Nutritional and Other Neuropathies Associated with Gastrointestinal Di.sorders
12/28/02
Laurence J Kinsella, MD, FACP
Chief, Division of Neurology and Neurophysiology
Forest Park Hospital
Associate Professor, Neurology
Saint Louis University

Gluten Sensitivity Neuropathy (Celiac Disease)
This is a proposed autoimmune disorder induced by celiac disease. Wheat, barley, and oats are
composed of gluten that may induce an antibody reaction in susceptible individuals. These
antibodies are thought to be directed against Purkinje cells and other nervous system tissue
leading to a variety of disorders including cerebellar ataxia, neuropathy, and myoclonus.
Hadjivassiliou reviewed 35 reports of neurologic disorders associated with celiac disease in 83
patients (mean age 48, M=F). These included ataxia (29), peripheral neuropathy (29), myopathy
(13), ataxia with myoclonus (9), myelopathy (4), and dementia (6). The same author has reported
up to 40% of patients with idiopathic peripheral neuropathy have anti-gliadin antibodies
(Hadjivassiliou, 2002).
The neuromuscular manifestations include sensorimotor axonal neuropathy, axonal motor, and
mononeuropathy multiplex. All patients were found to have anti-gliadin antibodies, either IgG or
IgA. Of all patients with positive antibodies, only 35% have an abnormal intestinal biopsy,
suggesting that neurologic symptoms may occur without GI symptoms. HLA DQ2 is found in
90% of patients with celiac disease so this offers an additional confirmatory test. Further study is
needed of this potentially important cause of neurologic illness.

Cobalamin deficiency may be caused by a number of malabsorption syndromes, most commonly
pernicious anemia, which accounts for well over 80% of all cases of B-12 deficiency. In up to
10% of patients, the cobalamin deficiency may be due to food cobalamin malabsorption, which
results from achlorhydria and an inability to separate cobalamin from food due to inadequate
gastric acidity. A number of other malabsorptive syndromes of the lower gut, such as bacterial
overgrowth, tapeworm infestation, Crohn's disease, and ulcerative colitis, may also result in
cobalamin deficiency (Green and Kinsella 1995; Savage and Lindenbaum 1995).
Post gastroplasty neuropathy and Strachan's syndrome remain a mystery in terms of the exact
etiology but are probably polynutritional in origin, with a heavy emphasis on thiamin deficiency.

Pyridoxine excess
Toxic doses of pyridoxine may also result in a large fiber sensory peripheral neuropathy
(Schaumburg et al 1983; Parry and Bredesen 1985; Dalton and Dalton 1987). Mega doses of
pyridoxine may produce a sensory neuropathy after several weeks of use, generally in excess of 2
grams per day. It has also been reported with longstanding use of as little as 200 mg a day.
Symptoms of paresthesias, ataxia, and burning feet occur 1 month to 3 years after starting
pyridoxine.
Axonal degeneration, reduced myelin fiber density, and myelin debris have all been demonstrated
in sural nerve biopsies. After stopping the pyridoxine, few patients entirely resolved, but most
improved. Individuals who use large doses of B-complex vitamins are under the false impression
that, because B-complex vitamins are water soluble and, therefore, are excreted in the urine, it is
not possible to take too much. In fact, 200 mg doses of pyridoxine are commonly found as
single tablets in pharmacies and are sufficient to cause a sensory neuropathy after many months
of exposure.
Strachan's syndrome
In 1888, Henry Strachan, a British medical officer stationed in Jamaica, described a syndrome of
painful peripheral neuropathy, ataxia, optic neuropathy, and stomatitis among sugarcane workers
(Strachan 1897). Denny Brown and others found similar ailments among allied troops liberated
from prisoner of war camps after World War II (Denny-Brown 1947). Other symptoms included
sensorineural deafness, dizziness, confusion, spastic leg weakness, foot drop, Wernicke's
encephalopathy, and rare cases of neck extensor weakness and myasthenic bulbar weakness. Poor
nutrition, hard physical labor, and concurrent infection were thought to be exacerbating factors.
Fischer performed autopsies on a series of Canadian prisoners of war, the most prominent
pathologic findings were demyelination of the posterior columns of thoracic and cervical spinal
cord (Fischer 1955).
More recently, an outbreak of optic and peripheral neuropathy closely resembling Strachan's
syndrome occurred in Cuba from 1992 to 1993 following a loss of food and fuel imports from
the former Soviet Union (Roman 1994). Fifty thousand people developed either isolated or
combined optic neuropathy, painful sensory neuropathy, dorsal lateral myelopathy, sensory neural
deafness, spastic paraparesis, dysphonia, and dysautonomia. Forty- five percent developed
centrocecal scotoma and optic neuropathy only, often following a period of weight loss. A
number of possibilities were proposed, including vitamin B-complex and thiamin deficiency,
cyanide intoxication, viral infections, and mitochondrial deletions. Heavy alcohol and tobacco use
were found most frequently in those with optic neuropathy (tobacco-alcohol amblyopia). Clinical
evidence of neuropathy was often lacking despite the severe symptoms (Thomas et al 1995).
Sural nerve biopsy showed axonal degeneration of large myelinated fibers. Most patients
responded to supplementation of B-complex vitamins.

Vitamin E deficiency
Vitamin E is fat soluble and found in abundance in vegetable oils and wheat germ. It is carried
in portal blood to the liver, and alpha- tocopherol transfer protein binds it and recycles vitamin E
in the liver for incorporation into low density and very low density lipoproteins. The patients at
risk for development of vitamin E deficiency include those with hypo or abetalipoproteinemia,
other disorders of the pancreas and liver, such as cystic fibrosis, protein-calorie malnutrition,
familial vitamin E deficiency, and other malabsorption states (Jackson et al 1996). Symptoms
include areflexia, cerebellar ataxia, cutaneous sensory impairment, position and vibratory sense
abnormalities and less commonly, ophthalmoplegia, muscle weakness, nystagmus, extensor plantar
responses, ptosis, and dysarthria. The peripheral neuropathy is usually limited to the legs and is
mild, axonal, and sensorimotor in nature (Brin et al 1986).

13. Diagnostic Evaluation
Thiamin deficiency may be assessed by the transketolase assay. Because the carbohydratemetabolizing enzyme transketolase requires thiamin pyrophosphate, a deficiency will lead to an elevation in the red blood cell transketolase. The assay is most sensitive when performed with and without a thiamin pyrophosphate challenge. Serum thiamin levels are unreliable due to low sensitivity and specificity. MRI of the brain will occasionally show an abnormal signal in the periaqueductal gray matter and midline structures. Cobalamin deficiency may be due to a variety of disorders, most commonly pernicious anemia. Approximately 78% of patients with cobalamin deficiency will be found to have a proven or probable defect of intrinsic factor production from the gastric parietal cell (pernicious anemia). Perhaps 10% of patients have food-cobalamin malabsorption due to hypo- or achlorhydria, a disorder that affects from 16-40% of the elderly ( Hurwitz et al, 1997). The rest are due to a variety of causes including malabsorption from inflammatory bowel disease, tape worm infestation, blind loop syndrome, chronic H2 blocker therapy, gastric bypass, and serum binding protein abnormalities. In a patient with signs and symptoms of cobalamin deficiency, one should begin with a cobalamin assay. If the serum cobalamin assay result is less than the lower normal limit, a measurement of intrinsic factor antibodies should be taken. If this test is positive, the diagnosis of pernicious anemia is confirmed, and a Schilling test is not necessary. In pernicious anemia, some laboratory evidence of an autoimmune process is often found. Anti- parietal cell antibodies are present in 90% and intrinsic factor antibodies in 60% of patients with pernicious anemia. Antiparietal cell antibodies have a 10% false positive rate. Though it lacks sensitivity, the test for intrinsic factor antibodies is much more specific.

In patients with serum cobalamin levels in the lower normal range, but in whom one still
suspects clinical cobalamin deficiency, one should measure levels of homocysteine and
methylmalonic acid (Snow, 1999; Kinsella and Green, 1995). Methylmalonic acid may be
measured in serum or urine. The urinary assay is more specific in patients with renal
insufficiency. If either metabolite is elevated, then serum intrinsic factor antibodies and gastrin
should be measured. The serum gastrin level is often elevated in pernicious anemia and is a
marker for achlorhydria, a cause of food- cobalamin malabsorption.
The presence of hypersegmentation may be a sensitive marker for cobalamin deficiency, even in
the absence of anemia or macrocytosis. If metabolites or the serum gastrin are elevated, a
Schilling test may be performed to identify cobalamin absorption, which is usually the result of
autoimmune parietal cell dysfunction that occurs in pernicious anemia. Technically, patients with
classic pernicious anemia have an abnormal test result when radioactive cobalamin alone is given
by mouth (Part I). This abnormality is corrected when the test is repeated with intrinsic factor
(Part II). Abnormally low secretion of cobalamin in the Part II Schilling test indicates an
intestinal cause for the cobalamin malabsorption, such as inflammatory bowel disease. The Part II
Schilling test may be repeated, after giving antibiotics or vermacides to exclude bacterial
overgrowth ("blind loop syndrome") or fish tapeworm infestation due to diphyllobothrium latum,
rare causes of cobalamin deficiency through competition for intraluminal cobalamin.
A normal Part I test in a patient with cobalamin deficiency may be observed in total vegetarians.
It may also occur in patients with food-cobalamin malabsorption who show normal absorption of
crystalline cobalamin but are unable to digest and absorb cobalamin present in food due to
achlorhydria. This defect can be identified using a modified Schilling test in which radioactive
cobalamin is administered with food (Carmel, 1990).
Pyridoxine deficiency will cause elevations in serum homocysteine and cystathionine, and assays
are commercially available. Urinary assays for xanthurenic acid and other pyridoxine metabolites
may be performed following tryptophan loading.
Vitamin E deficiency can be reliably investigated using the serum alpha- tocopherol level. Adult
patients without malabsorption and a clinical picture consistent with Friedrich’s ataxia and
neuropathy should be investigated for an autosomal recessive defect in the tocopherol transporter
protein gene of chromosome 8. Tocopherol transporter protein incorporates tocopherol into
chylomicrons. The serum tocopherol levels in these patients may be in the normal range;
however, they respond to high dose supplementation.

Strachan’s syndrome and are polynutritional in origin; therefore, a battery of vitamin deficiencies
should be sought, including thiamin, niacin, pyridoxine, and cobalamin. The pathophysiology of
post-gastroplasty neuropathy is probably multifactorial, due perhaps to a polynutritional and an
endogenous toxin produced as the result of the abnormal anatomy created by the surgical
procedure. This toxic hypothesis is supported by the fact that some have reported a resolution of
the symptoms following reversal of the surgical procedure whereas nutritional replacement alone
does not. Alternatively, there may be a nutritional factor that cannot be replaced adequately until
the procedure has been reversed.Pyridoxine deficiency will cause elevations in serum homocysteine and cystathionine, and assays are commercially available. Urinary assays for xanthurenic acid and other pyridoxine metabolites may be performed following tryptophan loading.
Vitamin E deficiency can be reliably investigated using the serum alpha- tocopherol level. Adult
patients without malabsorption and a clinical picture consistent with Friedrich’s ataxia and
neuropathy should be investigated for an autosomal recessive defect in the tocopherol transporter
protein gene of chromosome 8. Tocopherol transporter protein incorporates tocopherol into
chylomicrons. The serum tocopherol levels in these patients may be in the normal range;
however, they respond to high dose supplementation.