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 (Return to previous page of burning feet)

J Neurol Neurosurg Psychiatry 2000;69:447-452 ( October )

Neurological manifestations in chronic mountain sickness: the burning feet-burning hands syndrome

P K Thomasa, R H M Kingb, S F Fengb, J R Muddleb, J M Workmanb, J Gamboac, R Tapiad, M Vargasc, O Appenzellere

a University Department of Clinical Neurology, Institute of Neurology, London WC1N 3BG, UK, b University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK, c Peru, Cerro de Pasco, Peru,e New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, NM, USA

Burning paraesthesiae may be a troublesome symptom in several peripheral neuropathies. They are prominent in Strachan's syndrome, a condition originally found in the West Indies but which has subsequently been encountered under conditions of nutritional deprivation such as during the Spanish Civil War, in Japanese prisoner of war camps during the second world war and, most recently, in the epidemic of Cuban neuropathy that occurred in 1991-3. The precise nature of the nutritional deficiency in Strachan's syndrome has not been identified. None of our patients with CMS showed evidence of nutritional deficiency or alcoholism. Burning feet may occur in diabetic sensory polyneuropathy, particularly in the syndrome of acute painful diabetic sensory neuropathy when it is associated with severe contact hyperaesthesia of the skin. Diabetes was excluded in our patients.


Burning and tingling paraesthesiae distally in the lower limbs initially suggested the presence of a Small fiber neuropathy  and these symptoms were reported by all our patients with CMS and in all except one in the hands. This symptom was not restricted to the patients with CMS, however, being reported, in lesser degree and confined to the feet, in four out of five control subjects. There was evidence on neurological examination of a mild distal sensory polyneuropathy in three patients with CMS that predominantly affected small fibre modalities. The biopsy findings indicated the presence of a modest demyelinating neuropathy without a reduction in total myelinated fibre density and a reduced unmyelinated axon density in one biopsy. This altitude associated neuropathy is most


The first description of hypoxic neuropathy was given by Appenzeller et al in 1968, who reported a mild distal polyneuropathy in seven out of eight patients with severe chronic obstructive airways disease (COAD). Subsequently Faden et al  documented the presence of mild sensory loss and reflex depression in the legs in four out of 23 patients with chronic respiratory insufficiency.
The most detailed description of the underlying neuropathological changes in hypoxic neuropathy has been provided by Malik et al. Nerve biopsies obtained from six patients with COADshowed the presence of demyelination and remyelination, a reduced density of unmyelinated axons, and an increased thickness of the basal laminal layer around endoneurial capillaries. The findings in our patients with CMS conform to this apart from the lack of basal laminal thickening. It is of relevance that experimental hypoxia seems to have a selective effect on myelination in peripheral nerve. Benstead et al found that in rats reared under hypoxic conditions there is a selective maldevelopment of peripheral myelin, the myelin sheath being abnormally thin for axon diameter.


Basal laminal thickening around endoneurial microvessels is seen in many neuropathies but is most characteristic of diabetic neuropathy. The finding of reduced basal laminal thicknessin our patients with CMS is unexpected but not surprising. One possibility is that it is not part of a neuropathic process but represents an adaptive phenomenon to life at high altitude. Similar adaptive microvascular changes have previously been found in othertissues of high altitude native human beings and animals. It is not unreasonable that the finding of reduced basal laminal thickness in altitude associated hypoxia of nerves differs from that occurring in acquired disease associated hypoxic neuropathies such as that in COAD examined by Malik et al.24 Whereas thickening of the basal lamina layer is a non-specific finding in variousdiseases of peripheral nerves, thinness of this structure, on the other hand, is likely to be a lifelong adaptive process thathas now also been found to occur in the human sural nerve.
The relevance of the mild sensory neuropathy in patients with CMS to the occurrence of the burning feet-burning hands syndrome is questionable as patients with neuropathy related to COAD do not experience this symptom,  and there was no clinical evidence of neuropathy in seven out of our 10 patients with CMS,all of whom experienced burning feet and burning hands. Some other explanation is therefore necessary. In this connection, the improvement of the burning feet and hands on transfer to a lower altitude is of particular interest. The improvement took place over 2 weeks for the lower limbs and 1 week in the upper limbs. On returning to high altitude, the symptoms recurred in the hands before the feet. This fairly rapid time course suggests that the regression is not related to structural restitution. The time course is also too rapid for it to be due to a reduction in blood viscosity, as normalisation of the packed cell volume is known to take about 2 months.  Conversely, it is not rapid enough for it to berelated to a direct effect of transfer to normal ambient oxygen concentrations.
The duration and the pattern of disappearance of the symptoms would be consistent with the resolution of a dysfunction involving a factor delivered to the periphery by fast axonal transport. This has a rate of 400 mm/day  One possibility would be delivery of nitric oxide synthase. Nitric oxide has a strong vasodilatory action and its lack at the periphery could lead to reduced vascular perfusion. The effect of hypoxia on nitric oxide synthase gene expression in central and peripheral neurons has been examined in rats by Prabhaker et al. The expression of neuronal nitric oxide synthase (nNOS) mRNA was found to be increased by 10.4 (SD 1.3)% in the vagal nodose ganglia and by 2.0 (SD 1.4)% in the cerebellum. No significant effect was detected for endothelial nitric oxide synthase (eNOS). As CMS is a neuronal maladaptation syndrome, it is conceivable that the upregulation of the nNOS synthase gene in response to hypoxia fails to occur, resulting in a reduced delivery of nNOS synthase to the periphery. This would be corrected by transfer to the higher atmospheric oxygen concentrations at sea level. The pattern of reappearance of symptoms on return to high altitude from sea level would also be consistent with this interpretation, the recurrence affecting the hands before the feet. This is the opposite of the usual pattern for distal "length related" neuropathy, but would be in accordance with the depletion of a factor delivered by axonal transport. Although this hypothesis for the occurrence of the burning feet-burning hands syndrome in CMS is speculative, observations on nNOS concentrations in peripheral nerve in patients with CMS with this syndrome would be of interest.