of neoplastic cancer or benign tumors: uterine cancer; uterine fibroids; generalized lymphomas with thyroid localization; brain tumors: meningioma; ovariancysts; prostate adenoma; lipomas;
– Heart rhythm disorders: paroxysmal and chronic atrial fibrillation, atrial and ventricular extrasystolic arrhythmias and cardiac conduction disorders;
– Strokes: constituting ischemic stroke, transient stroke and haemorrhagic accidents;
– Profound thrombophlebitis of the lower limbs;
– Hypocalcemic tetany, hypomagnesemic tetany;
Neurological manifestations in patients with thyroid pathologies occurred slowly in a large number of cases, fact cited in the literature .
Also, neurological suffering led to, in many cases, the diagnosis of the causing thyroid pathology. Thus, from the total of thyroid disorders with secondary neurological suffering, approximately 80% were patients known with a thyroid disease, at which the neurological signs occurred slowly and 20% were cases in which neurological side effects led to diagnosing the primary thyroid condition.
In most cases, neurological manifestations were installed progressively, fact confirmed by other studies .
The high frequency of clinical neurological manifestations in the study group both in the moment of admission as well as during their evolution imposed further research to establish their etiology.
The study highlights the clinical and epidemiological aspects regarding the neurological manifestations in thyroid diseases with the following conclusions:
75.12% of the patients with thyroid disorders followed for 5 years presented neuropsychiatric manifestations, fact cited in the literature ;
Thyroid diseases and neurological suffering imply either common etiology or a relationship based on cause and effect;
The thyroid conditions are more frequent in women 94.48% than in men 5.52% and the neuropsychiatric manifestations are as well more common in women .
Neurological manifestations generally occurred progressively in the majority of the cases, rarely acute;
Neurological damage occurred lately in the patients known with thyroid disorders but in a greater number of cases the neurological affection was revealing for detecting the primary thyroid condition;
Remission of neurological signs and symptoms under the basic treatment of thyroid disorders was generally obvious;
A definite conclusion of the study is that very often patients with different types of thyroid disorders present themselves initially in the neurology ward due to the fact that the thyroid symptoms can often be confused with a neurological disease, fact citated in other studies .
In hyperthyroidism we encountered central nervous system manifestations, muscular manifestations, and peripheral nerve system manifestations:
Central nervous system manifestations included psychiatric disorders, headaches and training vertiginous syndromes, loss of consciousness, strokes, seizures, suffering of the central nervous system through thyrotoxicosis crisis.
Psychiatric manifestations are extremely common in these cases from mild to severe such as schizophrenia, paranoia etc. Patients are often wrongly labeled and initially treated in psychiatric wards for mental diseases when in reality the symptoms are caused by thyrotoxicosis.
Headache and vertigo were often encountered, sometimes requiring, because of their resistance to treatment, a brain CT.
Syncope and fainting episodes were also frequent in patients with hyperthyroidism, being a reason for which a large number of patients presented themselves in the neurology service.
Ischemic stroke was less common in patients with hyperthyroidism and more common in those with hypothyroidism from the study group, in the cases of thyrotoxicosis this occurred in patients with heart rhythm disorders caused by dysthyroidism who also presented other risk factors. In the followed patients, 40% of the cases with toxic thyroid adenoma developed a stroke during their evolution.
Seizures associated with hyperthyroidism, although probably with no endocrinopathy causal relationship were reduced after associating anticonvulsant therapy with antithyroid synthesis treatment.
Thyrotoxicosis crisis imposes an urgent differential diagnosis through confessional syndrome, psychomotor agitation, generalized convulsive seizures, fever, signs and symptoms of neurological or infectious type that require the neurologist to proceed with an urgent differential diagnosis.
Muscular manifestations occurred in patients with old hyperthyroidism which was generally therapeutically neglected.
These included common accuses such as muscle weakness, muscle cramps, myalgia which were reduced by treatment with antithyroid synthesis drugs.
Regarding the thyrotoxic myopathy, in the study group we have encountered only chronic thyrotoxic myopathies, although in other studies there are frequently cited cases of acute thyrotoxic myopathies.
Chronic thyrotoxic myopathy occurred exclusively in women, other studies indicating that it occurs mainly in men with hyperthyroidism.
Chronic muscular affection particularly affected the pelvic muscles, muscle enzymes were within normal limits (CPK) and the muscle biopsy was nonspecific. The electromyography confirmed the diagnosis. This data is confirmed by other studies.
Ocular myopathy was present in a small number of cases, it was either unilateral or bilateral, its improvement being hardly noticeable during the treatment.
Forms of unilateral exophthalmos, especially those associated with training headache in patients that weren’t know with hyperthyroidism, imposed a differential diagnosis and had confusions with intracranial expansive processes. Neuroimaging investigations, preferably brain MRIs were indispensible in establishing the diagnosis. Diplopia as a first sign of hyperthyroidism or preceding with months or even years the thyrotoxicosis, imposed the differential diagnosis with ocular form of myasthenia gravis.
Peripheral nerve system manifestations:
Sensory and sensorymotor type neuropathies, through vascular lesions caused by hypoxia, lipid and protein metabolism disorders, were rarely encountered in patients with hyperthyroidism, the evolution being slow and favorable during the treatment with antithyroid synthesis drugs, data which was confirmed in other studies.
In the study group we have not encountered any cases of myasthenia gravis or periodic hypokalemia paresthesia associated with hyperthyroidism, although these associations are frequently cited in other studies.
A special mention that we make is for the TSH secreting pituitary adenoma with secondary hyperthyroidism which brings together the clinical signs of thyrotoxicosis, without infiltrative ophthalmopathy with headache and/ or focal neurological signs, depending on the evolutionary stage. Paraclinically we detect increases of thyroid hormones and TSH, the clinical suspicion requiring neuroimaging confirmation, preferably MRI.
In hypothyroidism we also encountered central manifestations, muscular manifestations, cranial nerve manifestations, neuromuscular junction manifestations and peripheral nerve system manifestations:
Central manifestations: included psychiatric disorders, training headaches and vertigo, strokes, seizures and myxedematous coma.
Psychiatric manifestations encountered in the studied patients with hypothyroidism included forms ranging from mild to severe, which created a confusion during the diagnosis. They have reduced after the initiation of the substitute thyroid hormones treatment.
Training headaches and vertigo syndromes associated with hypothyroidism, resistant to the treatment for the symptoms, sometimes imposed neuroimaging investigations such as CT or MRI, which detected brain and cerebellar atrophies.
Ischemic stroke was commonly encountered in patients with hypothyroidism (more frequently than in those with hyperthyroidism), such as arterial stenosis, which were confirmed through Doppler examinations, possibly caused by the dyslipidemia which was determined by the hypofunction of the thyroid. The thyroid hormone therapy reduced the symptoms of pseudobulbar type seen in patients from the study group.
Epileptic seizures associated with hypothyroidism, although probably with no causal relationship with dysthyroidism, had their frequency reduced when combining anticonvulsant treatment with thyroid hormone replacement therapy.
Hypothyroidism worsened Parkinson’s disease picture, stressing bradylalia, bradipsychia, movement disorders, mnesic disorders. Although there is no causal relationship between the two disorders, hormonal therapy in patients with hypothyroidism who also had Parkinson’s disease led to reducing the symptoms in these patients.
Myxedematous coma presented a problem of differential diagnosis for the neurologist, in the study group all the patients with this type of suffering
initially presenting themselves in the neurology ward. A comatose condition, hypothermia to which no known etiology requires urgent endocrinological investigations.
Muscular manifestations were influenced more by the duration of the hypothyroidism state than by its severity. They included:
Frequent accuses such as myalgia – predominantly nocturnal, muscle cramps, muscle fatigue were improved thyroid hormone replacement therapy.
Myopathies were encountered exclusively in women, in chronic forms, predominantly affecting the scapulohumeral and pelvic belts. They were associated with high values of CPK and muscle biopsy was nonspecific. Clinical improvement was obvious under treatment with antithyroid hormones after only a few months from its initiation.
Cranial nerve manifestations:
Among the cranial nerves, the most affected in hypothyroidism were the acoustic- vestibular nerve and the facial nerve, this one being probably affected by entrapment type phenomena.
In post-surgical thyroidectomy hypothyroidism (not through radioactive iodine), there were cases of recurrent nerve palsy through faulty surgical techniques.
Neuromuscular junction manifestations:
Myasthenia gravis was associated with hypothyroidism in the study group, although in other studies it is characteristic of it to associate with hyperthyroidism. It is possible that some cases of hypothyroidism to have been caused by previous autoimmune types of thyroiditis, whose damage may have caused the hypofunction of the thyroid and to which the autoimmune mechanism may be the same with the one that causes myasthenia gravis.
Peripheral nerve system manifestations:
Entrapment neuropathies targeted specifically the median nerve, their evolution being favorable under treatment.
Sensory and motor pseudo myopathy neuropathies were relatively common in patients with hypothyroidism. They have improved slowly, clinically and regarding the electrophysiological parameters during hormone replacement therapy.
We noted an increased association of various forms of hypothyroidism with tumors with various localizations, as well as diabetes, data which was quoted in other studies.
In benign tumors and thyroid cancers:
Benign thyroid tumors are not accompanied by typical neurological symptoms.
Psychiatric disorders such as depression, organic personality disorder, drug addiction, sleep disorders were frequently associated with thyroid carcinomas.
Persistent accuses such as headache, vertigo, balance disorders imposed the performing of a brain CT or an MRI, which detected brain metastasis, lacunar strokes, generalized cortical atrophies or which confirmed an ischemic stroke.
We detected cases with brain metastasis without other metastasis in other organs.
Compression phenomena of the cervical sympathetic chain and of the mediastinum structures were rarely encountered in patients from the study group.
Thyroid cancer was associated in some cases with cancers with other sites: meningioma, cervix cancer.
In acute and subacute thyroiditis there were no typical neurological symptoms, we have predominantly seen headaches, vertigo, myalgia, physical asthenia which were not clinically objectified.
In chronic thyroiditis there were sensory neuropathies associated, clinically confirmed through the decrease of CSV. There weren’t registered any cases of patients with myasthenia gravis and chronic thyroiditis in the study group.
In affections determined by iodine deficiency:
Euthyroid goiter it was not associated with any characteristic neurological changes, accuses such as headache, vertigo, acroparesthesia improving under treatment with potassium iodide.
Cases of bulky cervical goiter or endothoracic goiter led to compressive phenomena of the mediastinum structures and of the cervical nerve-vascular package, the diagnosis of the thyroid pathology being established, in some cases, in the neurology ward.
Iodine deficit during childhood
Adult patients with iodine deficiency during their childhood have presented mental retardation, dysarthria, epilepsy with generalized convulsive seizures, hearing loss, data which was confirmed in other studies.
In iatrogenic thyroid pathologies:
Neurological manifestations determined by hyperthyroidism and especially by hypothyroidism can occur through iatrogenic causes, mainly due to prolonged treatment with Cordarone, which is an antiarrhythmic drug commonly used as chronic treatment in cardiology.
In thyroid pathologies in elders:
Regarding the elderly, hypothyroidism manifested through confusional states with low tolerance to cold, bradylalia, bradipsychia, sleepiness and hyperthyroidism manifested through physical asthenia, confusion, adynamia, headache, vertigo, balance disorders for which, in many cases, the patients presented themselves in the neurology service.
The clinical trial has revealed the following aspects:
The early detection of the thyroid pathologies and of the neuropsychiatric sufferings secondary to the thyroid pathologies and also the proper treatment can only lead to the increase of the quality of life of the patients and in lowering the health expenses for these group of patients.
The general practitioner must form a multidisciplinary medical team with the neurologist and endocrinologist, in order to early diagnose the patients with various thyroid pathologies and secondaryneuropsychiatric sufferings.
Thyroid affection must be considered in cases of neuropsychiatric signs and symptoms of uncertain etiology. Therefore, we consider this clinical study very useful for the neurologist, endocrinologist, psychiatrist, neurosurgeon, cardiologist but also for the decision making in public health assistance.
The present study may find its utility in supporting the prevention programs for thyroid pathologies (which, evolving, may be complicated by neuropsychiatric manifestations), and it may benefit directly the patient but also the doctors.
This paper opens new neuroendocrine research topics regarding the thyroid pathologies with secondary neurological manifestations.
FT3-free serum triiodothyronine
FT4-free serum thyroxine
H.E.-hematoxylin eosin staining
TcO- technetium isotope
TSH-adenohypophysis thyrotropin hormone
VCM-motor conducting velocity
VCS-sensory conducting velocity