Funicular spinal disease E53.8+G32.0*

Synonyms

Funicular myelosis; myelopathy; funicular myelosis; funicular spinal cord disease; subacute combined degeneration (SCD) of the spinal cord;

First author

Richard Henneberg (1868- 1962) first coined the name "myelitis funicularis" for funicular spinal disease. However, since it is not an inflammatory process, he proposed the name "funicular myelosis" (Czerny 1935).

Dorothy Hodgkin was awarded the Nobel Prize in Chemistry in 1964 for the structural elucidation of cobalamin (vitamin B12) (Berlit 2011).

Funicular spinal disease is a neurological-psychiatric syndrome in which there is primarily vitamin B12 deficiency (Herold 2022), and more rarely folic acid (Ende- Henningsen 2018) or copper deficiency (Hacke 2019). Frequently, vitamin B12 deficiency is additionally accompanied by folic acid deficiency (Gröber 2013).

Funicular spinal disease may affect the following structures:

- medullary pyramidal tract

- posterior funicular tracts

- cerebellar lateral tracts (Gröber 2013).

Funicular spinal disease occurs predominantly in the elderly (Heckl 2022).

Approximately 60% of patients with pernicious anemia show symptoms of funicular spinal disease.

In about 25% of patients with laboratory-proven Vit. B12 deficiency and neurological disorders, there are no other hematologic changes. Interestingly, there is an inverse correlation between severity of hematologic and neurologic disease. To date, the cause of this is unknown (Gröber 2013).

Folic acid deficiency represents the most common vitamin deficiency in Western Europe and North America (Ende- Henningsen 2018).

Funicular spinal disease is caused by:

- 1. vitamin B12 deficiency

Vitamin B12 deficiency can be caused by insufficient intake, impaired absorption, impaired utilization (e.g. by cytostatic drugs, congenital disorders in folic acid metabolism) and by increased consumption (Berlit 2011).

This can be caused by, for example:

- nutritional deficiency

- Intestinal diseases including fish tapeworm infestation, fungal infestation of the intestine (Hacke 2019).

- metabolic disorders with disturbed vitamin B12 utilization

- Decreased production of gastric acid (occurs preferentially in the elderly)

- Drug-induced by e.g. proton pump inhibitors (Gröber 2013), anticonvulsants, biguanides, hydantoins, calcium-binding substances, phenylbutazone, nitrofurantoin, cytostatics (Hacke 2019)

- Alcohol abuse (Kasper 2015)

- Anorexia nervosa (Berlit 2011)

- Malabsorption in e.g., atrophic gastritis with e.g., deficiency of anti-intrinsic factor, autoantibodies against occupant cells (parietal cells) (Wolpert 2015)

- Nitrous oxide abuse (Wolpert 2015)

- Following bariatric surgery (Dudorova 2015)

- Z. n. gastrectomy (Hacke 2019)

- 2. folic acid deficiency

This occurs preferentially in e.g.:

- Pregnancy

- lactation

- chronic alcoholics (Ende- Henningsen 2018)

- 3. copper deficiency (Hacke 2019).

This can occur in the context of the following diseases:

- Wilson's disease

- malnutrition

- Zinc overdose

- Menkes syndrome

- intestinal malabsorption (see copper)

Risk groups for Vit. B12 deficiency are:

- vegetarians and vegans

- Increased need for Vit. B12, e.g. in autoimmune diseases, HIV-infected persons, pregnant women, etc.

- chronic kidney diseases

- gastrointestinal diseases

- Long-term therapy of e.g. metformin, H2 blockers, proton pump inhibitors (Gröber 2013)

Vit. B12 deficiency leads to a loss of myelinated sensory (afferent) fibers in the spinal cord and peripheral nervous system (Kasper 2015). Hydroxycobalamin plays a role in this process. However, it is as yet unclear what ultimately leads to damage of the myelin sheaths (Hacke 2019).

Characteristically, demyelination of the posterior cords in the spinal cord occurs first, followed by demyelination of the lateral cords (Heckl 2022).

Due to the defective myelin sheaths, a demyelinating disease develops through a combined degeneration of the lateral and posterior funiculi of the spinal cord (Gröber 2013).

- Vit. B12 deficiency:

About 90% of vitamin B12 is stored in the liver. Symptoms only appear after years of deficiency (Ende- Henningsen 2018).

- Folic acid deficiency:

In this case, symptoms appear after about 20 weeks of a diet low in folic acid (Ende- Henningsen 2018).

Patients initially complain of sensory deficits with balance disturbances, ataxia, paresthesias, and weakness in the legs. The symptoms develop subacutely within a few weeks or months (Hacke 2019). Only in the advanced stage can spasticity and paraplegia occur (Heckl 2022).

There is always a symmetry of symptoms. I. d. R. these symptoms are more pronounced in the lower extremities than in the upper (Gröber 2013).

In case of myelin sheath atrophy of the posterior cords, there is a disturbance of proprioceptive perception (Heckl 2022) (information originating from inside the body [Funke 2020]).

There is:

- Primarily a deterioration of the vibration sensation and the sense of touch (Heckl 2022).

- Gait unsteadiness

This occurs particularly with eyes closed or in darkness (Heckl 2022). Patients typically look down when walking (Kasper 2015).

- Spinal ataxia (Herold 2022).

This leads to uncoordinated movements and balance problems (Heckl 2022).

If the pyramidal tract is affected, the following symptoms may occur:

- Paresis (Herold 2022).

The pareses are distally accentuated (Heuß 2019).

- Pyramidal tract signs (Herold 2022).

- Spasticity of all extremities

- Bladder and bowel incontinence (Heckl 2022).

In addition, there may be:

- Polyneuropathy of the extremities with

- painful paresthesias

- tingling

- furry feeling

- areflexia of the lower extremities

- psychotic symptoms (Herold 2022)

- catatonia

- depressions

- dementia-like symptoms (Gröber 2013)

- clumsiness in writing (Wolpert 2015)

- Eye muscle paralysis (rare)

- Optic atrophy (rare)

(Hacke 2019)

In addition, the typical symptoms of vit. B 12 anemia may also exist (see d.)

- Tuning fork test

The earliest and most sensitive test shows a disturbance of depth sensitivity (Herold 2022).

- Laboratory tests (see d.)

- Physical examination:

Here may exist: Decreased sense of position and vibration, hypalgesia and hypesthesias of the extremities,. Polyneuropathies (Wolpert 2015).

Intrinsic reflexes may be increased, but sometimes not triggerable (Hacke 2019).

Hunter- glossitis may exist (mucosal atrophy in the upper gastrointestinal tract with reddened tongue (Hacke 2019).

- Lhermitte's sign

Lhermitte's sign may be present (specific electrifying sensory disturbances of the extremities and trunk when the head is flexed).

(Heckl 2022)

- Romberg sign

Here the patient stands with feet close together and eyes closed. If there is swaying to the point of falling, the test is considered positive (Masuhr 2013).

A positive Romberg may be present at a late stage of the disease as an expression of sensory ataxia (Heckl 2022).

- Nerve conduction velocity

This shows a reduction in sensory and motor nerve conduction velocity (Hacke 2019).

- Magnetic resonance imaging

Signal enhancements of the posterior strands can be visualized in the T2-weighted sequences. The myelon appears partially (in the early stage [Ende- Henningsen 2018]) distended (Hacke 2019). As the disease progresses, a hyperintense signal (Ende- Henningsen 2018) then occurs due to demyelination of the posterior strands or pyramidal tract (Herold 2022).

The posterior cord degeneration of the affected spinal cord segments presents as an inverted V-shaped hyperintensity in the cross-sectional T2-weighted image (Ende- Henningsen 2018).

- Vit. B12

The direct measurement of the Vit. B12 level is only considered a screening procedure.

If the serum level is low and normal, an additional determination of methylmalonic acid (MMA) and homocysteine with the question of a possible Vit. B12 deficiency is recommended (Heuß 2019).

- Methylmalonic acid

Methylmalonic acid should be determined if the Vit. B12- level is normal, since in this case a metabolic deficiency of Vit. B12 may be present (Gröber 2013). Methylmalonic acid is a highly sensitive functional indicator that increases in the presence of Vit. B12 deficiency (Gröber 2013).

- Homocysteine

Homocysteine represents another metabolite besides methylmalonic acid that should be measured at normal Vit. B12 levels (Heuß 2019).

The homocysteine plasma level is usually elevated (Wolpert 2015).

If methylmalonic acid plus homocysteine are within the normal range, a Vit. B12 deficiency can be excluded with almost 100% certainty (Gröber 2013).

In patients with renal insufficiency, however, the values for homocysteine and methylmalonic acid may be distorted, which is why the additional determination of active holotranscobalamin is recommended here (Hacke 2019).

- Holotranscobalamin

A decreased value is considered the earliest evidence of a negative Vit. B12 absorption balance (Heuß 2019).

- Hematological changes

These may be in the form of macrocytic hyperchromic anemia and hypersegmented granulocytes (Hacke 2019), but need not be present (Wolpert 2015).

- Antibodies

If the patient has autoimmune syndromes such as v. a. atrophic gastritis, antibodies against occupancy cells or intrinsic factor should be determined (Hacke 2019).

- Folic acid / copper

Folic acid and copper should also be determined, since a deficiency can cause similar symptoms or can also trigger degenerative spinal disease. In addition, a combined deficiency state is not uncommon (Hacke 2019).

Histopathologically, multifocal spongy vacuolization occurs after edema in the posterior and lateral tracts in the spinal cord. In the edema phase, the disease process can still be arrested by appropriate substitution (Heckl 2022).

- Chronic progressive, spinal manifestation of multiple sclerosis.

- subacute forms of myelitis such as sarcoidosis, cervical myelopathy, HIV myelopathy, and lupus erythematosus

- infectious myelitis, e.g., caused by pathogens of the herpes group

- spinal form of meningeosis carcinomatosa

- paraneoplastic myelopathies (Ende- Henningsen 2018)

- Disease patterns in which, in addition to the spinal appearance, there is also a polyneuropathy, such as in the case of

- AIDS-associated myelopathies

- paraneoplastic syndromes

- late stage of Lyme disease

- Lupus erythematosus (Ende- Henningsen 2018).

In copper deficiency-associated myelopathy, differential diagnosis should exclude:

- funicular myelosis (Ende- Henningsen 2018).

- Vitamin B12 deficiency:

The causal therapy consists of the elimination of malnutrition and abstinence from alcohol, if this is present (Herold 2022).

Even if the laboratory findings do not indicate a vitamin B12 deficiency, an attempt at therapy with the preparations mentioned below should be attempted if the symptoms are corresponding (Hacke 2019).

The therapy consists of treatment with e.g. cyanocobalamin (Vit. B12) or 2 active coenzyme forms: methylcobalamin or adenosylcobalamin.

The active coenzyme forms have different metabolic functions (methylcobalamin together with folic acid is involved in hematopoiesis and infantile brain development, adenosylcobalamin is important for carbohydrate. fat and amino acid metabolism as well as myelination). These two supplements should therefore be given in combination (Thakkar2015).

In deficiency states due to malnutrition, the daily dose is between 10 - 100 µg until the level is normalized. In case of intestinal diseases, malabsorption or utilization disorders, higher doses are required (Gröber 2013).

In practice, therapy is predominantly administered parenterally.

Dosage recommendation: Initially 1,000 µg / week i. m. or s. c. until the blood count has normalized. Subsequently, a lifelong substitution of 1,000 µg i. m. or s. c. should be given every 1 - 3 months (Herold 2022).

A randomized controlled trial by Butler (2006) showed that oral administration may have the same efficacy. Herold (2022), however, points out that only 1% is absorbed with oral substitution.

- Folic acid deficiency:

Causal therapy also consists of elimination of malnutrition and abstinence from alcohol (Herold 2022).

In the acute stage of the disease, the patient should be administered 15 mg folic acid / d i. m. for the first 3 - 5 days, then 2 - 3 x 5 mg / d orally or 10 - 15 mg i. m. for the subsequent 2 - 3 weeks. After that, the stores are replenished (Ende- Henningsen 2018).

The maintenance medication is 5 mg folic acid / d orally (Herold 2022).

In the early stages, neurological symptoms of vitamin B12 deficiency are still reversible, but once axonal degeneration has occurred, they are irreversible (Herold 2022). Therefore, residual symptoms remain in about 50% of patients (Berlit 2011).

In most cases, substitution therapy is required for life (Berlit 2011).

In the case of unclear neurological disorders, Vit. B12 deficiency should always be considered, even if anemia is not present (Herold 2022).

Adjuvant Vit. B12 administration is recommended in particular for elderly people, patients with neurological diseases and patients on long-term medication to improve cognitive performance and reduce the risk of brain atrophy (Gröber 2013).

At the beginning of substitution therapy, there may be an initial worsening of neurological symptoms in rare cases (about 2%). However, this is always of a temporary nature (1 - 4 weeks). However, if there is no improvement in symptoms after 3 months, the diagnosis should be reviewed (Berlit 2011).

1. P. Berlit (2011) Clinical neurology. Springer Verlag Berlin / Heidelberg 580 - 585
2. Brandt T, Hohlfeld R, Noth J, Reichmann H, Nacimiento W, Papke K, Brassel F, Klassen P D (2014) Spinal cord diseases: basic principles, diagnosis and therapy for clinic and practice. W. Kohlhammer Publishers Stuttgart 104 - 105.
3. Butler C C, Vidal- Alaball J, Cannings- John R, McCaddon A, Hood K, Papaioannou A, McDowell I, Goringe A (2006) Oral vitamin B12 versus intramuscular vitamin B12for vitamin B12 deficiency: a systematic review of randomized controlled trials. Family Practise 23 (3) 279 - 285.
4. Czerny A, Kraus F, Müller F, von Pfaund M, Schittenhelm A (1935) Results of internal medicine and pediatrics. Published by Julius Springer Berlin 347
5. Dudorova E Y, Damalin I V, Khatkov I E (2015) Neurological complications due to vitamin deficiencies after bariatric surgery. Ter Arkh. 87 (12) 117 - 121
6. Ende- Henningsen B (2018) Clinical neurology: funicular myelosis. e -Medpedia DOI: https://www.springermedizin.de/emedpedia/klinische-neurologie/funikulaere-myelose?epediaDoi=10.1007%2F978-3-662-44768-0_72
7. Funke U (2020) Interaction and communication in autism spectrum disorders: leading to language with Komm!Ass. Verlag W. Kohlhammer GmbH 21
8. Gröber U, Kister K, Schmidt J (2013) Neuroenhancement with vitamin B12 - Underestimated neurological significance. Nutrients 5 (12) 50 31 - 50 45.
9. Hacke W, Wick W, Schwab S, Ringleb P, Brendszus M (2019) Neurology. Springer Verlag Berlin / Heidelberg 699 - 700
10. Heckl S, Bender B, Gohla G, Baumgartner K, Horger M (2022) Typical MRI features in funicular myelosis. RöFo advances in the field of X-rays and imaging techniques. Georg Thieme Verlag KG. DOI: 10.1055/a-1981-1315
11. Herold G et al (2022) Internal medicine. Herold Publishers 40 - 41
12. Heuß D et al. (2019) Diagnosis of polyneuropathies, S1- guideline. German Society of Neurology, guidelines for diagnosis and therapy in neurology. AWMF- registration number: 030 / 067.
13. Kasper D L, Fauci A S, Hauser S L, Longo D L, Jameson J L, Loscalzo J et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 163, 640, 643, 648
14. Masuhr K F, Masuhr F, Neumann M (2013) Dual series: neurology.Georg Thieme Verlag Stuttgart 84.
15. Thakkar K, Billa G (2015) Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion. Eur J Clin Nutr 69 (1) 1 -2
16. Wolpert F, Barath K, Brakowski J, Renzel R, Linnebank M, Gantenbein A R (2015) Funicular myelosis in a butcher: it was the cream cans. Case Rep Neurol Med. article ID 827168, DOI: https://doi.org/10.1155/2015/827168