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MONONEVRITIS MULTIPLEX-NEW INSIGHTS
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Mononevritis in children can have more clinical aspects, and can be deceptive even to experimented physicians. Th e multiple etiologies andthe complex investigations needed to put a diagnosis can lead to underrecognizing this condition, resulting to severe and regrettable traitment options.Mononevritis multiplex give multifocal and asymetric lesions, they can have acut or chronic presentation and in time can get symmetric.Objectives: We want to put on table the most various causes of the disease, the onset symptomes of the disease and the fi ne diff erential diagnosis, so facilitatingto the doctors which send the case to the specialist, diagnostic clues and so shorteninig the delay of diagnosis and the correct therapeutic approach.Gold standard are the modern diagnostic test, MRI, EMG, immunologisc tests.
Material and methods: We took the literature on this fi eld in the last fi ve years, Medline, Pubmed , classic bibliography and other sources.Results: Th e costs for the diagnosis are generally high so the patient must be reff ered to tertiary care center in neuromuscular and/or genetic disease.Treatment comes after a correct diagnosis involving mostly the treatment of the underlying cause and the supportive care for the disabilities generatedby the disease. Often ther is used cotricotherapy and immunoglobulines but also Azathioprine and Ciclophosphamide. Important are the surgicalmycrotechniques for the corection of the invalidant lesions which can alter the nerve function and the functionality of the patient, so for example the anticlawprocedure is saving the nerve after the lesions of the ulnar nerve.Conclusions and discussions: Th e rapid treatment of monoevritis multiplex gives miniem sequelaesor complete recovery. After a correct diagnosis thepatinet is having a multimodal care plan. Th e role of each medical, surghical or physical therapy is approximately of equal importance , an individualisedtherapy is needed after the etiology of the disease and the patients characteristics. Educations of the patients is important for example in obesity educationof dietetic habits and the avoidance of positions which can lead to nerve compression and ischemia of the nerve as also avoidance of intnese physical eff ort.Th e patient must get the highest capacity of cuntioning, for to regain his daily rituals, to can rehabilitate motor and social, this inabilities aff ecting hissocial and his family life and of the members of the family. Future research brings new substances active on the limbic cortex having role in the aff ectiveand pain behaviors now beeing tested on mice. So we can look in an integrative manner to the mononevritis multiplex concept from molecular medicineto the classical clinical aspects of it which can make us attentive on it.
Mononevritis multiplex can be defined as a multiple mononeuropathy with multiple lesions of more peripheric nerves (from different nervous plexi). The deficits are assymetric and are motor, sensorial or mixed . As the disease progresses the multifocal character estompates and it becomes more symmetric . Duration of the disease can be days or years,
Mononevritis can cause also pain which is profound and is more intense in the night and often showing dorsalgia, thigh pain or the inferior limb . The neuropathic processes from childhood can worsen and processes which get better in time. Those which improve in time are the aquired like vitamine deficiencies, toxic, immune mediated, or focal mononeuropaties. The progressive ones are the hereditary/genetic like the group of the sensoriomotor hereditary neuropaties, and the immune mediated neuropathies. Generally when this mononeuropathies have an earlier onset in chuildhood their course and prognosis are worse compared with those of which onset is in adult life. There are some exceptions like the children which present as floppy infants due to a congenital neuropathy with respiratory difficulties and which can recover to walk independently .
Table I. Causes of mononevritis multiplex
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CELIAC DISEASE: The neurologic complication of the celiac disease like epilepsy, ataxia, neuropathy, headache and migrains are present in 10% of patients with celiac disease, but the involvement of the periferic nervous system in children with celiac disease is not frequent. The neuropathy associated to the celiac disease takes the form of a sensorial neuropathy with distal sensory loss, paresthesias, gait disturbances.
Rare we can see an acute rapid progressing syndrome like inflammatory demyelinating polyneuropathy, mononevritis multiplex, pure motor neuropathy, and autonomic dysfuntion were reported as being asociated to the celiac disease or with anti-gliadin antibodies or antiendomysium .
TANGIER DISEASE: Alfalypoproteinemia is a rare disease, transmitted autosomal recessive which produces a severe deficiency of the high density lypoproteins (HDL) in plasma, and storage of cholesterol esters in different tissues, in the tonsils, spleen, corneea, spinal cord. The gene ATP bindingcassete transporter ABCA1 also known as the Cholesterol Efflux Binding Protein with locus 9q31. ABCA1 plays a key role in the elimination of the lipids from the cell. The disease starts between 2-67 years of
age, and can evolve like a multiple mononeuropathy wiuth favourable but fluctuating outcome or isolated mononeuropathy at the limbs beside other forms like psudosyringomyelia with dissociated sensibility or senzitivo-motory polyneuropathy symmetric slowly progressive .
DIABETES MELLITUS: The associated risk form the beginning of diabetus with proeminent symptoms at 5 years are: 4-10% and at 25 years 13- 15%. The medium time of developing neuropathia in diabetes mellitus is 8 years. The neuropathic manifestations is diabetes mellitus are more frequent in the type 2 (26% compared to those with diabetes mellitus type 1 (8%). When the onset is early inchildhood it looks to be asymptomatic but it exists with sensory loss. In most cases it is pansensory but it can involve selectively just nerve fibers of certain thickness like are the small one. The thermal threshold is reduced, pain is present from the beginning of the disease implying large fibers. The sense of vibration is reduced. There an exist paresthesias. Ahilian reflexes absent. The lombosacrat plexopathy can exist under the name of proximal diabetic neuropathy, spinal amyotrophy, diabetic multifocal neuropathy.
The general prevalence: 0,08 % from total cases. more often in type II diabetes (1,1%), than in type I (0,3%). Symptoms weakness, asymetry, the weakness is proximal, in the cvadriceps and in the thigh adductors, psoas. Distal weakness at the ankles and fingers, related to the sacral plexus or the lombar nervous emergerging. The pain is located more on the hip and thigh and can be severe and can last month after the onset of the disease. The loose of sensibility is distal and symmetric. Osteotendinous reflexes are normal or reduced. Associated factor: poor diabetes control, loose in weight, noninsulinodependent diabetes mellitus. Differential diagnosis includes: Lumbosacrat plexopathy, cauda equina lesions.
Multifocal denervation in the paraspinous muscle and of the inferior limbs. Nerve driving speeds: axonal loss, little CMAPS (Compund muscle action potential) and little SNAP’s (sensory nerve action potential).
Patophysiologic substrate:inflammatory and umoral vasculopathy with accumulation of mononuclear cells and/ or polymorphonuclear near the little vessels. The endoneural capillaries get thicker with accumulation of C5b-9 complement and extravasation of hemosiderin near the vessels. The treatment is focused on the control of pain, and the control of the diabetes but it there can be used corticosteroids like Solumedrol and intravenous
Immunoglobulines with slow recovery in 6 months to 24 months after the control of diabetus mellitus .
In reality this complication occurs often in child diabetes mellitus but often it is overlooked . The neuropathy in diabetes mellitus is more frequent as the duration of the diabetes mellitus increases, when it exist poor glicemic control and when the age is greater . Diabetic ketoacidosis complicating diabetes mellitus can lead to intravascular disseminated coagulopathy which can cmplicate with mononeuritis multiplex due to the thrombosis of vasa nervorum and prolonged ischemia .
POLYARTERITIS NODOSA is a rare vasculitis in childhood. The infantile form of polyarteritis nodosa is recognised as the severe form of Kawasaki disease. In children there exist a cutaneous form, a infantile form and a systemic form. In literatura there was noted one case with mononevritis multiplex .
MUCOPOLIZAHARIDOSIS (MPS) are a group of diseases with an incidence of 100% of carpal tunel syndrome in the MPS I, II and VI form. If this patients are operated the electrophysiologic testing becomes much better . The lysosomal storage diseases are frequent cuases for the heredopaties which determine the carpal tunnel syndrome in children. After surgical decompression it was found a great compression of the nerve due to the thickening of the flexor retinaculum.
The hystopathology of the thickened tissue has showed fibers and a thickened flexor retinnaculum. At electron mycroscopy macrophages with membrane –vacuolated zebra bodies . The bilateral carpal tunnel syndrome can complicate mucopolyzaharidosis III (pseudo-Hurler polydystrophy) . Measuring echografic the median nerve emerging from the carpal tunnel and at the medium third average of the forearm at patients with MPS II the nerve was found thicker than in healthy subjects. Other echografic manifestations found in this condition were hypoechogenity,thickened muscular fascia, irregular contour, and Dopler ultrasoundanomalies .
AUTOIMMUNE HEPATITIS For many petients with autoimmune hepatitis the extrahepatic manifestations are well-known, when they are on long term and very long term follow up. Concomitant autoimmune disorders were described in 20-25% of patients with autoimmune hepatitis in adults and children. So they can have joint pain, chronic juvenile artritis, connective tissue diseases, skin rush, fever, celiac disease, IgA deficit, Chron’s disease, ulcerative colitis, Syogren syndrome, systemic lupus erythematosus, glomerulonefritis, fibrosing alveolitis, hemolytic, uveitis, mononevritis multiplex, polymyositis, multiple sclerosis .
SYSTEMIC LUPUS ERYTHEMATOSUS
The prevalence of neuropsychiatric manifestations in pediatric population is 28% and in 1999 the subcommitee of American College of Rheumatology has proposed the existence 19 neuropsychiatric syndromes in systemic lupus erythematosus in children, and 7 of them involve the peripheral nervous system. Mononevritis multiplex is the most common form of presentation when the periferic nervous system is involved but it can be also with acute and chronic demyelinating neuropathy as also distal sensory-motor neuropathy. Mononevritis is caused by the lesions of vasa nervorum it can occur their occlusion what leads to ischemia which in turn leads to Wallerian degeneration .
HENOCH SCHONLEIN PURPURA or
IgA vasculitis is multisystemic, it may involve the nervous system with headache, ataxia, seizures or altered mental status. Even if rareely when the periferic nervous system is involved, we can have peripheric facial palsy, Guillame Barre syndrome, brahial plexopathy, peroneal neuropathy but it can manifest also as mononevritis multiplex which receives tratment with steroids .
HIV ASSOCIATED MONONEVRITIS
Vasculitis associated HIV infection is more frequent in adults, where it is the first manifestation of the disease but it can appear after the other symptoms of AIDS has developed and it manifest as a symmetric sensoriomotor or like a syndrome which evolve with mononevritis multiplex. The inflammatory infiltrates are with T CD8 cells, and macrophages .
DENGUE FEVER When it implies the central nervous system it associates febrile convulsions, encephalopathy, aseptic meningitis, intracranial hemorrhage, intracranial thrombosis, subdural effusions, mononeuropathies, polyneuropathies, Guillaume-Barre syndrome, and transverse myelitis .
LEPRAE: Hansen disease, is still a major cause of neuropathies in developing countries. Mycobacterium leprae infects and injures Schwann cells, the deficits first begin sesitive and than progress to motor. The pure neuritic form is rare, whitout the characteristic stigmata .
LYME DISEASE is caused by spirochete Borrelia Burgdorferi, through the tick bite. There are three stages: Stage1 begins after one month and is characterised with cutaneous rush in 80% of cases and symptoms like myalgias, stiff neck, fever, headache, arthralgia. In the second stage it can develop periferic neuropathies at 15% of cases but also chronic migrans erythema after some weeks from the bite, as also aseptic lymphocitic meningitis which manifested with headache, mononevritis multiplex, myelitis, cerebellar ataxia. The third stage can appear after 2 years with myelopathy, encephalopathy, neuropathy, psychiatric disturbances .
HEREDITARY MONONEVRITIS MULTIPLEX WITH BRACHIAL PREDILECTION (Hereditary Brachial Plexus Neuropathy) is an autosomal dominant disorder which consist of painful amyotrophia with sensory disturbances, more frequent in girls, it can be associated with pregnancy (it appears in the third trimester) with onset in the first, second or third decade, any nerve from the brachial plexus may be affected the nerve and the normal conduction velocity in the distal segements of the limbs differentiates them from the hereditary neuropathy .
The neuropathic pain is in relation with the production of H2S. The expression of cystation beta synthase and the production of H2S at the level of L4-L6 were studied and there was detected to have a role in neuropathic pain. Amoinooxiacetic acid (AOAA) is an inhibitor of cystation beta synthase (CBS) AOAA lowers significant the activation of NFkB (p65) . There are 5 types of proteins NFk-B in mammals (RelA/NFk-B-p65), RelB, c-Rel, NF-_B1/ NFkB-p105 and NF-_B2/NFkB-p100). They form a variety of homo- and heterodimers, and each of them has a distinct set of genes . In the case of systemic diseases as it is in systemic lupus erythematousus a vasculitis was detected by sural nerve biopsy .
Necrotizing arteritis is the most common pattern of vascular implication in mononevritis multiplex, often implying the little precapilar arteries of the vasa nervorum leading to ischemia randomly distributed along the course of a nerve .
The patient can present withacute or subacute motor or painful sensory deficits which are limited at one nerve or can be multifocal. There can be associated symtoms of systemic vasculitis implying more organs and systems like fever, night sweats, swelling of the joints, nasal or oral infection, or skin lesions. In systemic and nonsytemic vasculitis can occur weight loss, fatigue, myalgia, or arthralgia. Laboratory findings include functional renal tests, glycemia, the leucocyte formula, inflammatory markers, autoantibodies associated with systemic vasculitis, hepatitis B serology, hepatitis C serology, HIV serology, EMG, ureea, creatinine, cryoglobulins, serum complement, Borrelia antibodies, cytoplasmic and perinuclear antibodies (c-Anca, p-Anca) rheumatoid factor, ANA, doublestranded DNA, anti-SSA antibodies or anti SSB, seric angiotensin conversion enzyme, electrophoresis of proteins and immunofixation, chest X ray, nerve and muscle biopsies. Antibodies anti-Sm, anti topoisomerase 1 antibodies, anti –Scl 70), and anticentromere antibodies (ACA), skin biopsy, biopsy of the lipps, anti-Hu antibodies, CSF analysis, abdominal and pelvic CT scan, abdominal , thoracal and pelvic PET scan, conventional angiography, magnetic resonance angiography .
For vasculitis advocates anemia, leukocytosis, eosinophilia, high erythrocyte sedimentation rate or C reactive protein, antinuclear antibodies, doublestranded- DNA, anti-neutrophil cytoplasmic antibodies (ANCA), anti-neutrophil perinuclear antibodies (P-ANCA), VIII factor related antigen (von Willebrandt), crioglobulinemia, immune circulant complexes, hematuria, other specific autoantibodies, for example SS-A/Ro, SS-B (Sjogren syndrome) anti- SCL-70 antibodies (scleroderma) anti-RNP antibodies (mixed connective tissue disease) .
Ulnar position related ulnaropathy is very rare in children, but it can happen and that’s why it is underestimated in children, especially that it can appear in anesthetized child. The patients respond to the conservative treatment of the neuropathy less favorable than the adults and the response depends on the pathogenetic mechanism of the ulnar nerve lesion.
Underrecognition from the anesthesist or the surgeon of the possibility of this kind of injury can lead to forensic disputes . Instable ulnar neuropathy can be surgically treated. The ulnar nerve can be subluxated and pushed to the median epicondyl with flexion of the elbow so the nerve becomes „instable”.
The surgical treatment reduces the symptoms in children which are numbness and tingling .
Nervous lesions after the fractures or the elbow dislocation. The supracondilar fractures of the humerus are very common in the pediatric population. Initially 10-16% of the patients have lesions of the ulnar nerve and the paralysis of the median nerve in 6,4% of the radial nerve in 2,6% .
Fibular (peroneal) neuropathy of the child and the adolescent. At the head of the fibula there are nerve conduction blocks in 35% of the patients. Deep axon loss was identified in 77% of cases. Where as the superficial axonal fibular loss were identified in 45% of cases. Pathophysiology was axonal in 72% of the cases most demyelinating in 6% of cases and mixed in 22%.
Peroneal nerve paralysis following a proximal synovial tibiofibular cyst is rare. There are two macroscopic forms extraneural and intraneural cysts.
It is not a common but it needs to be rapid recognised and treated, in this cases the recovery is complete .
Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) due to the deletion of 17p11.2 In this sistuations can exist more pattterns of neuropathy: multiple mononeuropathy, mononeuropathies, chronic sensorimotor polyneuropathy, chronic sensory neuropathy, brachial unilateral plexopathy. The presentation of the hereditary neuropathy with liability to pressure varies and includes pain. The most frequent model is of an assymetrical motor neuropathy with focal slowing of nerve conduction velocity in specific areas . Hereditary Neuropathy with Liability to Pressure (HNPP) are related to the PMP22 gene deletion . When the PMP22 gene is deleted the most common presentation is peroneal paralysis (45%) followed by brachial plexus palsy (25%) .
The patients have o typic phenotype with episodes of focal weakness and/or sensory loss and low nerve conduction velocities at the common sites of compression as it is for the tibial nerve at the knee and the median nerve at the elbow. Between the episodes the patients are symptom free and have apredominent sensory, mild neuropathy. If it exist a Threonine 118
Methionine mutation (T118M) than a mild dominant transmitted neuropathy is produced. It was reported a association of the deletion of the 17-th chromosome (17p11.2-p12) with a mutation T118M on the allele PMP22. The mechansim is the reduces expression of the PMP22 gene caused by the deletion of the 17p11.2-p chromosome which leads to an alterated myelin with sensibility to pressure, and the mutantT118M protein is expressed and in myelin incorporated resulting a more severe lesion of the myelin when this two mutations are coexisting in the same person .
Sensory-motor neuropathy are a heterogeneously group of disorders with an incidence of 1/2500 persons. Characteristic features are distal extremities atrophys (the anterior tibialis is afffected more often on onset) and absent or reduced deep tendon reflexes, pe cavus, impaired sensitivity, disturbances of walking.
CMT and CMT1 are more frequent because of the dupplication of the gene PMP 22. With the locus on the 17p11.2 chromome. CMT1b has an anormal P0 protein with the defect on the chromosome 1 .
Carpal tunnel syndrome there was made a comparative study on 6-th class children which used paper books or electronic books and there was studied the motor and sensory nerve conduction velocities on the median nerve. The study showed that there were no differences between the use of electronic books or printed on paper in children who had this syndrome . Carpal tunnel syndrome is more frequent in obese patients. Obesity is a growing public health problem in teens and many diseases of the adults associated with obesity are found nowadays in the pediatric population . The persons with Down syndrome are more exposed to have carpal tunnel syndrome . Carpal tunnel syndrome can follow after electrocution in chidlren but this entity is more rare, and is difficult to recognise but we must think on it. The symptoms can be confounded with neuropraxia.
After electrocution edema and inflammation occurs in the tissues which make pression on the median nerve which is located in the carpal tunnel. The specificity and sensitivity of Tinel and Phalen sign are not well documentated. In a study on adults it was shown that the carpal tunnel syndrome appears after 5 months after the electrocution. In children this signs can be mild and can go unnoticed . Neuropraxia is a peripheric nerve injury and is considered to be milder.
It is a transitory motor or sensory nerve conduction block, whitout nervous degeneration even if the motor involvement is more frequent. The axons are not damaged . The most common symptom of carpal tunnel syndrome is acroparesthesia. The Tinel Test involves medial nerve percussion on its forearm to the fist joint in the direction of the distal end. It is positive when paresthesia occur in the nerve distribution area. It is positive in the proportion of 58-67% of the patients with EMG positive and in 20% of cases we can have the positive Tinel sign without compression phenomena. The Phalen test consist of the flexion of the hand joint to the maximum, and if after 60 seconds numbness and paresthesia appear on the first three
In the carpal tunnel syndrome the ulnar nerve can be instable even after surgical decompression, so the approach to the surgical approach for ulnar nerve decompression should be done with great care .
The carpal tunnel syndrome can be familial, it was found a family where this syndrome was in three generations, from father to son and appeared in the first decade the median nerve being compressed by the carpal transverse ligaments. It is suggested that thickening of the ligaments may constitute the disorder that will give rise to the carpal tunnel syndrome .
Tarsal tunnel syndrome is a focal compressive neuropathy. It is underdiagnosed and affects the plantar margins of the foot. The role of conservative versus surgical interventions in the various stages of the disease remains unclear .
Progressive sciatic paralysis due to pseudoaneurysm. In children it is difficult to diagnose an extrinsic cause of lumbar radiculopathy or polyneuropathy. Thus there may be traumatic or iatrogenic pseudoaneurysms of the iliac arteries. The authors report a case in which a child had an osteotomy for a dissecans osteochondritis that generated a bilateral hip dislocation, and at 12 months occurred a sciatica of a limb which progressed to paralysis. The solution was endovascular embolisation and secondary hematoma evacuation .
Intraneural ganglion of the common peroneal nerve in children. Intraneural ganglions are non neoplastic cystic formations contained in the epineurium of the peripheral nerve, the most common being at the level of the fibula’s extremity. This diagnosis should be taken in the drop of the foot in children, because in this cases exist a potential therapeutic approach and recovery . The cysts can also be localized in the tibial nerve. These cysts can be recurrent to these nerves, requiring more operations .
Sciatic post-injection palsy in children. The most important complaints in children are pain and gait disturbances after injection. The sciatic nerve os the longest and thikest nerve from the body and has two components the tibial nerve and the peroneal, the latter being more often affected due to its posterolateral position and the lower amount of supporting connective tissue. Post-injection sciatic paralysis due to gluteal injection may occur with severe paresthesia and neurological complications .
Trauma of the nerves in the neonatal period. Their therapy is often based on physical rehabilitation therapy and surgical procedures even there are microsurgical new procedures, research is made on developing neuroprotective agents like the molecule P73 tested on rat animal models which stoppes the death of the periferic neurons and stoppes the pathologic mobilisation of the spinal microglia .
Acute inflammatory demyelinating polyneuropathy (AIDP). The diagnosis is more clinic. There will be excluded the acute medullar lesions like difficulties in bladder motor activity. An acute medular syndrome is the anterior spinal artery syndrome. In the case of inflammatory neuropathy we have ascendent paralysis in association with an infection in 60-70% of cases, with diminished or absent reflexes. Progressive weakness is present in more than one limb and is progressing in four weeks and typic exists a relative symmetry. A variant is Miller Fisher syndrome which associates oftalmoplegia, ataxia and areflexia and antiglicoside GQ1b antibodies (Mori 2001). When cauda equina is involved the diagnosis is in 83% of cases favourable to Guillain Barre syndrome and is present in 95% of the typic cases. The complications are less severe when therapy include intravenous immunoglobulin. Worse prognosis have the cases with anti-GM1 antibodies .
Sciatic nerve involvement due to medullary compreesion in children there can exist intrarahidian cysts which determines symptoms of sciatica .
The treatment of mononevritis multiplex implies the underlying cause, pain treatment, and other therapy oriented to maintain the muscle strength and the movement control of the affected side .
Pain management is done with antidepressants Amittriptylin, Nortriptylin, Imipramine, desipramine, duloxetine, Venlafaxine XR, antiepleptic drugs like, Gabapentin, Pregabalin, Carbamazepine, Oxcarbazepine, Lamotrigin, Topiramate, others Mexiletine,Tramadol, Capsaicin 0.075% topic tid-qid burning . In some situations like in systemic lupus erythematosus we can use intravenous Solumedrol 30 mg/kg, (maximum 1 gram/day) for 5 days followed by Prednsilonomum 80 mg/day oral use. But it can appear gastric hemorrhage .
The surgical repair of the ulnar nerve is made with an anti-claw procedure (capsuloraphy of the metacarpophalangeal joints and the pulley method) the surveillance period being 39 months in one study but good visible results are after 3 months. This procedure prevents claw deformity of the hand .
In other situations there are used echographic nerve conduction blocks for the tarsian tunnel syndrome which can appear in some syndroms .
Education of the patient. Obese children must be informed that weight loss is beneficial for the treatment associated with the specific intervention in the disease .
A good treatment of the mononevritis multiplex can lead to complete recovery. The long lasting inflammation of neurons can lead to permanent nervous lesion so the treatment must be started as early as possible as the symptoms become more proeminent .
Limited injuries to nerves lead to fenotipic modifications in the pyramidal neurons from the prelimbic cortex of the mice. A substance MMPIP 6-(4-methoxyphenyl)-5-methyl-3- pyridinyl-4-isoxazolo[4,5-c]pyridin-4(5H)-one, which is a negative allosteric modulator of the metabotrop glutamat 7 receptor, influences pain and the affective and cognitive behavior in the neuropat mice, and regained the equilibrum between the excitatory and inhibitory responses of the neurons in the prelimbic cortex in mice. Researches were made also on 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one, XAP044 another selective agnet for mGluR7 .
It is known that frequent pain can lead to emotional and behavioral disturbances in adolescents .
So we can take an integrative approach to mononeuritis multiplex from molecular medicine toclassical clinical signs which can gain our attention for this rare but important field.