Rory Hafford looks at conditions associated with damaged basal ganglia, including Restless Leg Syndrome and Parkinsonism
It is easy to see, back in the day when medicine was grappling for some sort of evidence base, how the diagnosis of ‘possession’ was all the rage. Just consider for a moment the array of disorders issuing forth from the black hole that is the basal ganglia:
l Hemiballismus – a sudden flinging out of limbs on one side of the body, as if to prevent a fall or to grab something… that is not there;
l Athetosis – a snake-like writhing movement of parts of the body, particularly the hands, which are often seen in cerebral palsy; and
l Chorea – a series of rapid uncontrolled movements of muscles all over the body.
The basal ganglia, the chief culprit in this unwelcome medical drama, is the seat of a wide range of dyskinesias, resulting from damage to the ganglia or its connections.
The most famous disease of the basal ganglia is the shaking palsy of Parkinsonism (more of which anon). There is another scourge that is finding its way into this body of the medical literature, that of Restless Leg Syndrome (RLS).
RLS is a mystery. Nobody knows for sure, at present, what the exact cause is. Brain autopsies have pointed the finger at the dopaminergic system and iron insufficiency in the substantia nigra (study published in Neurology, 2003). Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine.
The condition was first described by Swedish Neur-ologist Karl-Axel Ekbom back in 1945; consequently it is sometimes referred to as Ekbom syndrome.
Two types of RLS
Broadly speaking, there are two types of RLS: primary RLS occurs during early adulthood, with progressive symptoms; and secondary RLS, which is normally brought on by a complication of another health condition such as iron deficiency anaemia, kidney failure or Parkinson’s disease.
People have great difficulty actually describing the sensations, which just adds to the mystery of this condition. It is compared, by some, to a burning sensation, or an itching or ‘tickling feeling’ in the muscles, or even like ants crawling under the skin.
It affects both men and women (curiously, more women present) and it gets progressively worse as people get older, with more people over the age of 65 finding their way to their GP with RLS.
There are a number of licensed treatments for RLS, which work directly on the dopamine system in the brain and suppress the unpleasant sensations and the urge to move repetitively and incessantly.
In 2003 the National Institutes of Health in the US came up with a criteria for the condition. It includes the following:
1. An urge to move the limbs with or without sensations;
2. Improvement with activity;
3. Worsening at rest; and
4. Worsening in the evening or night-time.
When it comes to the treatment options, the dopamine agonists are currently the preferred choice (Neurologist, 2007).
Controversy abounds in RLS. Many doctors are yet to be convinced that it is a distinct syndrome; others consider it a real entity that has specific diagnostic criteria. The US National Institute of Neurological Disorders and Stroke rowed into the controversy recently with a definitive definition; they published an information sheet characterising the syndrome and then acknowledged it as a ‘difficult diagnosis’.
The dopamine effect
Parkinsonism is the name given to a clinical syndrome comprising impairment of voluntary movement (hypokinesis), rigidity and tremor. Its incidence is roughly 1 in every 1,000, rising to about 1 per cent in those over 60 years (Simpson & Cull). The condition is caused by lesions in the basal nuclei and is associated particularly with damage to the interconnecting system between the substantia nigra and the corpus striatum.
Indeed, most of the information that has accumulated regarding the actions of the basal ganglia in humans has been derived from studies of the effects of damage to those brain areas.
Functionally, the basal ganglia are associated with the subthalamic nuclei and the substantia nigra (so called because many of its cells are pigmented with melanin) of the midbrain and the red nucleus.
The nigrostriatal pathways utilise dopamine as a neurotransmitter and Parkinsonism is associated with dopamine deficiency. The precise pathophysiology and the interdependent biochemical abnormalities in Parkinsonism are not fully defined.
Tremor
Tremor is usually the feature that causes the patient to seek advice. Traditionally, it first involves the fingers and spreads to priximal parts of the arms; it may later extend to the tongue and the legs. Head tremors are rare in Parkinsonism.
Tremor may be absent altogether during the course of the condition and, if it is present, it may well diminish as rigidity progresses. There can also be a number of insidious signs evident, like a gradual reduction in size and legibility of a patient’s handwriting. Other fine movements are attacked, like the fastening of buttons and laces. Even the simple pleasure of turning over in one’s bed can become a painful and impossible chore.
The condition was not formally recognised until 1817, when the physician James Parkinson brought it to prominence in an essay entitled, “The Shaking Palsy.” The actual term ‘Parkinson’s disease’ was coined later by Jean-Martin Charcot.
The Swedish scientist Arvid Carlsson was awarded the Nobel Prize in the 1950s for his work on underlying biochemical changes in the brain, brought about by PD. L-dopa entered the clinical sphere in the late 1960s and a treatment regime was firmly laid down.
Attack on HQ
Wherever you see the tremors mentioned, there also is mention of the basal ganglia. In classical neuroanatomy, the basal ganglia is where it is at. It’s the HQ where the generals pull the strings.
A rich variety of chemical transmitters has been identified within the basal ganglia, which receives information from throughout the frontal lobe cerebral cortex, in addition to the motor cortex and from the substantia nigra in the uppermost part of the brainstem.
More than this, it has been shown (through the use of fluorescent tracers) that the darkly staining neuronal cell bodies of the substantia nigra, responsible for its name, contained the neurotransmitter dopamine.
Tellingly, the number of these neurons is severely reduced in the brains of patients suffering from Parkinsonism. On examination, there was further damage, chiefly in the depletion of noradrenaline and serotonin.
Another feature of Parkinson’s disease is akinesis – a paucity of movement and slowness in starting and/or finishing movements. According to medical scientist Tom Serars, these movements are initiated by an act of will and are carried out automatically.
In so doing, they are implanted through motor programmes ‘refined by practice throughout life’. This is the domain that the basal ganglia appear to be involved in.
Recent research has shown the sheer breadth of the function of the basal ganglia: consisting of multiple segregated pathways, involving the entire frontal cortex, drawing on parallel processing to permit the planning, execution and co-ordination of myriad movements.
Future directions
Future research directions in the management of Parkinson’s disease include gene therapy and neural transplantation. Gene therapy is currently focused on a virus to transport genes into different parts of the brain which, in turn, is designed to promote the production of enzymes to help guard against further damage. As of this year, there are a number of major clinical trials ongoing which involve the use of gene therapy.
Deep brain stimulation is currently one of the favourite surgical options, but it is not alone. Other surgical therapies have also shown promise, including pallidotomy, which focuses on the globus pallidus.
Neural transplantation began as a dedicated study back in 1980. Initial reaction was positive but, as the studies progressed, enthusiasm waned. One of the main drawbacks was an excessive release of dopamine by the transplanted tissue, leading to increased dystonias (Neuroscientist, 2002).
When it comes to neural transplantation, the spotlight is now firmly fixed on the controversial stem cell approaches. However, the jury is very much out on this.
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