Restless leg syndrome, periodic limb movements, febrile seizures and Attention deficit hyperactivity disorder in an Indian family.

Restless leg syndrome (RLS) is a common neurological disorder which can affect individuals of all age groups and incidence increasing with age. It can cause severe sleep disruption and negatively impact quality of life of an individual. Its diagnosis is clinical, based on essential criteria of International RLS Study Group. It can be idiopathic or associated with various medical and other neurological disorders. Idiopathic RLS can be sporadic or may have a familial inheritance, with several genetic loci been reported till date. RLS has a strong association with periodic limb movements, both sleep and awake. Very few studies of familial RLS/Periodic limb movements in sleep and their associations have been reported. We report an Indian family with autosomal dominant RLS/PLMS, with RLS and PLMS as well as psychiatric disorders, febrile seizures and Attention Deficit Hyperactivity Disorder in different family members, over three generations.

Introduction

Restless leg syndrome (RLS) is a disorder of combined sensory and motor dysfunction first described by Swedish neurologist Ekbom in 1945.[1] It is characterized by an urge to move the legs, usually accompanied by uncomfortable sensations in the limbs. The sensations usually are worse during inactivity and often interfere with sleep, leading to walking discomfort, chronic sleep deprivation, and stress.[2]

Epidemiological studies suggest that prevalence of RLS in the general population is between 1.2 and 15%.[34] It is twice as common in females in comparison with males.[5] RLS may be idiopathic or may be secondary when associated with other conditions like iron deficiency, low serum ferritin levels, pregnancy, end-stage renal disease, diabetes mellitus, and rheumatoid arthritis.[6-8] Some neurological disorders are also related to RLS, like spinocerebellar atrophy, peripheral neuropathy, spinal canal stenosis, lumbo-sacral radiculopathy, myelopathy, and Parkinson's disease.[910] In children, RLS is associated with attention deficit hyperactivity disorder.[11-13]

The diagnosis of RLS is made clinically on the basis of the following 4 essential criteria:

An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs.

The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying down or sitting.

The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.

The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night.

There are additional features that support a diagnosis of RLS, like presence of family history of RLS, periodic leg movements, response to dopaminergic therapy, sleep disturbance, and no abnormality in medical and physical evaluation.[14]

Idiopathic RLS appears to run in families, suggesting a genetic basis for the disorder.[1516] Twin studies have been consistent in showing that RLS has a genetic etiology.[1718] Several loci for RLS have been reported. These include one autosomal recessive locus in a French-Canadian pedigree and four autosomal dominant loci in a North Italian pedigree, one each from the United States, South Tyrol, and large French–Canadian pedigree.

Nearly 80% of people with RLS have Periodic Limb Movements in sleep (PLMS) or awake state.[19] These are involuntary repetitive segmental movements of the lower and/or upper limbs, consisting of flexion of the thighs, knees, ankles, and big toe with fanning of the small toes, occurring in sleep or awake state.[20] A higher incidence of PLMS has also been found in asymptomatic first-degree relatives of early onset RLS subjects. PLM may also be associated with narcolepsy, sleep apnea syndrome, REM sleep behavior disorder, and normal elderly subjects. PLMS during wakefulness has been recognized as a sensitive and specific RLS marker.[21]

Presently, no family studies of RLS/PLMS or their associates are available from the Indian subcontinent. We describe a family with autosomal dominant RLS/PLMS and report their clinical details, associations and investigative data including serum ferritin and polysomnography.

Materials and Methods

Our proband, 65 years old male, presented with complaints of pain in both lower limbs in the evening and night, urge to move the legs and relieved by walking, along with rapid jerky movements of limbs for more than 25 years. These movements used to occur both in awake state as well as in sleep, causing severe sleep disruption. These were more common during periods of rest, after activity and never occurred during action or movement and were relieved on walking. Occasionally while sitting, because of these movements, patient had a tendency to lose his balance. Clinical history suggested diagnosis of RLS with PLMs (sleep and awake). Family history revealed similar complaints suggestive of (RLS and / PLMS) and some neuropsychiatric disorders in his daughters, sons, and grandchildren. Family tree is shown in Figure 1.

Figure 1

Familytree

Besides the clinical examination, the Index case and 8 family members underwent all routine investigations along with serum ferritin levels and an overnight supervised polysomnography (PSG) at our sleep laboratory. The diagnoses of RLS and PLMS were based on the standard international criteria.[14]

Observation

Hemogram, renal and liver functions were normal. Serum ferritin levels were below normal in the proband and his two daughters and affected grandson. Nerve conduction studies were normal. The index case had PLM in sleep, rapid and jerky in nature, occurring very frequently every few seconds throughout the night, predominantly involving both lower limbs, with frequent awakenings causing severe sleep disruption. The associated symptoms of RLS, no Electroencephalography (EEG) correlate, occurrence only during rest, and subsequent dramatic improvement with pramipexole ruled out the possibility of these movements being myoclonus. Five other family members were also found to have PLM in sleep, PLMS index ranging from 16 to 30/hr, more in the first 3 to 4 hours of sleep and stages 1 and 2 of Non Rapid Eye Movement (NREM )sleep. One of these family members was unaware of these movements. All 3 (100%) subjects with RLS had PLMS, while only 50% of patients with PLMS fulfilled the criteria for RLS [Table 1]. The index case was started on treatment with Dopa agonist (pramipexole) and he had relief in his symptoms of RLS as well as marked reduction in the leg movements [Figures 2 and 3]. Treatment was also started for his daughters and grandson. Benzodiazepine (clonazepam) was started for young daughter. Benzodiazepines (clonazepam) with pramipexole were given to elder daughter and Levodopa to grandson who had attention deficit hyperactivity disorder (ADHD) along with PLMS. Both daughters and grandson had marked relief in their symptoms.

Table 1

Clinical attributes of family members

Figure 2

Pretreatment polysomnography overview of the index case

Figure 3

Post-treatment polysomnography overview of the index case

Discussion

RLS and PLMS are relatively common sleep problems with limited descriptions from India[2223] The impairment of dopaminergic transmission (involvement of D3 subtype receptors) and iron metabolism is supposed to be involved in the pathogenesis of RLS and PLMS. There are several studies showing relation between dopaminergic system and RLS.[2425] A low serum ferritin level (less than 50 μg/l) has been associated with greater severity of RLS, more frequent PLM, and with a reduction in the quantity of sleep, as determined by PSG.[26] The iron containing enzyme, tyrosine hydroxylase, catalyzes the hydroxylation of tyrosine to dihydroxyphenylalanine (levodopa) which is carboxylated to form dopamine. Iron is therefore a rate limiting step in the formation of dopamine. RLS and PLMD might be induced by inhibition of dopamine formation through lack of iron.[27] In patients with a serum ferritin level of less than 18 μg/l, treatment with oral iron supplements resulted in improvements in the severity of the symptoms of RLS and, in some patients, the complete resolution of the symptoms.[28] A 68% decrease in cerebrospinal fluid (CSF) ferritin and a greater than three-fold increase in CSF transferrin, indicative of low brain iron, have been reported in patients with idiopathic RLS.[29] Allen et al also demonstrated lower iron concentrations in the substantia nigra and putamen in proportion to severity of symptoms in RLS patients compared with controls.[30] We have also found decreased serum ferritin levels in index case and family members who had RLS/PLMS.

Family history of RLS is positive in nearly 50% of patients with idiopathic RLS.[31] Familial cases have a younger age at onset[32] and a more slowly progressive course,[33] as seen in our case and his family members. Linkage studies in RLS families have revealed several loci including chromosome 12q, 14q, 9p, 20p, 2q, 16p.[34] Genetic studies could not be done in our case due to lack of defined genetic loci and financial constraints in our set up, which is a limitation of the study.

RLS/PLMS occur in a higher percentage of children with ADHD.[11-13] In the described family, one grandson with PLMS also had history of ADHD and was started on treatment with levodopa. The pathogenesis of this association includes genetic linkage, common dopaminergic deficit, or sleep disruption. Treatment with levodopa/dopamine agonist is effective in improving symptoms of both.[35] Our patient also had significant improvement not only in PLMS, but also in ADHD, resulting in betterment of his scholastic performance.

Neuropsychiatric disorders like major depression, anxiety, and panic disorder have also been strongly associated with RLS/PLMS.[36-38] The explanations include common pathophysiological mechanism of dopaminergic deficiency, insomnia, and use of antidepressants. RLS being a highly familial disorder, the increased risk of specific depressive and anxiety disorders could have a genetic etiology as well.[39] Two of the family members in the study had history of psychiatric disorder (anxiety/depression).

Treatment of RLS includes avoidance of drugs which can worsen or precipitate RLS/PLM, e.g, selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline), venlaflaxine, antihistaminics, and caffeine, correction of iron deficiency, and management of underlying condition like uremia. Drug therapy includes the following three major classes of drugs: dopaminergic agents (levodopa, bromocriptine, pergolide, and pramipexole), opioids (propoxyphene, oxycodone, methadone), and benzodiazepines (clonazepam, nitrazepam, triazolam). Other pharmacological agents which have been evaluated in various studies for subjective improvement in RLS symptoms include carbamazepine, valproic acid, gabapentin, and baclofen. Dopaminergic drugs are however considered the first line of management of idiopathic RLS.[40]

Thus, we report a unique Indian family with RLS, PLMS, febrile seizures, psychiatric disorders, and ADHD in family members. A detailed history of these associations in family members of patients with RLS/PLMS should hence be carefully sought. Early recognition and treatment of these disorders and their correlates can markedly improve the quality of life in these patients.