Differential Diagnosis of Progressive Generalized or Symmetrical Flaccid

EDWARD R. ISAACS, M .D

Assistant Professor, Department of Neurology, Medical College of Virginia, H ea/th Sciences Division of Virginia Commonwealth University, Richmond, Virginia

Progressive flaccid paralysis occurring over ape­ The patient was a 15-year-old boy with a pro­ riod of hours or days is usually associated with gressive flaccid paralysis which began with leg pains the Landry-Guillain-Barre-Strohl syndrome. 1•2 •3 This and a gait disturbance; he required tracheostomy 72 symptom complex is often accompanied by a history hours later. Two weeks prior to this he suffered a flu­ of a previous flu-like illness, antecedent myalgias, and like illness and the day before he became weak he had subjective sensory complaints of tingling or simply a been mowing a field freshly sprayed with insecticide. "tight" sensation in hands and feet. The paralysis Initial examination showed a flaccid and that ensues either ascends from the feet and legs or absent deep tendon reflexes, but the CSF was normal descends from the facial muscles to involve all or with no cells and a protein less than 50 mg/ 100 ml. most of the voluntary skeletal musculature. Along Nerve conduction studies done on arrival at the hos­ with paralysis of the intercostal and diaphragmatic pital and the next day showed normal distal latencies, musculature, severe cases may also involve other cra­ nerve conduction velocities, and F wave latencies. In nial nerves as well as the autonomic nervous system. some of the severely weakened distal muscles no com­ In all cases the deep tendon reflexes are markedly pound action potential could be elicited and in others diminished or absent early in the course of the dis­ these potentials were of low amplitude and not aug­ ease. Sensory abnormglities are usually mild or ab­ mented by 30 Hz trains of supramaximal stimula­ sent. Confirmatory diagnostic studies include exam­ tion . During the second week of total paralysis, distal ination of the cerebral spinal fluid (CSF) which latencies were slightly prolonged and conduction ve­ shows no or few mononuclear cells and an elevated locities had decreased. The spinal fluid remained nor­ protein. Nerve conduction studies may show pro­ mal. After the third week, the patient began to re­ longed distal latencies, slowing of nerve conduction cover, initiating movements in arms and legs. Nerve velocities, and prolonged F responses which measure conduction studies now showed definite prolongation the radicular segments of the nerve. Overall progno­ of distal latencies and prolonged F wave latencies. sis is difficult to predict, with recovery taking weeks The spinal fluid now had an elevated protein and no to months. Fatalities can occur despite optimal care cells. By the fifth week strength had returned and the in an intensive care unit. Electromyographic evidence patient was weaned from the respirator. of denervation suggests a more prolonged course with a greater chance of residual . A typical forms Discussion of this syndrome are more difficult to diagnose as can The absence of the early electromyographic and be illustrated by the following case history: spinal fluid changes1 usually associated with a post­ infectious polyradiculopathy instigated a search for other disorders which may present in a similar fash­ Correspondence and reprint requests to Dr. Edward R. Isaacs, Department o f Neurology, Box 698, Medical C ollege of ion. In devising a systematic approach towards a Virginia, Richmond, Virginia 23298. differential diagnosis in this atypical case, it was help-

112 MCV QUARTERLY 13(3): 112-115, 1977 ISAACS: PROGRESSIVE GENERALIZED OR SYMMETRICAL FLACCID PARALYSIS 113 fut to consider the component parts of the motor Diphtheria toxin, although rapidly fixing to pe­ unit, specifically the anterior horn cell, axon (pe­ ripheral nerve, has a delayed effect as it appears to ripheral nerve), , and the block myelin production.• Consequently, the turn­ muscle fibers innervated by that anterior horn cell. over of new myelin is inhibited, resulting in progres­ sive demyelinization of the peripheral nerve weeks to Anterior Horn Cell Disease months later. Despite the characteristic clinical fea­ Most of the anterior horn cell diseases that are tures of diptheria, long delays between the time of the encountered today are chronic and progressive and initial infection and the subsequent neuropathic com­ are not likely to be confused with the clinical presen­ plications may make the association difficult. Paraly­ tation under discussion.4·5 However, there remains sis begins and may be localized to cranial nerves the possibility of the emergence of a new neurotro­ involving, in particular, the palate and the pupil with phic virus or the occurrence of acute poliomyelitis in a characteristic fatigue of accommodation, More the uninoculated. Poliomyelitis presents as a biphasic rarely, facial and extraocula r muscles are also in­ illness beginning as a flu-like syndrome which remits volved. A certain number of patients then develop a within 48 hours. Headache, severe myalgias and men­ generalized peripheral sensori-motor neuropathy ingismus mark the next phase, with the spinal fluid with loss of reflexes, mild sensory loss, and peri­ showing a pleocytosis of 50 to 250 cells, an elevated pheral weakness. A tachycardia is oftentimes asso­ protein (100 to 250 mg/ 100 ml), and a normal glu­ ciated with the peripheral neuropathy, as well as cose. Some cases may then progress with muscle fas­ spinal fluid changes of elevated protein with or ciculations and paralysis. If mild, the paralysis can be without pleocytosis. A similar onset and cause have quite asymmetrical, but if severe, it may appear sym­ also been described in the neuropathy associated metrically and involve bulbar musculature. Deep ten­ with extra faucial diphtheria. don reflexes may be exaggerated early, but these are The hepatic porphyrias,9 especially the acute lost in the paralytic stage of the disease. intermittent and variegated forms, can cause paraly­ sis following the abdominal and psychic manifesta­ Peripheral Nerve tions. Oftentimes, pain precedes the weakness in af­ Acute polyneuropathies or polyradiculoneurop­ fected muscles, which usually involves the upper athies most often fall within the symptom complex of limbs first and especially proximal muscles and wrist the Guillain-Barre syndrome,1,2 A wide variety of extensors. Progression may be stepwise over one to infective agents are capable of producing a state four weeks and involves limbs, trunk, cranial, and likened to experimental allergic neuritis with mono­ autonomic nerves. The spinal fluid protein is slightly cytic infiltration, edema, and demyelination of the increased and there are few monocytes. Nerve con­ peripheral nerve as the common pathological reac­ duction studies are frequently normal since it is the tion. Such agents appear to combine with cell mem­ axons which suffered a primary insult and not the branes, triggering an aberrant immune response myelin. Other abnormal metabolic states, such as which is directed towards cell membrane and, con­ hepatic and renal failure, as well as diabetes, are more sequently, myelin, Generalized inflammatory states likely to cause chronic neuropathies and do not pre­ as seen with systemic lupus erythematosus are ca­ sent as acute paralytic states. pable of producing a syndrome indistinguishable Exposure to toxic substances,10 either during from the postinfectious variety. Furthermore, this their manufacture or use, can be the cause of progres­ syndrome has also been caused by infiltrations of sive, flaccid paralysis. C ases a re usually sporadic and plasma cells in association with multiple myeloma. in some this reaction seems to be determined by In some patients there is a tendency to suffer individual susceptibility. Cases can appear so typical from a chronic relapsing steroid-dependent form of a that without a history of exposure to en~rin, aldrin, polyradiculoneuropathy ,6 ' 7 In these patients the onset dichloro-diphenyl-trichloroethane (DOT), or di­ is usually more gradual, over one to two weeks, and chloro-diphenyl-dichloroethane (ODD), a diagnosis usually does not involve cranial nerves or respiratory of acute, infective polyneuritis may be made. The muscles. With the use of steroid medication, the pa­ ingestion of thallium salts11 found in rodenticides and tients become asymptomatic, although nerve con­ insectides can cause an acute polyneuropathy in addi­ duction studies still remain abnormal. In the event of tion to gastrointestinal disturbances. The neuropathy steroid withdrawal there is an exacerbation of all is mostly sensory, affecting the lower extremities, and symptoms with a progressive paralysis. is associated with migratory arthralgias. In some pa- 114 ISAACS: PROGRESSIVE GENERALIZED OR SYMMETRICAL FLACCID PARALYSIS

tients paralysis may be generalized, involving respira­ muscular weakness which involves cranial nerves. tion and associated with circulatory difficulty as q-1e Deep tendon reflexes are usually preserved and there autonomic system is involved as well. Usually, with is no sensory loss. Myasthenics may develop acute massive doses, central nervous system symptoms pre­ paralysis due to under-medication, or as a result of dominate with hallucinations, convulsions, 'and exposure to drugs which have milq presynaptic death. Several weeks after the ingestion of thallium, blocking properties and do not ordinarily affect non­ alopecia occurs and this is what implicates thallium susceptible individuals.18 Postsynaptic blockade can poisoning. 1 also occur as in cholinergic crises when It would be an oversimplification to state that is not degraded at the receptor site. Such blocks can there are a wide variety of agents capable of produc­ occur in the myasthenic secondary to overmedication ing polyneuropathy-heavy metals, drugs, and toxic with antiacetylcholinesterase-type drugs•·16 ·11 or in in­ chemicals-but for the most part these do not pric:sent dividuals who have . been exposed to organophos­ as acute neuropathic polyneuropathies. New sub­ phates such as tri-orthocresyl phosphate. 10 Or­ stances are found capable of producing the syndrome ganophosphate compounds are not only capable of and isolated case reports continue to appear in the producing an acute but also cause literature. Examples of this are the ascending poly­ severe demyelinating types of polyneuropathies usu­ radiculopathies associated with the ingestion of the ally after a latent period of one to three weeks after fruit from poisonous shrubs 12 as well as r1c:ports of exposure. this syndrome as a complication of hyperalimenta- tion.13 . Muscle Fibers Primary and secondary periodic paralyses are Neuromuscular Junction classified as hypokalemic, hyperkalemic, and nor­ Neuromuscular blockade can occur either pre­ mokalemic depending upon the serum potassium at synaptically or postsynaptically and cause a rapidly the time of the paralysis.4·19 The onset is rapid and progressive, generalized, or selective paralysis. Pre­ progressive and usually follows exercise, exposure to synaptic blockade is thought to be the mechanism of cold, or the ingestion of a heavy meal. During a action in tick paralysis.14 Five to six days after the severe attack, deep tendon reflexes are depressed and attachment of certain female gravid ticks, usually there is an inability to i'nitiate muscle contraction by located on the scalp, there is a rapid ascending paral­ electrical stimulation. Motor nerve conduction veloc­ ysis which may begin with a gait disturbance and ity may thereby be unobtainable. Spinal fluid is nor­ ~yalgia. If the tick is not removed, this may proceed mal. The diagnosis may be su~pected in the heredi­ to respiratory embarrassment. Spinal fluid is usually tary forms which are recurrent and by the potassium normal. The substance which the tick secretes must levels during the attack. The hyperkalemic20 and nor­ be quite potent, but it would also seem to have a mokalemic19 forms may be associated with the onset rather short half-life since symptoms improve within of myotonia after exposure to cold between attacks. hours of removing the tick. · The secondary periddic paralyses are usually spo­ Presynaptic neuromuscular blockade appears to radic. Hypokalemic p~riodic paralysis may be seen as be the mechanism of action of botulinus toxin. 15 the pres~nti~g _comp.!a(nt _o~. a_s a complication ~r Twenty-four to 48 hours after the ingestion of the thyrotox1cos1s m certain md1v1duals. Hypokalem1c toxin, ocular motor weakness, pupillary paralysis, periodic paralysis is also seen in association with an·d respiratory paralysis occur, usually p'receded by a hyperaldosteronism' · as wet( as a complication of gastrointestinal disturbance. Progression to general­ thiazides and sprirJolactone.4 · Hyperkalemic forms ized paralysis can also occur. Nerve conduction stud­ occur in association with renal and adrenal failure. It ies are usually normal, neuromuscular blockade would be extremely unusual for other myopathies to being demonstrated by high frequency stimulation present as rapidly :progressive· paralysis. With fulmi­ ;ith subsequent augmentation in the compound ac­ nant forms of polymyositis or in rhabdomyolysis tion potential. with associated myoglobinuria, patients are ex­ Postsynaptic neuromuscular blockade can occur tremely ill, muscle~ are quite painful and the serum due to the inability of the postsynaptic membrane to creatinine phosph0okinase levels should be very respond to acetylcholine as it would in the myas­ high.19 thenic crisis.4· 16 ·11 Occasionally mya'sthenia gravis As with many conditions involving the nervous may begin with an acute, generalized severe form of system, the ability to localize the site of a particular ISAACS: PROGRESSIVE GENERALIZED OR SYMMETRICAL FLACCID PARALYSIS 115

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