Nodding Disease

Jo Poole looks into the mystery disease that has killed thousands of children in rural Africa.

The Daily Mail have pegged it “the zombie disease” haunting North Uganda and tribe witch doctors blame it on vengeful spirits left over from the activities of the Lord’s Resistance Army. But more commonly it has been called ‘nodding disease’.

Tragically, it primarily strikes children between 5 and 15, causing them to nod continuously when they begin to eat or experience cold, leading to the gradual evolution of seizures, mental retardation and stunted growth. It clusters in villages and typically every family has at least one affected child in the hotbed regions. Horrifyingly, there’s no cure. Whilst there are roughly 3000 cases of the disease in Uganda, a drop in the ocean compared to cases of malaria or dysentery, nearly 1000 of these appeared in the last 6 months of 2011 alone.

Moreover, whilst children can recover from the aforementioned illnesses, nodding disease represents a lifelong deterioration that leaves children unable to walk, eat, or even communicate, curled up in the dirt experiencing seizures and incontinence. Many meet their deaths as the result of drowning or falling into fires. One mother laments that, as psychosis progresses, the children tend to wander off and never return, recounting stories of dogs bringing back their corpses.

The same lady, mother of two afflicted children, 10 and 12, says how she treats them as flowers in the home, knowing they will serve no real purpose. She ties them up when she works in the garden so they can’t wander off or injure themselves. They cannot feed, wash or dress without aid, and serving food inevitably triggers fits. This family, like many others, has been socially ostracised and reportedly taxis refuse to take afflicted children to and from school, when they are still able to attend.

So what is Nodding Disease?

Nodding disease was first documented in 1962 and multiple studies since have agreed it is a unique form of epilepsy. The nodding is caused by a transient loss of muscle tone in the neck as the brain begins to experience aberrant electrical activity, and then a seizure sets in. The seizures appear to range from absence seizures (staring into space), to both partial and complex generalised seizures with lack of consciousness, fitting and incontinence. Whilst many of these attacks are spontaneous, a significant number are triggered by food and cold weather. Thus it may represent a form of reflex epilepsy akin to those already known, such as HWE (hot water epilepsy), characteristically brought on by warm baths, or the more familiar photosensitive epilepsy, triggered by flashing lights.

Whilst anti-epileptic drugs have been used to some effect in cases of nodding disease, they do not eradicate seizures completely and are also unable to reverse growth and cognitive impairment. Untreated epilepsy, even in the West, leads to irreversible brain damage. In the case of children, where growth and development are still underway, epilepsy can produce profound mental retardation. Additionally, growth is disrupted as hormonal control is erratic.

MRI and other neuroimaging studies show pronounced hippocampal deterioration and glial cell abnormalities. Not only does the hippocampal degeneration explain some of the mental impairment seen in nodding Disease, but a study last decade observed that epilepsies originating in the temporal lobe (which overlies the hippocampus) sometimes produced head nodding in children but never in adults.

Glial cell activation and post-infective gliosis in infection-induced epilepsies has been linked to ineffective drug control and increased recurrence. Thus the glial cell perturbation seen in nodding disease may underlie the reason current therapies are not completely successful. It is worth mentioning, however, that any reduction in seizure frequency is deemed beneficial, since every seizure evinces cumulative damage to the brain.

Why is it affecting children in North Uganda?

There has been a strong link between nodding disease and the worm parasite O. volvulus. Not only does nodding disease occur in the same geographical areas as the parasite, but 70-90% of cases are positive for this infection. The most common cause of epilepsy worldwide is central nervous system infection, especially by parasites. Both tapeworm and malaria are also known to cause epilepsy, and roundworm larvae transmitted by racoon faeces cause sporadic epilepsy outbreaks in regions of North America. Therefore, it is highly possible O. volvulus causes nodding disease, though there are a few discrepencies.

Firstly, O. volvulus is also prevalent in a lot of areas where nodding disease is not present. However, this is not to say that affected areas just contain a different strain with different behaviours – typically this worm causes ‘river blindness’ due to the larvae’s preference for the eye and subsequent immune attacks. Secondly, whilst skin and blood has tested positive for the worm, there is no evidence for the parasite entering the central nervous system, no evidence on brain scans, and cerebrospinal fluid tests negative.

Despite this, a number of researchers have pointed out that more specific tests have demonstrated central nervous system infection (based on PCR) and that the larvae called microfilariae could still be present in the brain without appearing on imaging. They also pointed out that just because subjects were not actually infected at the time of testing, did not mean they had not been infected before the onset of nodding disease. This is particularly relevant because anti-helminthic medications have been provided free of charge for the last decade, and children would have been treated for the worm when admitted to hospital. Unfortunately, by this time the damage is done.

Vitamin B6 deficiency has also been linked to nodding disease, highlighted by the fact there is a well-known type of vitamin B6-deficient infant epilepsy experienced worldwide. Furthermore, a large percentage of afflicted children with nodding disease are B6 deficient, thus trials are ongoing for vitamin replacement alongside epileptic treatment.

Does it only affect children?

One of the most curious things reported about the epidemic is the age of those afflicted. It does not seem to affect adults, though they can also be infected by the parasite. In fact, some adults do get the disease. Moreover, nodding disease leads to premature death, so many infected as children simply do not reach adulthood. But the effect of brain disturbance in developing children is much more profound than in adulthood, as evidence by the effect of alcohol on the foetus, or cannabis smoking leading to psychosis when smoked in the sensitive teenage years. There may also be more inflammatory immune responses in children compared to adults, leading to more disseminated brain damage, glial cells (affecting the severity and treatability of epilepsy) tend to be more reactive in young brains. There may also be age-related differences in the way the parasite can cross the blood-brain-barrier, a stunch defender of a clean brain environment.

Adult epilepsy is actually still far higher in regions with O. volvulus infections, it just lacks the distinctive head nodding that characterises the childhood variant – which one study has already found to be a child-specific symptom even in ‘normal’ temporal lobe epilepsies. Thus nodding disease may just be a tragic expression of a parasitic epilepsy that afflicts children and adults differently, rather than a disease targeting children only. There have also been studies that suggest parasitic infections induce cross-reactivity, causing autoimmune inflammation in the central nervous sytstem, and this may be a possible mechanism for nodding Disease.

There could also be a genetic component, since it clusters in families and villages. There are a number of chromosomal defects that produce syndromes with epilepsy, mental retardation and stunted growth. Perhaps this on top of malnourishment and parasitic infection leads to the mysterious presentation of nodding disease in children.

What can be done?

Forceful efforts are underway to eradicate O.volvulus, but malnourishment is a much larger problem. Education will hopefully bring patients in before progressive neurological changes occur. Whilst people cry there is an epidemic brewing, it must be remembered that until recently the Ugandan people considered epilepsy as demonic possession, and would not have brought children for treatment. Thus the increase in diagnosed cases may reflect a wider social tolerance rather than an increase in incidence per se.

Although thousands of children have been afflicted by this merciless illness, epileptic and anti-helminthic treatments do make a difference. Furthermore, the situation has really caught the eye of Western science and multiple studies are underway to discover the root cause. In ten years let us hope nodding disease will be consigned to the history books.

“Eating Epilepsy Characterised by Periodic Spasms” [DOI: 10.1055/s-2002-37080]
C. Nakazawa, S. Fujimoto, M. Watanabe, M. Tanaka, M. Kageyama, T. Ishikawa, Y. Watanabe
Neuropediatrics, 2002, 33(6):294-297

“Perilesional gliosis and seizure outcome: a study based on magnetization transfer magnetic resonance imaging in patients with neurocysticercosis”
S. Pradhan, M. K. Kathuria, R. K. Gupta
Annals of Neurology, Aug 2000, 48(2):181-7

“Onchocerciasis-related epilepsy? Prospects at a time of uncertainty”
B. Marin, M. Boussinesq, M. Druet-Cabanac, J. Kamgno, B. Bouteille, P. M. Preux
Trends in Parasitology, Jan 2006, 22(1):17-20

Image: ugandaspeaks.com

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