Linköping  University  Medical  Dissertations  No.  1249  

               

Cryptogenic  Polyneuropathy  Clinical,  Environmental,  And  Genetic  Studies  

Jonas  Lindh  

 

 

 

 

 

Department  of  Clinical  and  Experimental  Medicine,  Faculty  of  Health  Sciences  

Linköping  University,  SE-­‐581  85  Linköping,  Sweden  

Department  of  Internal  Medicine,  Ryhov  County  Hospital,  SE-­‐55185  Jönköping,  Sweden  

 Linköping  2011  

     

                                                                               © Jonas Lindh, 2011

Printed by LIU-tryck, Linköping, Sweden, 2011

ISBN: 978-91-7393-118-2

ISSN: 0345-0082

       

                                                                               

      To  Ulrika,    Andrea  &  Philip  

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List  of  Papers    The  thesis  is  based  on  the  following  papers,  which  will  be  referred  to  in  the  

text  by  their  roman  numerals.  

 

I.  Lindh J, Tondel M, Österberg A, Vrethem M. Cryptogenic

polyneuropathy: clinical and neurophysiological findings. J Peripher Nerv

Syst. 2005; 10(1): 31-7.  

 

II.  Tondel M, Lindh J, Jonsson P, Vrethem M, Persson B. Occupational

determinants of cryptogenic polyneuropathy. Neuroepidemiology. 2006;

26(4): 187-94.  

III.  Lindh J, Tondel M, Persson B, Vrethem M. Health-related quality of

life in patients with cryptogenic polyneuropathy compared with the

general population. Disabil Rehabil. 2011; 33(7): 617-23  

 

IV. Lindh J, Söderkvist P, Fredriksson M, Hosseininia S, Tondel M,

Persson B, Vrethem M. Polymorphism of GSTT1, GSTM1 and epoxide

hydrolase in cryptogenic polyneuropathy. Accepted By Brain and

Behavior.    The articles are reproduced with the kind permission of the respective publisher.

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Contents

 

LIST  OF  PAPERS   4  

ABBREVIATIONS   7  

INTRODUCTION   9  

Cryptogenic  polyneuropathy   11  Definition   11  Background   19  Pathology   21  Neurophysiology   24  Epidemiology   26  Sensory  symptoms  and  findings   28  Motor  symptoms  and  findings   29  Prognosis   30  Treatment   31  

Effects  of  environmental  toxins  on  the  peripheral  nervous  system   31  

Metabolism  of  hexacarbon  solvents   33  

Genetic  Factors   37  

Health  Related  Quality  Of  Life  (HR-­‐QoL)   41  SF-­‐36   44  EQ-­‐5D  (EuroQol)   46  Other  dysfunction  scores   48  

Diagnostic  approach  to  peripheral  neuropathies   49  Careful  history   52  Detailed  physical  and  neurological  examination   53  Electrophysiological  studies   53  Laboratory  studies   54  

HYPOTHESIS  &  AIMS   59  

PATIENTS  AND  METHODS   60  

Patients   60  

Data  collection   64  Medical  records   64  Neurophysiology   65  Questionnaires   66  Blood  samples   66  

RESULTS   67  

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Study  I:  Clinical  and  neurophysiological  findings   67  

Study  II:  Occupational  determinants   69  

Study  III:  Health  related  quality  of  life   70  SF-­‐36   71  EQ-­‐5D   74  EQ  barometer   74  

Study  IV:  Genetic  polymorphisms   75  

Additional  results   76  Evaluation  of  symptoms   76  Quality  of  life   79  Diabetes  risk  evaluation   80  

DISCUSSIONS  AND  CONCLUSIONS   81  

Clinical  picture   81  

Health  related  quality  of  life   84  

Exposures  in  work  and  leisure  time   87  

Genetic  polymorphisms  and  risk  of  cryptogenic  polyneuropathy   91  

Conclusions   93  

ACKNOWLEDGEMENTS   96  

REFERENCES   99          

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Abbreviations    2,5-HD 2,5-Hexandione

BMI Body Mass Index

CI Confidence Interval

CIAP Chronic Idiopathic Axonal Polyneuropathy

CIDP Chronic Inflammatory Demyelinating Polyneuropathy

CMAP Compound Muscle Action Potential

CMT Charcot-Marie-Tooth disease

COR Crude Odds Ratio

CSPN Cryptogenic Sensory and sensorimotor PolyNeuropathy

CV Conduction Velocity

CYP2E1 Cytochrome P450 2E1

DADS Distal Acquired Demyelinating Symmetric

Polyneuropathy

DML Distal Motor Latency

EMG ElectoMyoGraphy

EPHX Epoxide HydroXylase

EQ-5D EuroQol

ESR Erythrocyte Sedimentation Rate

GST Glutathione S-Transferase

GSTM Glutathione S-Transferase Mu (µ)

GSTT Glutathione S-Transferase Theta (ϑ)

HIV Human Immunodeficiency Virus

HR-QoL Health Related Quality of Life

ICD International Classification Of Diseases

IGT Impaired Glucose Tolerance

LOR Logistic Odds Ratio

MAG Myelin Associated Glycoprotein

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MBK Methyl n-Butyl Ketone

mcs Mental Component Summary

mEPHX microsomal Epoxide HydroXylase

MGUS Monoclonal Gammopathy of Uncertain Significance

OGTT Oral Glucose Tolerance Test

OR Odds Ratio

PAH Polycyclic Aromatic Hydrocarbons

pcs Physical Component Summary

QOL Quality Of Life

QST Quantitative Sensory Testing

SF-36 Short Form 36

SNAP Sensory Nerve Action Potential

TSH Thyroid Stimulating Hormone

VAS Visual Analogue Scale

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Introduction    Cryptogenic polyneuropathy is characterized by a dying-back neuropathy and

patients present with symmetrical, distal loss of sensory and motor function in

the lower extremities that extends proximally in a graded manner. The result is

sensory loss in a stocking-like pattern, distal muscle weakness and atrophy, and

loss of ankle reflexes.  Peripheral neuropathies are common neurological problems. They are caused by

disordered function and structure of peripheral motor, sensory, and autonomic

nerves. The overall prevalence in western communities, and also among Parsis

in Bombay, is about 2,400 per 100,000 population (2.4%), but in individuals

older than 55 years, the prevalence rises to about 8,000 per 100,000 (8%) [14,

17]. Other studies show a highly variable prevalence depending on the criteria

for polyneuropathy and the population studied (e.g., general population, primary

care, hospital, university hospital, neuropathy center). The prevalence in poor

populations is not known, but leprous neuritis is still highly prevalent in

Southeast Asia, India, Africa, and Central and South America [41] and it can be

expected that polyneuropathy is at least as common in these areas as in wealthy

populations.

There are many disparate known causes of polyneuropathy, such as diabetes

mellitus, alcohol, heredity, inflammatory disorders, ischemia, paraneoplastic

conditions, deficiency states, infections, toxins, and others. Leprosy (Hansen’s

disease) is a major cause of neuropathy globally, especially in tropical and

subtropical regions [41, 69], but is extremely rare in the Nordic countries. In an

Italian primary care population, the prevalence of polyneuropathy was highest in

patients with diabetes (18.3%), followed by alcoholism (12.5%), non-alcoholic

liver disease (10.9%) and tumor (7.1%) [13]. The most common clinical

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condition in the patients with cryptogenic polyneuropathy in the same study was

hypertension.

Different terms for the condition are used in the literature. Chronic Idiopathic

Axonal Polyneuropathy (CIAP) [45, 75, 82, 121, 138, 146, 170, 180, 183, 189]

is used by several authors. Other names of the same or closely related conditions

are: chronic polyneuropathy of undetermined cause [107], and Cryptogenic

Sensory Polyneuropathy (which also includes sensory-motor neuropathies) [67,

98, 190], painful sensory neuropathy [133], sensory-predominant painful

idiopathic neuropathy [91], burning feet syndrome [36, 161], and distal small

fiber neuropathy [62, 77, 160]. The two latter conditions are, however, most

likely a separate condition. In some cases the same author uses different terms

for the same condition in separate articles [189-191]

It remains unclear how thorough the investigation of the patient’s

polyneuropathy should be before calling it cryptogenic. Cryptogenic

polyneuropathy should probably not be considered as a distinct disease, but

rather a clinical syndrome with different mechanisms leading up to the same

clinical picture. Nevertheless, the syndrome is clinically useful as the patients

share the same clinical findings and prognosis [67].

   

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Cryptogenic  polyneuropathy    

Definition    

Figure:  Schematic  drawing  of  the  spinal  cord  with  a  sensory  nerve  entering  through  the  dorsal  root  and  a  motor  nerve  exiting  through  the  ventral  root  into  the  plexus  and  finally  forming  a  peripheral  nerve.        

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By common definition, the peripheral nervous system includes the cranial

nerves, the spinal nerves with their roots and rami, the peripheral nerves, and the

peripheral components of the autonomic nervous system. The dorsal and the

ventral roots are attached to the spinal cord by a series of filaments. After

passing the subarachnoid space, each root enters a dural sac and the dural

sheath. Immediately peripheral to the spinal ganglion of the dorsal root,

corresponding dorsal and ventral roots join to form a spinal nerve. The dural

sheaths become confluent at the ganglion, and then merge with the epineurium

of the spinal nerve. Each spinal nerve quickly divides into a dorsal and a ventral

ramus. The dorsal rami supply the back; the ventral rami supply the limbs and

ventrolateral part of the body wall. In the cervical and lumbosacral regions, the

ventral rami intermingle and form plexuses from which the major peripheral

nerves emerge. As a general principle, each ramus entering a plexus contributes

to several peripheral nerves, and each peripheral nerve contains fibers derived

from several rami [38].

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 Figure:  Schematic  drawing  of  a  nerve  cell  with  its  myelinated  axon  connecting  to  a  muscle  fiber.    

Peripheral nerve fibers are divided into two different groups, myelinated and

unmyelinated nerve fibers. A nerve fiber is defined as an axon with its

associated Schwann cell, which creates the myelin sheath. The nerve fibers are

then arranged together in bundles or fascicles and then grouped into nerves. The

nerve sheaths contain the intrinsic blood and lymphatic vessels as well as the

nervi nervorum, which supply the connective tissue and vessels with sensory

and autonomic fibers [38].

The terms "polyneuropathy," "peripheral neuropathy," and "neuropathy" are

frequently used interchangeably, but are distinct. Polyneuropathy is a specific

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term that refers to a generalized, relatively homogeneous process affecting many

peripheral nerves, with the distal nerves usually affected most prominently.

Peripheral neuropathy is a less precise term that is frequently used

synonymously with polyneuropathy, but can also refer to any disorder of the

peripheral nervous system including radiculopathies and mononeuropathies.

Neuropathy, which again is frequently used synonymously with peripheral

neuropathy and/or polyneuropathy, can refer even more generally to disorders of

the central and peripheral nervous system. Symmetric distal sensory loss,

burning, or weakness typically characterizes polyneuropathy. The

polyneuropathies must be distinguished from other diseases of the peripheral

nervous system, including the mononeuropathies and mononeuropathy

multiplex (multifocal neuropathy), and from some disorders of the central

nervous system [38].

Cryptogenic polyneuropathy is in essence a diagnosis of exclusion, established

after a careful medical, family, and social history, neurologic examination, and

directed laboratory testing. Patients must have a slowly progressive distal

symmetric sensory or sensorimotor polyneuropathy on neurological clinical

examination, and axonal degeneration on neurophysiological examination.

Different authors have dealt with this in different ways. Richard Hughes defined

CIAP as patients having a late onset symmetrical peripheral neuropathy of

undetermined cause. The patients must have a had previous investigations

including at least a clinical history and examination, urine analysis, blood count,

erythrocyte sedimentation rate (ESR), renal, liver and thyroid profiles, random

glucose, hemoglobin, vitamin B12 and folic acid concentrations, serum protein

electrophoresis, antinuclear factor and chest radiograph [82]. Peter Erdmann

made the diagnosis if the patients had a slowly progressive distal symmetric

sensory or sensorimotor polyneuropathy on neurological clinical examination,

and axonal degeneration on neurophysiological examination. Erdmann and

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coworkers required normal values for hemoglobin, hematocrit, leukocytes,

platelets, ESR, serum glucose, renal function and electrolytes, liver enzymes,

serum calcium and phosphorous, creatinine kinase, serum protein, transketolase,

vitamins B1, B6 and B12, thyroid function, immunoelectrophoresis, antinuclear

antibodies, cryoglobulins, and rheumatoid factor. All their patients had

undergone a routine chest X-ray [45]. Hoffman-Snyder used another definition

of CIAP. Their inclusion criteria were (1) a documented history of positive

sensory complaints more than 3 months in duration, with or without neuropathic

pain; (2) a detailed neurological examination; (3) a fasting, non-gestational 2h-

Oral Glucose Tolerance Test (OGTT) using a 75-g oral D-glucose (dextrose)

load; (4) nerve conduction studies; and (5) a diagnosis of CIAP. Patients were

excluded if they had documented evidence for a known cause of chronic axonal

polyneuropathy, such as presence of a family history of neuropathy and

“hammer” or “claw” toe deformities. Patients were also excluded in they had

documentation of a toxic or pharmacological exposure or coexisting medical

conditions associated with neuropathy such as chronic alcoholism; metabolic

disturbances; diabetes mellitus; hypothyroidism; and autoimmune conditions

such as connective tissue diseases, including sicca syndrome, malignancies, or

human immunodeficiency virus (HIV) or other active infections (e.g., Lyme

disease, Hansen disease, hepatitis C); general weakness except for distal leg

muscle weakness; abnormal results on complete blood cell count, electrolyte

levels, liver function studies, vitamin B12 levels, Thyroid Stimulating Hormone

(TSH) levels, and serum protein electrophoresis with serum immunofixation.

HIV testing was not routinely performed in this low-risk population, and nerve

conduction studies excluded features of demyelination [75].

Gil Wolfe and Richard Barohn instead used the term Cryptogenic Sensory and

Sensorimotor Polyneuropathy (CSPN). They defined CSPN on the basis of pain,

numbness, and/or tingling in the distal extremities without symptoms of

16

weakness. Sensory symptoms had to occur in a roughly symmetrical pattern in

the distal lower extremities or upper extremities or both and evolve over weeks

to months. On examination, patients had to demonstrate distal sensory deficits

not confined to an individual peripheral nerve. Slight weakness in foot or hand

muscles were permitted [191]. In a second article Wolfe and colleagues added

information about laboratory testing. Routine laboratory tests consisted of a

complete chemistry panel and blood cell count, ESR, antinuclear antibodies,

rheumatoid factor, vitamin B12 level, thyroid function tests, syphilis serologic

screening, and serum protein electrophoresis with immunofixation

electrophoresis. Patients with monoclonal proteins were included in the study

population only if plasma cell dyscrasias were ruled out after evaluation by an

oncologist and a diagnosis of monoclonal gammopathy of uncertain significance

(MGUS) was made. Patients with identifiable causes of neuropathy such as

diabetes, chronic alcohol use, metabolic disturbances, endocrine abnormalities,

connective tissue diseases including sicca complex, malignant neoplasms, HIV

or other infections, pertinent toxic or pharmacological exposures, hereditary

neuropathy or amyloidosis, and primary amyloidosis were excluded by history

and laboratory testing [190]. Their definition was criticized by Peter James

Dyck for being too broad [33].

It is still unclear if idiopathic small fiber neuropathy is a specific entity or a

subgroup of cryptogenic polyneuropathy [30, 67]. In our studies we decided to

exclude patients with an isolated small fiber neuropathy.

A diagnostic problem is the “normal” neurological deterioration, both clinically

and neurophysiologically, in older people. For example, in healthy people older

than 60 years, sural responses may be absent [188]. Loss of proprioception has

been reported to occur in 28% and hyporeflexia, in 12% of healthy men between

17

64 and 73 years of age [153]. One way to handle this in studies is to add an

upper age limit for the diagnosis.

There is, as previously mentioned, no strict definition or even consensus about

which disorders have to be ruled out to diagnose the patient with a cryptogenic

polyneuropathy. It is very important to rule out diabetes, which has been

reported to account for more than one-third of polyneuropathy cases [177].

Nevertheless, many cases of impaired glucose metabolism can be found in a

patient series of cryptogenic polyneuropathy. A high prevalence of impaired

glucose metabolism has been found in those with neuropathic pain [117].

However, the relationship between impaired glucose metabolism and

polyneuropathy has been questioned [35].

Peripheral neuropathy is one of the most common reactions of the nervous

system to toxic chemicals. Many industrial, environmental, and biological

agents, heavy metals, and pharmaceutical agents are known to cause toxic

neuropathies. Medications, most notably anticancer drugs, are the leading

offenders in clinical practice today. All forms of neuropathies may be caused by

toxic agents [69]; however, in most cases, it is difficult to assess the individual

patient exposures and which substances are relevant.

Some studies have dealt with the contribution of “hereditary factors” in patients

with cryptogenic polyneuropathy. Singleton et al. [152] showed that 5.6% of

patients had first-degree relatives with foot sensory loss, weakness, or

deformities. Hughes et al. [82] reported that 12% of patients had relatives with

foot abnormalities. Hereditary neuropathies can present at all ages [177].

Other causes that need to be ruled out are inflammatory disease, chronic

alcoholism, metabolic disturbances, endocrine abnormalities, vitamin B12/folic

18

acid deficiency, critical illness, and acute inflammatory demyelinating

neuropathies, HIV, borreliosis or other infections, monoclonal gammopathy and

malignancies (especially myeloma and small cell carcinoma of the lung).

To summarize, different authors have used different terms for the same

condition and authors using the same term are still using different definitions.

There is no consensus document about how to define cryptogenic

polyneuropathy or CIAP known to the author. If a document was available, it

would have to be updated regularly as new information about the mechanisms of

the genesis of polyneuropathy become available. Both in clinical practice and in

research, however, a choice has to be made about how many investigations to

perform, before calling the disorder idiopathic or cryptogenic.

We chose to use a broad definition based on clinical grounds. We defined

polyneuropathy as one or more typical symptoms (numbness, pain, postural

instability, paresthesias, distal weakness, burning sensation, muscle cramps,

icing sensation, hypersensitivity to touch) with a distal distribution and at least

two of three clinical findings (distal deficit of sensation, reduced distal muscle

strength, and impaired or lost deep tendon reflexes). We regarded the diagnosis

as probable if patients had one or more of the symptoms above and only one of

three clinical findings as well as a chronic slowly progressive clinical course.

Patients whose diagnosis was based on neurophysiological findings alone were

not included.

A more detailed discussion about the diagnostic workup is presented in the

chapter “Diagnostic approach to peripheral neuropathies”. In our studies the

following laboratory investigations had to have been performed with normal

results: hemoglobin, fasting blood glucose concentration, vitamin B12

(cobalamin), folic acid, and thyroid function.

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Background    

The cause of cryptogenic polyneuropathy is, as the term implies, not known.

One suggestion has been that it is an inflammatory disorder. Clonal expansions

of T cells were strikingly high in patients with CIAP, as compared with elderly

normal controls, elderly controls with degenerative neurologic diseases, and

elderly patients with idiopathic chronic inflammatory demyelinating

polyneuropathy [54]. The relevance of T-cell clone expansion in relation to the

pathogenesis of idiopathic sensory neuropathies is still not clear, but some cases

can improve with treatment with steroids. In a recent study a significant increase

in C reactive protein (CRP) was found in patients with CIAP compared to

controls [142].

Another hypothesis is that the metabolic syndrome gives rise to chronic

ischemia, which causes the polyneuropathy. The metabolic syndrome is a

constellation of entities including impaired glucose tolerance, truncal obesity,

hypertension, and dyslipidemia [142]. Different mechanisms for polyneuropathy

secondary to the metabolic syndrome have been proposed. Patients with chronic

idiopathic axonal neuropathy more often have manifest cardiovascular disease

and cardiovascular risk factors than controls [80, 169]. In developed countries,

type 2 diabetes is the most common defined cause of axonal neuropathy in

middle and old age. Neuropathy is a common complication of chronic

hyperglycemia: the overall prevalence in patients with diabetes is 45–60%, and

in more than half of patients followed longitudinally, clinical symptoms of

neuropathy developed within 25 years of diagnosis [152]. As a consequence,

screening for diabetes is appropriate in evaluating patients with idiopathic

neuropathy. It is still controversial whether impaired glucose tolerance or

20

impaired fasting glucose gives rise to polyneuropathy. Some reports have found

an increased frequency of impaired glucose tolerance [75, 122, 152, 165],

though others have found contradicting results [82, 117]. Other studies have

found both impaired glucose tolerance and hypertriglyceridemia in increased

frequencies [81, 138, 139, 154]. Hughes and co-workers found using a logistic

regression analysis that environmental toxin exposure and hypertriglyceridemia,

but not glucose intolerance or alcohol overuse, were significant risk factors that

deserve further investigation as possible causes of cryptogenic polyneuropathy.

These findings, on the other hand, did not support that mild/moderate

hypertriglyceridemia was an independent risk factor for development of

neuropathy.

Another hypothesis is that chronic pain, stress and depression are common in

cryptogenic polyneuropathy patients and may predispose these patients to the

metabolic syndrome and impaired glucose tolerance [142]. If impaired glucose

tolerance is identified, the progression to diabetes is slow; frank diabetes

develops in only 20-35% of patients with impaired glucose tolerance during 5-

years of follow up [49]. However, the metabolic syndrome is an important factor

to consider as it is possible to treat and successful treatment prevents other

complications for the patient.

It is often believed that toxic substances in the environment cause many cases of

cryptogenic polyneuropathy. Hughes found that this was one of the main causes

in CIAP [82].

   

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Pathology    

In cryptogenic polyneuropathy nerve conduction and nerve biopsy studies are

compatible with a length-dependent axonal neuropathy [66, 88, 107, 121, 190].

Axonal degeneration is the most common pathological reaction of the peripheral

nerve. In most instances, axonal neuropathy is a chronic process, but changes

may appear on nerve conduction studies as early as 3 to 5 days after the onset of

22

acute axonopathy caused by the rapid pace of Wallerian degeneration [61].

Systemic metabolic disorders, toxin exposure, and some inherited neuropathies

are the usual causes of axonal degeneration [69]. The myelin sheath breaks

down concomitantly with the axon in a process that starts at the most distal part

of the nerve fiber and progresses toward the nerve cell body, hence the term

dying-back or length-dependent neuropathy [69]. The selective length-

dependent vulnerability of distal axons could result from the failure of the

perikaryon to synthesize enzymes or structural proteins, from alterations in

axonal transport, or from regional disturbances of energy metabolism [69].

After nerve transection, axons and their myelin sheaths regenerate. This process

begins in the distal end of the proximal stump. Axons then form growth cones

and begin regenerating, and at the same time Schwann cells divide rapidly [38].

23

The pathological features in sural nerve biopsy specimens consist of axonal de-

and regenerative changes without evidence of inflammation. At the

ultrastructural level an increased thickness of endoneurial vessel basal lamina

can be observed indicating that ischemia plays a role in the development of the

polyneuropathy, but this is a non-specific finding [19, 171]. Sural nerve biopsy

shows an unspecific, axonal type neuropathy, mostly with secondary

demyelination [66]. In skin biopsies a reduction in intraepidermal nerve fibers is

observed [117].

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The clinical picture in demyelinating polyneuropathies is quite different than in

axonal injury. In demyelinating polyneuropathies, every part of the nerve can be

affected and the typical neurophysiological finding is slowing of conduction

velocity. If recovery occurs, it is more rapid and if there is no concomitant

axonal injury, it will be more complete even though a loss of conduction

velocity can often be measured.

Neurophysiology  

The typical finding in cryptogenic polyneuropathy is mild nerve conduction

abnormalities consistent with an axonal, predominantly sensory polyneuropathy

[67]. In the typical distal, symmetric sensory, or sensorimotor neuropathy, there

is an initial loss of sensory nerve amplitude in a length-dependent fashion

followed by loss of motor amplitudes with gradual spread of these abnormalities

25

to the shorter nerve segments in the upper extremities [61]. This is largely

because the more distal nerve segments are farther from their cell bodies. In

some axonopathies, alterations in axon caliber, either axonal atrophy or axonal

swelling, may precede distal axonal degeneration [69]. Later in the course of

severe axonal disorders, conduction velocities may become abnormal because of

secondary demyelination or loss of the fastest conducting fibers [61]. Because

axonal regeneration proceeds at a maximal rate of 2 to 3 mm per day, recovery

may be delayed and is often incomplete [69].

Axonopathies result in low-amplitude sensory nerve action potentials (SNAPs)

and compound muscle action potentials (CMAPs), but they affect conduction

velocities only slightly [69]. In cryptogenic polyneuropathy the findings are

usually mild [107]. A problem with nerve conduction studies is, however, that

nerve conduction velocity and amplitudes decrease with increasing age and are

dependent on height and sex. The effect of height is greater than that of age

[143]. Absent sural SNAPs combined with spontaneous muscle fiber activity in

the anterior tibialis muscle support the diagnosis of neuropathy, since such

abnormalities are rarely found in healthy, older individuals [180]. There is also

evidence that finger circumference alters the amplitude of sensory recordings as

does the patient’s Body Mass Index (BMI). The sensory and mixed nerve

amplitudes are significantly lower in obese persons, but there are no differences

in nerve conduction velocities [23]. An index based on 12 electrophysiological

parameters has been suggested, which enables detection of slight impairments of

nerve conduction. The relatively low variability between recordings of the index

makes it suitable to follow the progression of a polyneuropathy with repeated

measurements over time [157].

In patients with prominent symptoms, demyelinating features on nerve

conduction studies are often found, giving rise to a combined axonal and

26

demyelinating polyneuropathy [107]. Sensory involvement is, in most cases,

more profound than motor involvement [191]. Sensory and motor nerve

conduction abnormalities typically consist of reduced amplitudes with normal or

minimal distal latency and conduction velocity changes [191]. In many of the

patients who presented with burning, painful paresthesias from resumed

idiopathic distal small-fiber neuropathy, the nerve conduction studies are normal

[62].

In a recent Dutch study of CIAP patients with pain, quantitative sensory

threshold and autonomic tests showed more frequent abnormal test results

compared to the healthy control group. The cold threshold and heat pain test in

patients with CIAP were both affected. The RR interval variation of deep

breathing tests and spectral analysis of RR intervals showed a significant

decrease in the high-frequency power [30]. It remains unclear if all patients with

cryptogenic polyneuropathy have small-fiber neuropathy or only those with

pain.

An electromyography (EMG) of distal muscles shows acute, chronic, or both

kinds of changes. Denervation activity such as fibrillation potentials or sharp

waves are found in approximately two-thirds of patients [191]. Patients with

cryptogenic polyneuropathy who have only sensory signs commonly have motor

involvement on electrophysiological studies.

 

Epidemiology    The age of onset is predominantly in late middle age, with a median age of

symptom onset between 50 and 60 years and a range of 12 years and up [62, 66,

67, 91, 107, 119, 190]. It can, however, be argued that in early presenting

polyneuropathy a cause is likely to be found and that hereditary or metabolic

27

reasons are the most plausible. Men are overrepresented by as much as a 3:1 to

4:1 ratio [107, 119, 136].

Symptoms have usually been present for many years before the patient presents

to the neurologist [67]. Most reports are from western countries, but some

reports are available from developing countries indicating that it is a common

condition there as well [17, 85].

Community studies have reported that symptomatic peripheral neuropathy may

be seen in approximately 3% of the elderly [13, 14], but other studies have

found a prevalence up to 8%, which is likely due to patient recruitment methods

and wider age limits. The prevalence of idiopathic polyneuropathy in the Parsi

community of Bombay (Mumbai) in India was 0.21%. They classified 20% of

noncompressive neuropathies as idiopathic [17]. Diabetes is said to be the most

common cause of peripheral neuropathy in the elderly [52, 80], and alcoholic

and nutritional neuropathies are also common [52, 80]. In a study from London,

all incident cases of neurological disorders were ascertained prospectively in an

unselected urban population based in 13 general practices over an 18-month

period. The age- and sex-adjusted incidence rates were calculated and they

found 54 cases of diabetic polyneuropathy and 15 cases of peripheral

neuropathies per 100,000 persons per annum [103].

In early studies the cryptogenic group was thought to comprise as much as 50-

70% of polyneuropathy [47, 52, 80, 95, 106, 111, 145]. However, later studies

have revised the frequency downward to 10-25% of patients despite a thorough

medical investigation [13, 17, 107, 115, 119, 146]. In these cases the

polyneuropathy is called cryptogenic. The reason for the lower percentage in

more recent series is probably because of improved understanding of the causes

of neuropathy and diagnostic advances. However, cryptogenic polyneuropathy

28

still remains a common clinical problem both for general practitioners and

neurologists at secondary and tertiary centers.

Sensory  symptoms  and  findings    

Most patients with cryptogenic polyneuropathy have a predominantly sensory

disease [67]. It is most commonly characterized by symmetrical, distal motor

and sensory deficits that have a graded increase in severity distally and by distal

attenuation of reflexes. The sensory deficits generally follow a length-dependent

stocking-glove pattern. By the time sensory disturbances of the longest nerves in

the body (lower limbs) have reached the level of the knees, paresthesias are

noted in the distribution of the second longest nerves (i.e., those in the upper

limbs) at the fingertips. When the sensory impairment reaches the mid-thigh,

involvement of the third longest nerves, anterior intercostal and lumbar

segmental nerves, gives rise to a tent-shaped area of hypoesthesia on the anterior

chest and abdomen. The involvement of recurrent laryngeal nerves may occur at

this stage with hoarseness [69]. The clinical picture is usually a mixed motor

and sensory neuropathy; however, in some cases it is a prominently sensory

neuropathy and in fewer cases, a predominantly motor neuropathy [107].

Discomfort or pain is a very common presenting symptom, reported in 65 to

80% of patients [62, 66, 119, 190]. The description of pain varies from patient to

patient, but the most common description is a nagging pain [45]. Other common

symptoms are numbness or tingling with or without pain, heavy feeling, or

weakness in the distal limbs [119, 191]. These patients complain of tingling,

prickling, numbness, or burning of the feet, and, often, stiffness of the toes.

Worsening of sensory symptoms with heat or cold exposure, activity, or fatigue

is commonly reported by patients [62].

29

On physical examination there is loss of pinprick sensation, together with loss of

vibratory sensation in the feet, absent ankle reflexes, and mild toe-extensor

weakness. Ability to sense vibration is the primary modality most likely to be

abnormal in the feet. Vibration sensation was reduced in all patients in

Notermans’ study, typically below the knees [119]. Pinprick and light touch is

also reduced in most of the patients and position sense is least affected on

sensory examination [119, 191]. These abnormal signs must be distinguished

from normal manifestations of the aging in the peripheral nervous system. Loss

of vibratory sense that is restricted to the toes can be a normal finding in healthy

elderly controls (e.g., present in 28% of individuals age 65 years and older).

Absent ankle reflexes are found in 38% of healthy controls older than 65 years.

In an Australian population study of persons 75 years or older, 26% and 28%

had impaired vibration sense and 20% and 21% absent ankle jerks on the right

and left side, respectively. The study also had a subgroup free of neurological

disease and in that group only, impaired vibration sense in the thumbs and gait

instability significantly worsened with increasing age [184]. Gait instability and

other symptoms of large fiber dysfunction are less commonly affected than

those of small fibers [67]. Joint position sense is also only affected in a minority

of patients [67].

Motor  symptoms  and  findings    Approximately two-thirds of patients with sensorimotor polyneuropathy can be

expected to have distal weakness and wasting [107, 119]. Motor weakness is

greater in extensor muscles than in corresponding flexors. For example, walking

on heels is affected earlier than toe walking in most polyneuropathies. It is

helpful to determine the relative extent of sensory, motor, and autonomic neuron

involvement, although most polyneuropathies produce mixed sensorimotor

30

deficits and some degree of autonomic dysfunction [69]. The typical finding on

examination is distal muscle wasting and weakness in the lower limbs, in some

cases quite pronounced with bilateral foot drop [107]. Muscle cramps occur, but

they are seldom severe [67].

The average time for symptoms to spread from the lower to the upper

extremities appears to be about 5 years [119]. It is rare for patients to report

symptoms restricted to the upper extremities. Autonomic and cranial nerve

findings are also rare in these patients [62].

Loss of reflexes is a common finding, most often found in the ankle and less

often in the upper extremities [191]. Total areflexia is rare.

Prognosis    

In an early study of cryptogenic polyneuropathy from the Neurological Unit at

the Manchester Royal Infirmary, 31 patients were followed-up from 1940 to

1950, of whom 16 had a negative outcome, and 7 of the patients died of the

disease [106]. Luckily, a great deal has improved since then. Today, both

idiopathic sensorimotor and sensory polyneuropathies pursue a very slowly

progressive course or reach a stable plateau [78, 107, 121]. The first more

modern patient series was published in 1973, but it includes cases that today

would be classified, even as Chronic Inflammatory Demyelinating

Polyneuropathy (CIDP) [78]. In McLeod’s series from the 1980s over 80% of

patients were unchanged or improved at a mean follow up of 3 years, and only

13% experienced significant disability from their neuropathy [107]. In more

recent studies, even after a course of more than 10 years, severe disability rarely

occurs. In most cases patients remain ambulatory without severe disability or

handicap [66, 88].

31

Spontaneous remissions have been reported at different rates. Grahmann

reported a complete or significant remission in 4 of 29 cryptogenic cases on

reevaluation and an even higher rate among cases that were initially classified as

cryptogenic but were later solved [66]. One possible explanation might be that

these were toxic neuropathies, which usually recover when the exposure ends,

but it cannot be excluded that even non-toxic cases might improve

spontaneously.

Treatment  

There is no specific therapy for cryptogenic polyneuropathy. The management

of these common neuropathies instead centers on the treatment of neuropathic

pain, provision of braces in some cases, and patient education and reassurance

about the favorable long-term outcome [191]. Options for the treatment of pain

based on clinical experience and studies in other neuropathies include tricyclic

antidepressants, gabapentin, carbamazepine, nonsteroidal anti-inflammatory

drugs, opioids, capsaicin [67] and lidocaine medicated plaster [11]. Treatment

response is often unsatisfactory.

Effects  of  environmental  toxins  on  the  peripheral  nervous  system    Exposure to neurotoxins may lead to dysfunction of any part of the central,

peripheral, or autonomic nervous system and the neuromuscular apparatus.

Neurotoxic disorders, especially those with an iatrogenic basis, are well

described. Hence, in any neurological condition, such as a peripheral

neuropathy, neurotoxins should be considered as possible cause. Peripheral

neuropathy is, in fact, one of the most common reactions of the nervous system

to toxic chemicals. Industrial, environmental, and biological agents; heavy

metals, and pharmaceutical agents are known to cause toxic neuropathies.

32

Medications, most notably anticancer drugs, are the leading offenders in clinical

practice today. Examples include cisplatin, taxanes, vincristine, metronidazole,

hydralazine, nitrous oxide, thalidomide, and phenytoin [69].

Neurotoxic disorders are occurring increasingly as a result of occupational or

environmental exposure to chemical agents and often go unrecognized.

Neurotoxic disorders are recognized readily if a close temporal relationship

exists between the clinical onset and prior exposure to a chemical agent,

especially one known to be neurotoxic. However, it is much more difficult to

identify neurotoxic agents when a group of persons are exposed to several

agents over a long period of time and the effects do not appear until several

years later [7]. This is common in industrial settings as well as in the home

environment. Suicide attempts with chemical agents and recreational drugs are

other possible causes of peripheral nerve damage.

For many agents only single case reports are available, but they may be

unreliable, especially when the neurological symptoms are frequent in the

general population. Epidemiological studies may be helpful in establishing a

neurotoxic basis for symptoms. However, it is difficult to perform good studies.

One major problem is finding adequate controls. A good study requires

matching of exposed subjects and unexposed controls, not only for age, gender,

and race, but also for social, and cultural background; and alcohol, recreational

drugs, and medication use. Laboratory test results are often not helpful in

confirming that the neurological syndrome is caused by a specific agent, either

because the putative neurotoxin cannot be measured in body tissues or because

the interval since exposure makes such measurements meaningless [7].

Most toxins produce symmetrical axonal degeneration in a dying-back (length-

dependent) pattern, eventually spreading proximally with continued exposure. A

33

number of toxic axonopathies also affect the central nervous system, showing

evidence of concurrent degeneration of dorsal column projections of sensory

neurons and optic nerve axons. Central axon involvement has been linked to

incomplete clinical recovery. Agents such as n-hexane cause simultaneous

degeneration of peripheral nerves, dorsal column axons, and corticospinal

pathways, often resulting in spasticity that may become apparent following

recovery from the peripheral axonopathy. Electrophysiological investigations

typically disclose an axonal pattern [69].

Metabolism  of  hexacarbon  solvents      Solvents are examples of foreign and potentially toxic, generally lipophilic,

substances absorbed into the body. They are therefore difficult to excrete as they

will be reabsorbed in the kidney or from the gastrointestinal tract after biliary

excretion and may remain in the body for long periods. The process of

detoxifying and excreting a substance is called biotransformation, which is a

complex process. The primary results of biotransformation are that the parent

molecule is transformed into a more polar metabolite, molecular weight and size

are often increased, excretion is facilitated, and elimination of the compound

from the body is increased. However, biotransformation may also underlie the

toxicity of a compound, of which n-hexane and methyl n-butyl ketone are both

examples [173].

n-Hexane, present in many commonly used organic solvents, is known to cause

primary axonal degeneration with secondary demyelination [24]. It is derived

from cracking of petroleum and from natural gas liquids. It is typically present

in motor fuels at 1 – 9 volume % and is currently employed in a variety of

industrial and commercial processes, including rubber, adhesive, ink, and paint

manufacturing, and in the extraction of vegetable oils for human consumption

34

[158]. Inhalation is the primary route of entry for n-hexane as well as methyl n-

butyl ketone (MBK). These solvents are also absorbed through the skin. Dermal

absorption is affected by the duration of exposure, and the size and condition of

any exposed area of skin [48]. Both n-hexane and MBK are lipophilic and easily

cross the blood-brain-barrier and rapidly reach an equilibrium in the brain [48].

n-Hexane concentration also increases rapidly within peripheral nerve fibers

after exposure. n-Hexane and its metabolites accumulate during chronic

exposures and are released from the liver when the exposure ends [48]. The

persisting effects of n-hexane and MBK are related to the ability of their mutual

metabolite 2,5-hexanedione (2,5HD) to cross-link axonal neurofilaments

chemically and to interrupt axonal transport mechanisms [48].

The clinical pictures of neuropathy as well as the histopathology of n-hexane

and MBK are identical [48]. Results of a nerve biopsy in a severe case of n-

hexane polyneuropathy showed giant axonal swelling due to accumulation of

neurofilaments, myelin sheath attenuation, and widening of nodal gaps [24]. n-

hexane induces hepatic cytochrome P-450 (CYP2E1, CYP2B6 and alcohol

dehydrogenases) [84] and is metabolized to the neurotoxic agents MBK and 2,5-

HD [158]. It is possible that individual differences in this specific metabolism

may account for the difference in susceptibility. Nerve conduction studies reveal

diminished amplitude of sensory nerve action potentials and slowed sensory and

motor nerve conduction velocities in the distal extremities of n-hexane-exposed

individuals [48]. Partial conduction block may also occur [128]. Acute

inhalation exposure may produce feelings of euphoria associated with

hallucinations, headache, unsteadiness, and mild narcosis. Thus, inhalation of

certain glues for recreational purposes causes pleasurable feelings of euphoria in

the short term but may lead to a progressive, predominantly motor neuropathy

and symptoms of dysautonomia after high-dose exposure and a more insidious

sensorimotor polyneuropathy following chronic use [6, 7, 63, 162]. Despite

35

cessation of exposure, progression of the neurological deficit may continue for

several weeks or rarely months before the downhill course is arrested and

recovery begins. Severe involvement is followed by incomplete recovery of the

peripheral neuropathy. When the polyneuropathy does resolve, previously

masked signs of central dysfunction, such as spasticity, may become evident [7].

36

     Figure:  Metabolism  of  n-­‐Hexane  and  MBK,  modified  from  Spencer  and  Schaumberg  [158]      2,5-HD is well known as the main neurotoxic metabolite of MBK and n-hexane,

widely used as solvents in many industrial processes [131]. The neurotoxicity is

potentiated by methyl ethyl ketone, which is used in paints, lacquers, printer’s

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,-.#$%&'"/0)*!1%23*!"#4523*!

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.#$3/;)&3#,#$%&'")"%!

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37

ink, and certain glues [7]. Several studies of the pathophysiology of

neuropathies due to 2,5-HD and identification of the parts of the nervous system

where 2,5-HD mostly exerts its toxic effect have been carried out [97, 159]. 2,5-

HD is mainly a product of intermediate metabolism in the human body and only

a minimal part could derive from n-hexane as a ubiquitous micropollutant [132].

Genetic  Factors    Biotransformation of exogenous and endogenous compounds may play a role in

individual susceptibility. The metabolism of biotransformation can be divided

into two phases. In phase 1, the original foreign molecule is altered by adding a

functional group, which can then be conjugated in phase 2. The conjugated

molecule can then be excreted. Normally, these steps lead to a less toxic

molecule, but in some cases, the opposite occurs. Glutathione is one of the most

important molecules in the cellular defense against toxic compounds. This

protective function is due in part to its involvement in conjugation reactions

[173].

The glutathione S-transferases (GST) are a family of enzymes responsible for

the metabolism of a broad range of xenobiotics and carcinogens [105]. The

enzymes catalyze the conjugation of glutathione with a wide variety of organic

compounds to form thioethers, a reaction that is sometimes a first step in a

detoxification process leading to mercapturic acid formation, which is a classic

excretion product of xenobiotics [105]. The GST enzymes have been shown to

protect organisms from reactive oxygen compound damage through their

abilities to bind with glutathione [72]. Two distinct superfamilies of GST

isoenzymes exist. The larger superfamily comprises cytosolic, or soluble,

dimeric enzymes that are principally, but not exclusively, involved in

biotransformation of toxic xenobiotics. The other superfamily is composed of

microsomal proteins primarily involved in arachidonic acid metabolism [72].

38

The GST family of soluble (cytosolic) enzymes is grouped into seven classes

based on structure, substrate specificities, and immunologic properties: alpha,

mu, kappa, pi, sigma, theta, and zeta. These classes are abbreviated in Roman

capitals with class members distinguished by Arabic numerals. GST isozymes

within a class share at least 40% homology of amino acid sequence, whereas

between classes there is less than 30% common identity. Within the M class,

five human isozymes were identified (M1 through M5), while two isozymes

were categorized in the GST T class (T1 and T2) [56]. By contrast with other

members of this superfamily, the class kappa GST is mitochondrial and, while

soluble, it is probably not located in cytoplasm [72]. Although different

transferases may exhibit overlapping substrate specificities, no common

substrate exists that is metabolized by all isoenzymes [72]. All GST enzymes are

dimers containing two subunits, with the identity of these subunits determining

the GST present [56]. In recent years, a wide array of GST functions has

received increasing attention, including the GST role in (1) conjugating

endogenous electrophiles, (2) maintaining intracellular redox status, and (3)

synthesizing and modifying leukotrienes and prostaglandins. Their ability to

conjugate electrophiles makes these enzymes critical in the detoxification of a

wide range of epoxides and certain other agents of environmental concern,

including pesticides, therapeutic drugs such as chemotherapeutic agents, or

dietary components [56]. Glutathione S-Transferase Mu-1 (GSTM1) and

Glutathione S-Transferase Theta-1 (GSTT1) are both polymorphic in humans

and deletions in the genes result in virtual absence of enzyme activity,

particularly with deletions in both genes (null genotype) [3]. The genetic

variations can change an individual's susceptibility to carcinogens and toxins as

well as affect the toxicity and efficacy of certain drugs. GSTT1-mediated

conjugation of halogenated solvents including bromobenzene,

bromodichloromethane, methylene chloride, and trichloroethylene may lead to

metabolic activation rather than detoxification [56].

39

The genes encoding the mu class of enzymes are organized in a gene cluster on

chromosome 1p13.3 and are known to be highly polymorphic [193]. The mu

class of enzymes functions in the detoxification of electrophilic compounds,

including carcinogens, therapeutic drugs, environmental toxins and products of

oxidative stress, by conjugation with glutathione. GSTM1 isoenzymes are

expressed predominantly in liver, followed by the testes, brain, and adrenal

glands, with low levels in lung [55]. GSTM1 null occurs as a large deletion,

which leads to complete loss of activity in homozygous variants [55]. It has

been reported that individuals with GSTM1 null genotype and high exposure to

solvents are at increased risk of developing solvent-induced chronic toxic

encephalopathy [166] and Parkinson’s disease [32].

The GSTT1 gene is situated on chromosome 22q11.2 [192]. One variant

involves deletion of the entire gene, GSTT1 null [130], and this variant lacks

enzyme activity. GSTT1 levels are highest in liver and kidney with low levels in

a variety of other organs [55]. The GSTT1 null genotype has, for example, been

associated with an about four-fold increased risk of myelodysplastic syndrome

[25]. In both the GSTM1 and GSTT1 genes, the null genotype has been

associated with an increased risk of optic neuropathies [3], adverse events,

including cognitive impairment after therapy, in patients with medulloblastoma

[10], but not in patients with Leber’s Hereditary Optic Neuropathy [86] nor

neuropathy in patients receiving oxiplatin-based chemotherapy [99].

Epoxide hydrolases play an important role in both the activation and

detoxification of a wide range of exogenous chemicals such as polycyclic

aromatic hydrocarbons (PAHs) [125]. Epoxides are three-membered oxirane

rings containing an oxygen atom and may be metabolized by the enzyme

epoxide hydrolase. This enzyme adds water to the epoxide to yield a dihydrodiol

40

[31]. Epoxides are often intermediates produced by the oxidation of various

substances. The enzyme exists in multiple forms with a broad range of substrate

selectivity against a diverse group of epoxides [31]. It is found mainly in the

endoplasmic reticulum in close proximity to cytochromes P450 [173].

Epoxides are metabolized via complex enzymatic mechanisms involving both

activation and detoxification reactions. Reactive and toxic epoxides are

frequently generated during PAH oxidative metabolism. Epoxides can be

detoxified partly by microsomal epoxide hydroxylase (mEPHX), which

catalyzes their hydrolysis, thereby yielding the corresponding dihydrodiols

[124]. Although this hydrolysis is generally considered to represent a

detoxification reaction because less toxic chemicals are produced, some

dihydrodiols generated from PAHs are substrates for additional metabolic

changes to highly toxic, mutagenic, and carcinogenic polycyclic hydrocarbon

diol epoxides. Thus, epoxide hydrolase plays the same dual role in

detoxification and activation of procarcinogens as found in some cytochromes

P450 and, as a consequence, may also play an important role in neurotoxicity

[68]. Epidemiological studies show that mEPHX activity in the liver, lung and

peripheral blood leucocytes varies as much as 50-fold in white populations

[125].

In humans, the gene is mapped to chromosome 1q42.1 [70], and is composed of

eight introns and nine exons, of which exons 2-9 are coding [31]. Two amino

acid polymorphisms have been identified in the coding region of exon three

(EPHX1 exon 3), the tyrosine 113 histidine (Y113H) exchange, results in a low

activity form of the enzyme [71], which may influence epoxide deactivation in

the cell. A decreased risk for lung cancer among African-Americans with the

low activity form of the enzyme has been found in Los Angeles, whereas the

risk did not differ among Caucasians in the same population [102]. Patients with

41

Leber’s Hereditary Optic Neuropathy who were homozygous for histidine 113

developed the disease earlier than those without this genotype [86]. The

polymorphism in exon four, histidine 139 arginine (H139R) has been suggested

as a high activity isoform of mEPHX [15, 155].

Furthermore, epoxide hydrolase plays an important role in the detoxification of

procarcinogens activated by some cytochrome P450s [15] and as a consequence,

may also play an important role in adverse drug responses. It should be noted

that some epoxides serve as important signaling molecules, regulating a large

variety of physiological functions, ranging from the regulation of vascular tone,

to inflammation, angiogenesis, and pain. Human soluble epoxide hydrolase,

which is expressed throughout the body, is, at present, regarded as the primary

enzyme in the metabolism of such endogenous epoxides [31].

The cytochrome P450 seems to be the most important phase 1 enzyme system

by which most drugs and other oxidants are metabolized [127, 173] and one of

these enzymes, cytochrome P450 2E1, is expressed in different tissues such as

liver, and nerve tissue [101]. To date, three CYP2E1 polymorphisms have been

identified in which the Rsa Ι has greater transcriptional and enzyme activity

compared to the wild-type allele [186], and was associated with higher risk of

developing alcoholic liver disease among Caucasians with alcohol abuse [135].

Health  Related  Quality  Of  Life  (HR-­‐QoL)    Traditionally, the physician’s evaluation of the patient’s symptoms and clinical

findings has been a primary focus in the practice of medicine. Over time,

outcomes such as survival, the ability to walk without aid, neurologic deficits,

dysfunctions, neurophysiological findings and anatomical findings like number

of nerve endings have been evaluated to help in medical decision making.

42

However, during the last ten years it has become increasingly important to

evaluate the patient’s own subjective experience and to estimate the cost in

relation to the improvement. This is particularly important in chronic conditions

for which there is no cure and where therapeutic goals are to relieve symptoms

and improve function and quality of life (QOL).

Quality of life is an often used but usually ill-defined term. It has been the

subject of attention across a range of disciplines, including medicine,

psychology, sociology, philosophy, economics, and geography leading to an

array of definitions [22]. One way to define QOL is that there is an upper level

with an overall assessment of well-being, which can include life satisfaction and

general perceptions of well-being. Lower levels incorporate broad dimensions

(i.e., physical, psychological, economic, social) and take account of the

individual components of each domain and allow for variations in their content

[22]. The World Health Organization in 1980 defined quality of life as an

individual’s perception of their position in life in the context of culture and

value systems in which they live and in relation to their goals, expectations,

standards, and concerns [187]. It includes the person’s physical health,

psychological state, personal benefits, social relationships and other factors as

well [1]. The range of dimensions is broad, and deciding which aspects to

measure depends on what you want to study.

QOL is also becoming an important component in the discussion between health

care providers and politicians, who, in part, will determine how limited

resources are allocated. Measuring QOL helps describe the nature and extent of

functional, psychological and psychosocial problems experienced by patients.

Furthermore, and of much relevance in an era of cost containment, a thorough

examination of an intervention’s effect on outcomes such as QOL and over-all

well-being is a key component in the evaluation of both effectiveness and cost-

43

effectiveness [22]. It is also important for the treating physician to have a good

understanding of the patient’s QOL before deciding how to treat the patient,

especially if expensive or potentially life threatening treatments are being

considered.

The state of being healthy is not only the absence of disease, but also a concept

that incorporates notions of well-being or wellness in all areas of life (physical,

mental, emotional, social, and spiritual) [1]. Health-related (HR)-QoL may be

described as the patient’s perception of disease impact on well-being. The three

dimensions of physical (impairment), mental (emotional status), and social well-

being are usually the most important ones. The experience of health is also an

important dimension, which can be divided into subgroups such as mental

health, etc.

There are two types of HR-QoL measures, generic and condition-specific. An

advantage of generic measures is that they can be used in people with a diverse

range of illnesses or health problems, therefore enabling comparisons between

groups. Generic measures are also useful when patients have several concurrent

conditions. However, these measures are often unable to focus on the specific

problems of a given condition [22]. Condition-specific scales are more sensitive

to changes within and differences between individuals with the specific

condition and are, therefore, suitable for treatment studies.

The severity of a patient’s polyneuropathy is the sum of a patient’s symptoms,

neurological signs, test abnormalities, dysfunctions, and other adverse

outcomes. An ideal scale or set of scales should provide a comprehensive and

sensible evaluation of the activities of daily living, walking, running and

climbing stairs, and measure motor, autonomic, or sensory functions as well as

the psychological effects of the disease. The benefit of these scales is that they

44

provide additional characterizing information on the intervention of the disease

in patients’ lives. In the case of treatment studies, the results indicate whether

the treatment makes a real difference in the lives of the patients and from their

own perspective. It is, therefore, an important and independent measure of the

meaningfulness of the intervention and of the consequences of the disease.

Several scales are available that quantitate neuropathic symptoms, impairments

and outcomes [34].

Most studies on HR-QoL in polyneuropathy have been performed on patients

with diabetic neuropathy. Increasing severity of polyneuropathy in diabetes is

related to decreasing HR-QoL with patients without symptoms having an

average 0.81 in EQ-5Dindex to 0.25 in diabetic patients with severe symptoms

[29]. The QOL scores of diabetic patients, who had polyneuropathy with mixed

pathogenesis and sensorimotor type, became worse with time, even if the

patients did not have any clinical symptoms of polyneuropathy [126]. The

presence and severity of neuropathic pain in different types of neuropathy has

been found to be associated with a lower reported HR-QoL in the domains of

physical and emotional functioning, sleep, role functioning and global QOL

[89]. Two independent studies have shown conflicting data whether patients

with neuropathic pain in CIAP have a poorer HR-QoL or not [45, 82].

SF-­‐36    A Short Form 36 (SF-36) has been used to evaluate quality of life. The SF-36,

which was developed by Ware and Sherbourne [185], assesses eight health

concepts during the last 4 weeks: physical functioning (PF), role limitations

because of physical problems (RP), social functioning (SF), role limitations due

to emotional problems (RE), mental health (MH), vitality (VT), bodily pain

(BP), and general health (GH) perception. Two norm-based (physical and

45

mental) scores can be calculated as summary scores. The score of the subgroups

as well as the final global score of the SF-36 changes between 0 and 100,

respectively, and higher scores better QOL. Different language versions of the

SF-36 are available, including Swedish [163, 164]. SF-36 is designed for self-

administration, telephone administration, or administration during a personal

interview. Normal values depend on sex, age, and socioeconomic status [18].

SF-36 does not cover all important health concepts, like health distress, family

functioning, sexual functioning, cognitive functioning, and sleep disorders. It

describes a general health status and is not specifically designed for

neuropathies or neurological disorders. SF-36 has, however, previously been

shown to be applicable to inflammatory neuropathies. Merkies showed that the

SF-36 scores of 113 stable patients with Guillain-Barré Syndrome, chronic

inflammatory demyelinating polyneuropathy (CIDP), or paraproteinemic

demyelinating neuropathies were lower than those of 1742 members of the

Dutch population and that neurological disability was related to lower scores in

PF and RE domains [108]. Abresch et al. measured QOL in people with

Charcot-Marie-Tooth (CMT) disease. They found that these patients had

significant bodily pain and that this was a much larger problem than had been

reported in the literature, with physical role and energy/vitality considerably

affected [2]. Ruhland and co-workers compared home exercise intervention with

a non-exercise control group in patients with chronic polyneuropathy, using the

SF-36 to assess impact on QOL. The exercise group improved on the role

limitations scales [148]. The SF-36 was chosen in our study because of its

brevity and its extensive use in clinical studies making it possible to compare

peripheral neuropathy with other medical conditions.    

46

   Table:  Interpretation  of  SF-­‐36  Health  Status  Scales    Concept   Abbrev

-­‐iation  No.  Of  Levels  

Meaning  of  Low  Scores  

Physical  functioning  

PF   21   Limited  a  lot  of  performing  all  physical  activities  including  bathing  or  dressing  

Role  limitations  due  to  physical  problems  

RP   5   Problems  with  work  or  other  daily  activities  as  a  result  of  physical  health  

Social  functioning   SF   9   Extreme  and  frequent  interference  with  normal  social  activities  due  to  physical  and  emotional  problems  

Bodily  pain   BP   11   Very  severe  and  extremely  limiting  pain  General  mental  health  

GH   26   Feelings  of  nervousness  and  depression  all  of  the  time  

Role  limitations  due  to  emotional  problems  

RE   4   Problems  with  work  or  other  daily  activities  as  a  result  of  emotional  problems  

Vitality   VT   21   Feels  tired  and  worn  out  all  of  the  time  General  health  perceptions  

GH   21   Believes  personal  health  is  poor  and  likely  to  get  worse  

 Based  on  Ware  and  Sherbourne  1992  [185]    

EQ-­‐5D  (EuroQol)      EQ-5D is a generic measure of health status, which is also known as EuroQol. It

is a patient completed questionnaire with a five-item scale that allows health

status to be addressed across five dimensions: (1) mobility, (2) self care, (3)

usual activities (work, study, household, family, or leisure),

(4) pain or discomfort, and (5) anxiety or depression. Each dimension is

subdivided into three categories, which indicate whether the respondent has no

problem, a moderate problem, or an extreme problem. EQ-5D also includes a

visual analogue scale (VAS; 0 denoting the worst imaginable health state and

100 the best imaginable health state). The three response categories combine for

243 possible health states. A weight can be assigned to each of the health states

and be used as the final score. The final score is one number where 0 is death

and 1 is the best health state. The resulting scores are used in economic

47

appraisals (such as cost utility analyses), in the construction of quality-adjusted

life years for the calculation of cost per quality of life year gained [12]. EQ-5D

has been widely used as a measure of QoL as well as in cost utility analyses.

The validity and reliability are high [20]. The Swedish version of EQ-5D was

used with permission from the EuroQol Group and the responses were analyzed

according to the manual [46].

Although EQ-5D is one of the most frequently used HR-QoL scales in medicine,

its use in polyneuropathy has been limited. It has, for instance, been used as a

secondary measure in an open-label, non-randomized study comparing

venflaxine and gabapentin as monotherapy or adjuvant therapy for neuropathic

pain in peripheral neuropathy. There were no significant improvements in EQ-

5D scores, EQ-5D domains of EQ-5D health status scores for any monotherapy

or adjuvant therapy group, but other scales showed reduction in pain and anxiety

[40]. In another drug therapy study using pregabalin, a modest reduction in pain

was found as well as improvements in anxiety and sleep, but no difference was

found in EQ-5D [112]. The effect of a home exercise program in persons with

chronic peripheral neuropathies mainly consisting of CIDP was tested. The

patients improved in the average muscle score and the RP, RE and SF scales of

the SF-36, but there were no significant changes in EQ-5D [148]. On the other

hand, a large study of pregabalin treatment of neuropathic pain containing more

than 1,000 patients showed statistically significant improvements in all

dimensions of EQ-5D except pain (p=0.059), which was markedly reduced in

other scales [116]. A criticism of EQ-5D is that it is not sensitive to change in

neuropathies as illustrated by these studies, but a strength is that it makes it

possible to make comparisons between different patient groups and that it can be

used to calculate cost-effectiveness.

48

From the patients’ perspective, most consider both SF-36 and EQ-5D as

questionnaires equally suitable. Among those who were more satisfied with a

short questionnaire (EQ-5D), several still preferred a longer and more

comprehensive questionnaire (SF-36). Health outcome assessment seems to be

acceptable, and even appreciated, by patients [118].

Other  dysfunction  scores    Since the planning of our studies, several polyneuropathy scores have been

published [64, 65, 109]. They have the advantage of being more specific for

problems in polyneuropathies, but they are more focused on motor functions and

do not describe the whole clinical picture of the disease. They are also affected

by concomitant disorders (which may be the cause of the neuropathy), poor

volition, medicolegal gain, and psychological changes. There are also tools

measuring neuropathic pain [50]. Ideally, in future trials, one or more generic

QOL scales would be combined with at least one polyneuropathy scale

depending of what kind of neuropathy is being studied and the design of the

study. These scales should be supplemented with objective measures such as

nerve conduction studies, summed scores of neurological signs, and test of

muscle strength.

   

49

 

Diagnostic  approach  to  peripheral  neuropathies    Cryptogenic polyneuropathy is in essence a diagnosis of exclusion. The

following is a guideline to rule out other relevant polyneuropathies and medical

conditions, especially treatable ones, and also to find possible exposures to toxic

agents, orally or in the environment and to identify hereditary cases.

The percentage of cases of neuropathies of undetermined cause has been

steadily declining from a past prevalence of 50–70% [47, 52] to approximately

10% [37, 107, 146] more recently. This decline reflects the recognition of new

disease entities as well as the availability of better diagnostic techniques,

including genetic studies. Intensive evaluation of these neuropathies with

unrecognized causes shows that most of these cases are either inflammatory–

demyelinating or hereditary in origin. When patients are reevaluated a few years

later, it is possible to find a cause in up to more than half of the cases [66, 146].

For the majority of these patients, this could have been known at the time of the

diagnosis of CIAP, because firstly, not all the necessary tests according to the

diagnostic guideline had been carried out, secondly, some test results had been

misinterpreted, and thirdly, in some patients the neurological examination had

been misinterpreted. In other patients there had been insufficient questioning on

the medical history or family history or the diagnosis CIAP was established at

an unusually young age. In the remaining patients it was the clinical course and

the repeated neurological examinations that changed the diagnosis [146]. Two

other studies found that in 29% and 36% of patients, respectively, a cause can be

found at a follow up of 2 to 3 years. These studies identified cases of alcohol

abuse, monoclonal gammopathy, malignancy, and vitamin B12 deficiency [66,

107]. In a more recent study a cause could only be identified in 4 of 75 patients

after a 5-year follow-up (CMT, CIDP and alcohol abuse) [121]. It can be argued

that a treatable cause of the polyneuropathy is not likely to be found and that

50

reevaluation is not cost effective. On the other hand, these studies were

performed in centers with special interest in polyneuropathies and the yield for

reevaluation is probably higher than in an everyday setting. At a minimum,

patients who deteriorate should be reevaluated.

51

     

52

 

Careful  history    As in all medical conditions, the medical history is of extreme importance.

Information regarding onset, duration, and evolution of symptoms provides

important clues. Knowledge of the temporal profile of disease (acute, subacute,

or chronic), distribution of symptoms (symmetric or asymmetric, sensory or

motor or both, distal or proximal) and the course (monophasic, relapsing, or

progressive) points to different specific neuropathies. In the case of cryptogenic

polyneuropathy it should be a progressive chronic, symmetric, sensory or

sensorimotor polyneuropathy.

It is important to rule out toxic exposures at work or during leisure time. Many

pharmaceutical agents have been reported to increase the risk of

polyneuropathy, for example, chemotherapeutical agents (vincristine, taxanes,

and cisplatin), antibiotics (isoniazid, nitrofurantoin, metronidazole), and

phenytoin [81, 177].

In many cases the history reveals that the neuropathy is hereditary without the

need for genetic testing [146]. It is also important to ask specific questions about

current and previous medical history, as the neuropathy can be secondary to

other medical conditions. Alcohol intake must be evaluated in a systematic way.

Other causes that should be ruled out are metabolic disturbances, endocrine

abnormalities, connective tissue diseases, amyloidosis, critical illness, and acute

inflammatory demyelinating neuropathies, HIV, borreliosis, or other infections,

monoclonal gammopathy and malignancies (especially myeloma and small cell

carcinoma of the lung).  

53

Detailed  physical  and  neurological  examination    

During the physical examination, the investigator should look for signs of other

medical conditions and especially signs of a malignancy. The skin should be

examined looking for signs of inflammatory diseases like sarcoidosis, Sjögren’s

syndrome or vasculitis. The extent of neuropathy should be evaluated including

sensory abnormalities (touch, vibration, heat, cold, pain, stereognosis and

proprioception), strength (proximal and distal), reflexes, and ataxia [21]. If

motor symptoms and findings dominate, then the diagnosis of hereditary motor

and sensory neuropathy type 2 should be considered, especially in younger

patients [170]. In patients with axonal neuropathy with MGUS, the arms were

more frequently affected and the disability was worse [120].

Electrophysiological  studies    Nerve conduction studies should, in principal, be performed on all patients with

clinical symptoms or signs of polyneuropathy [43, 181], with the possible

exception of patients with mild symptoms or very elderly patients. Cryptogenic

polyneuropathy is an exclusively axonal or combined axonal and demyelinating

polyneuropathy in which the axonal involvement is dominating. If the

demyelination is dominating, another cause should be sought. The

electrophysiological studies also characterize the distribution of involvement:

sensory only, motor only or both, and provide an objective picture of the parts of

the body that are involved.

Needle EMG plays a limited role in the evaluation of axonal neuropathy, but

remains important during initial diagnostic evaluation to exclude potential

clinical mimics (e.g., anterior horn cell disease, radiculopathy, myopathy).

Vrancken and colleagues investigated patients and controls older than 65 years

of age. They found that absence of the sural nerve sensory action potentials or

54

presence of spontaneous muscle fiber activity in the anterior tibial muscle was

common in patients, but exceptional in controls [180].

Important factors in patients that might influence the conduction velocities and

amplitudes are patient age and height [143], limb temperature, variants of

peripheral nervous system [61], and body mass index [23].

If nerve conduction studies and EMG are normal, quantitative sensory testing

(QST) for vibration and temperature detection thresholds should be considered.

An advantage of QST is that it assesses small fiber function. QST has been

reported to be a subjective test dependent on patients attention and cooperation

[191], while other authors argue that it has a high sensitivity at least for thermal

testing [67].

Laboratory  studies  

Several articles have been published recently discussing the laboratory work-up

of peripheral neuropathies [41, 42, 114]. Approaches vary from very limited

testing to the shotgun approach in which a large number of tests are performed

to rule out as many causes as possible. Saperstein has, for instance,

recommended that the initial laboratory testing should only include fasting

blood glucose, vitamin B12, thyroid function tests, and serum protein

electrophoresis including immunofixation electrophoresis [150]. The costs of the

test procedure, sensitivity, and specificity have to be considered. The cause of

most polyneuropathies is evident when the information obtained from the

medical history, neurological examination, and electrophysiological studies are

combined with simple screening laboratory tests. Laboratory test results must be

interpreted in the context of other clinical information since the etiologic yield

55

of laboratory testing alone is limited by the low specificity of many of the tests

[42].

If the history does not reveal the cause of the neuropathy, the following blood

tests are suggested: blood glucose (consider oral glucose tolerance testing),

complete blood count, ESR, renal function, liver function, vitamin B12, folic

acid, serum protein immunofixation electrophoresis, and TSH [41, 42, 114].

Whether or not OGTT should be performed is still under debate [138]. One

major issue is that the reproducibility of IGT (Impaired Glucose Tolerance) has

been found to be only fair to poor and the only study that used multiple OGTTs

was negative [138]. Vitamin B12 deficiency is relatively frequent in patients

with polyneuropathy, and the yield is greater when the metabolites of cobalamin

(methylmalonic acid and homocysteine) are tested. Serum methylmalonic acid

and homocysteine have been reported to be elevated in 5–10% of patients whose

serum B12 levels were in the low normal range of 200–500 pg/dL [42].

Homocysteine may also be elevated in pyridoxine deficiency and heterozygous

homocystinemia. Both homocysteine and methylmalonic acid may be elevated

in hypothyroidism, renal insufficiency, and hypovolemia [42].

IgM monoclonal gammopathies may be associated with autoantibody activity,

type I or II cryoglobulinemia, macroglobulinemia, or chronic lymphocytic

leukemia. IgG or IgA monoclonal gammopathies may be associated with

myeloma, POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-band

and skin changes) syndrome, primary amyloidosis, or chronic inflammatory

conditions [42].

Lumbar puncture is only necessary if an inflammatory neuropathy is suspected

or in cases of asymmetric axonal polyneuropathy in which borreliosis can be

expected [114].

56

In cases of a chronic sensory polyneuropathy or a rapidly progressing motor

polyneuropathy, an asymptomatic cancer has to be suspected. An X-ray of the

chest is the first option and the result is normal, a computer tomography of the

chest and abdomen should be considered [114].

Genetic testing shall not be performed in routine cases. The majority of

genetically determined polyneuropathies are variants of Charcot–Marie–Tooth

(CMT) disease, and genetic testing is available for an increasing number of

these neuropathies [140]. The clinical phenotype of CMT is extremely variable

[42]. Muscle cramping in the legs and feet and the absence of paresthesias favor

a hereditary neuropathy over other etiologies [37]. For patients with a

cryptogenic polyneuropathy who exhibit a classic hereditary neuropathy

phenotype (autosomal dominant, primary demyelinating), routine genetic

screening may be useful for CMT1A duplication/deletion and Cx32 (causing an

X-linked neuropathy, CMTX) mutations in the appropriate phenotype. Further

genetic testing may be considered in selected cases guided by the clinical

question [42].

Tests for antibodies are normally not indicated. Antibodies against Myelin

Associated Glycoprotein (MAG) should be tested for in cases of a

demyelinating polyneuropathy with distal sensory loss as in DADS (distal

acquired demyelinating symmetric polyneuropathy) [113]. High levels of

antibodies against gangliosides (GM1) are positive in 20-80% of patients with

multifocal motor neuropathy and support the diagnosis [60], but are, like other

antibodies against nerve structures, of low value in unselected cases of

polyneuropathy [60, 190]. In patients with sicca syndrome, tests for Sjögren’s

syndrome should be performed. However, polyneuropathy is a rare

manifestation of primary Sjögren’s syndrome, although the most common

57

manifestation is sensory- or sensorimotor-neuropathy. [129]. Anti-nuclear

antigen (ANA), rheumatoid factor (RF) or Anti-neutrophil cytoplasmic

antibodies (ANCA) tests are only indicated when patients exhibit vasculitis or

rheumatic symptoms [114]. Tests for sarcoidosis should only be performed if

the patient is symptomatic. Celiac disease should be evaluated with antibody

testing in cases with diarrhea, malabsorption, or cerebellar ataxia [114].

Infectious diseases should also to be considered. HIV infection has been

reported to have a prevalence up to 16% of cases of symmetrical neuropathy, but

the risk depends on the population studied [81]. In the area where our studies

were performed, the risk of borreliosis is high [73, 92].

When heavy metal toxicity is suspected, blood, urine, hair, and nail samples can

be analyzed [41]. To decide which tests to perform, the following need to be

considered: the area the patient is living in, the patient’s occupation, family

history, and symptoms. Thus, to choose the appropriate test panel, a careful

history and examination must be performed.

Nerve biopsy is only indicated if vasculitis is suspected, i.e., in axonal

polyneuropathy with subacute onset [114]. Sural nerve biopsy is of limited value

as findings in sural nerves are similar in CIDP and CIAP [19, 191] and the

procedure may result in sensory loss and neuropathic pain. Skin biopsy can

confirm the presence of small fiber neuropathy, but should be done by clinicians

with expertise in the technique [41].

Several reports have described patients with a progressive and disabling

idiopathic axonal neuropathy responsive to treatment (prednisone, intravenous

immunoglobulin), and it has been suggested that these patients could be affected

by an immune-mediated neuropathy with the axon as the primary

immunological target. In the normal case of cryptogenic polyneuropathy,

58

treatment is not efficacious and not recommended. A progressive or intermittent

disease course, asymmetric or proximal deficits, neuropathic pain, moderate to

severe disability, and abnormal laboratory findings were prominent in patients

with progressive idiopathic axonal neuropathy and in patients with vasculitic

neuropathy. A wide range of other possible clinical features has been observed

including cranial neuropathy, sensory ataxia, and small fiber neuropathy. Such

diversity of clinical manifestations has also been described in vasculitic

neuropathy [182], but not in CIAP. There is, however, no need for nerve

biopsies in CIAP as Vrancken and co-workers found that there is a small chance

of finding sural nerve vasculitis upon scrutinizing biopsy examination in

progressive idiopathic axonal neuropathy [182].     TABLE:  Routine  Work  Up  Blood  glucose  Complete  blood  count  ESR  Serum  electrophoresis  Renal  function  Liver  function  Vitamin  B12/folic  acid  TSH  Chest  X-­‐ray  Neurophysiology      

59

Hypothesis  &  Aims    

The previously published patient series on the clinical picture of cryptogenic

polyneuropathy are from the early 1990s or earlier. However, since then, the

diagnostic possibilities have improved considerably, especially for hereditary

and inflammatory neuropathies, and new causes of neuropathies have been

found. Despite the progress in determining an etiological cause for

polyneuropathy in many patients, there are still a considerable number of cases

with unknown etiology, thus regarded as cryptogenic. Even data published in the

late 1990s show that there are up to 10% of patients have MGUS in such

material [191]. This means that there is a need for descriptive studies on

cryptogenic polyneuropathy, both concerning symptoms, clinical and

neurophysiological findings, and QOL.

It is well known that many chemical compounds are toxic to peripheral nerves

and thereby can cause polyneuropathy. However, other new substances have

been found to cause neuropathy and we wanted to elucidate this field further.

Our hypothesis is that individuals with particular genotypes may have

difficulties in metabolizing certain environmental toxins and that this poor

metabolizer status make them susceptible to develop polyneuropathy following

exposure to such toxins.

60

Patients  and  Methods  

Patients    

 

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61

 

 

We collected data from three departments of neurology (University Hospital of

Linköping, Motala Hospital, and Ryhov County Hospital in Jönköping). The

hospital databases were searched for all outpatients between the ages of 40 and

79 years with a diagnosis of cryptogenic polyneuropathy from January 1, 1993

to December 31, 2000. Patients under the age of 40 years were excluded to

avoid including hereditary forms of polyneuropathy that had not yet been

diagnosed [121]. Older patients were not included in the study to exclude lesions

caused by the normal aging process in the nervous system and to avoid other

confounding diseases or medications. All patients were referred to the

departments of neurology from other physicians; usually a general practitioner,

and the neurologist continued the work up to exclude cases of known origin.

Patients with an ICD-9CM (International Classification of Diseases, 9th

Swedish edition) diagnosis of 356E, 356X, or 357X or an ICD-10 diagnosis of

G60.9, G61.9, or G62.9 (cryptogenic polyneuropathy) were included. The initial

inclusion was based on each neurologist’s judgment of the diagnosis because

there was no strict definition of cryptogenic polyneuropathy. In total, 255

patients fulfilled these criteria.

Population data obtained from the National Central Bureau of Statistics in

Sweden showed that the mean population aged 40–79 years in the study area

during that period was about 296,000. It is not possible to calculate incidence

during this period as most cases were probably diagnosed by general

practitioners and not evaluated by a neurologist.

In the study “Occupational determinants of cryptogenic polyneuropathy” (Study

II), all 232 patients who were still alive were included and were sent a

62

questionnaire. A total of 164 patients replied and were included in this study.

The reason for not excluding any patients was that we wanted the sample size to

be as large as possible so that power could be as high as possible.

In the other studies, we reevaluated the medical records, as we wanted to

ascertain that the polyneuropathy was cryptogenic/idiopathic. The following

laboratory investigations had to have been performed with normal results:

hemoglobin, fasting blood glucose concentration, vitamin B12 (cobalamin),

folic acid, and thyroid function. We defined polyneuropathy as one or more

typical symptoms (numbness, pain, postural instability, paresthesias, distal

weakness, burning sensation, muscle cramps, icing sensation, hypersensitivity to

touch) with a distal distribution and at least two of three clinical findings (distal

deficit of sensation, reduced distal muscle strength, and impaired or lost deep

tendon reflexes). We regarded the diagnosis as probable if there were one or

more of the symptoms above and one of three clinical findings. Patients whose

diagnosis was based on neurophysiological findings alone were excluded. We

also excluded patients when neurography showed a demyelinating neuropathy to

exclude inflammatory and hereditary neuropathies. These criteria were used to

reflect the clinical picture at a secondary center.

A total of 255 patients were retrieved from the databases, and of these, 168

fulfilled the criteria of cryptogenic polyneuropathy. A total of 136 patients

(81%) fulfilled the criteria of polyneuropathy and 32 (19%) had probable

polyneuropathy. The reasons for exclusion of 87 patients are listed in the table

below. Patients were not screened routinely for HIV because the prevalence in

the study area is low.    

63

 

Reason for exclusion n Alcohol + diabetes 1 Alcohol abuse 5 Alcohol + heredity 1 Basedow's Disease 1 Diabetes 9 Dominantly demyelinating 14 Hereditary polyneuropathy 2 Hypothyroidism + Ankylosing Spondylitis 1 Jejuno-ileal by-pass surgery 1 Monoclonal gammopathy 8 Phenytoin exposure 3 Polymyalgia rheumatica 4 PMR + testicular cancer 1 Rheumatoid Arthritis 1 Renal Failure 1 Simvastatin treatment 1 Sjögren's Syndrome 1 SLE 1 Tumors 8 Vitamin B12 deficiency 18 Vitamin B12 deficiency + phenytoin 1 Non-symptomatic polyneuropathy 4

 

When the genetic study (Study IV) was performed, 158 of the initial 168

patients were still alive, and they were asked to participate. Blood samples were

collected and analyzed from 79 of the patients (response rate 50%). The QOL

study (Study III) was performed during the same time period, but only those

patients aged 50 to 74 years were included. The upper age limit was selected to

the match the reference material and the lower age limit was used, as there were

only two patients, who had not reached 50 years of age.

The studies used different control materials, however all control subjects lived

in the same area as the patients and were in the same age range.

 

64

 

 

 

Data  collection    

Medical  records    The following features were recorded: age, sex, hospital, year of first symptom

and year of diagnosis, ICD-9 or ICD-10 code, symptoms and clinical signs at

first visit, and neurophysiological findings. The severity of the condition was

based on Prineas’ classification [136]: 0 = normal; 1 = minor motor and/or

sensory symptoms without functional deficit; 2 = minor to moderate symptoms

with functional deficit, including slight ataxia; 3 = severe symptoms with

functional deficit and at least some need for assistance; 4 = required assistance

in eating; 5 = not ambulant.

Initial material

I. Cryptogenic Polyneuropathy

II. Exposures III. Quality of Life

IV. Polymorphisms

n 255 168 164 62 79

Age Limits 40-79 40-79 40-79 50-74 40-79

% men 67,8 67,3 65,9 71,0 68,4

Mean age at diagnosis

64.3 (63.1-65.5) 64.2 (62.7-65.8) 63.3 (61.7-64.8) 58.0 (56.1-59.9) 63.2 (61.0-65.3)

Mean clinical severity

1.59 (1.51-1.66) 1.52 (1.43-1.62) 1.58 (1.48-1.67) 1.44 (1.30-1.57) 1.43 (1.30-1.55)

Mean neuro-physiological

severity 1.88 (1.76-1.99) 1.91 (1.76-2.05) 1.88 (1.73-2.02) 1.74 (1.51-1.97) 1.81 (1.60-2.02)

Mean number of symptoms at diagnosis

2,36 (2.22-2.51) 2.33 (2.16-2.50) 2.37 (2.20-2.54) 2.44 (2.19-2.69) 2.25 (2.03-2.48)

65

Neurophysiology    

Of the 168 patients, 139 were examined with neurography and 117 with EMG.

Nerve conduction studies were performed with surface electrodes using standard

techniques. Skin temperature was maintained at 33°C. The following nerves

were studied: median and/or ulnar motor and sensory nerves, peroneal motor,

and sural sensory nerves. Distal motor latency (DML), motor and sensory

conduction velocity (CV), the compound muscle action potential (CMAP)

amplitude, and the sensory nerve action potential (SNAP) amplitude were

recorded. A conduction block was defined as reduction of more than 30% of the

proximal: distal amplitude ratio. Axonal polyneuropathy was diagnosed if

neurography showed decreased or absent amplitudes of CMAP or SNAP and

relatively preserved CV (>70% of the lower limit of normal) and absence of

conduction block in at least two nerves. Denervation activity on EMG was also

regarded as a sign of axonal degeneration. Demyelinating polyneuropathy was

diagnosed if CV was <70% of the lower limit of normal (<35 m/s in the arms

and <30 m/s in the legs), or prolonged DML >150% of the upper limit of normal

in at least two nerves. Conduction block was also regarded as a sign of

demyelinating polyneuropathy. All others were classified as mixed axonal and

demyelinating. Normal reference values from each laboratory were used as cut-

off values. EMG recordings from the anterior tibial muscle were regarded as

either normal or chronic neurogenic (decreased interference pattern or motor

unit potentials with increased amplitude and duration). Denervation activity

(sharp waves or fibrillation potentials) was also recorded. The

neurophysiological findings were graded as follows: 0 = normal findings; 1 =

slight decrease of CMAP, SNAP, or CV in at least two nerves; 2 = all findings

between 1 and 3; or 3 = loss of sensory or motor responses in at least two

nerves.

66

Questionnaires    At two different time points, questionnaires were mailed to cases and referents.

The first questionnaire included questions about previous medical history,

symptoms and information on occupational and leisure time exposure to metal

dust, gases/smoke, solvents, engine exhausts, impregnating agents,

plastic/rubber, other chemicals, pesticides and vibrations. The subcategories

used in the questionnaire were chosen from substances suggested in the

literature to be neurotoxic.

In the second questionnaire the questions about symptoms were repeated and the

QOL instruments SF-36 and EQ-5D (EuroQol) were added.

Up to 4 reminders were sent to non-responders until they answered or refused

participation. For incomplete questionnaires, a telephone interview was

conducted with the subject.

Blood  samples    

Blood samples were collected from 79 of the patients fulfilling the criteria for

cryptogenic polyneuropathy (response rate 50%). The samples were analyzed

for the different genotypes of EPHX1 exon 3, GSTM1 and GSTT1. Whole

blood was collected and leukocyte DNA was isolated with Wizard Genome

DNA purification kit (Promega Inc., Madison, Wisconsin, U.S.A.). The GSTM1

and GSTT1 null genotypes were assessed in a multiplex polymerase chain

reaction (PCR) with β-globin as an internal control gene for a successful PCR-

amplification [9]. The amino acid polymorphisms in the mEPHX gene (EPHX1

exon 3) were determined by a PCR-RFLP (restriction fragment length

polymorphism) assay [96, 155]. For exon 3, there are 3 possible genotypes: YY,

YH and HH. The wild type normal activity allele is YY and the low activity

genotype is HH.

67

Results      

Study  I:  Clinical  and  neurophysiological  findings    Approximately twice as many men as women were affected with cryptogenic

polyneuropathy. The incidence of polyneuropathy increased with age. With

regard to clinical severity, 90 patients (54%) had slight symptoms and findings,

68 (40%) had moderately severe, and 10 patients (6%) had severe

polyneuropathy.

The mean age at first symptom was 61 years and at diagnosis, 64 years.

Regarding time from first symptom to diagnosis, 82% of the patients had a delay

from first symptom to diagnosis of less than 5 years, 14% had a delay of 6 to 10

years and 4% had a delay of more than 10 years. Patients with the longest delay

had more severe disease (clinical score 2.0 for >10 years compared with 1.5 for

<5 years), but there were no significant differences between the clinical or

neurophysiological scores in the groups.

The most common symptom was distal numbness, which was recorded in 115

case notes (65%). The patients with distal weakness or impairment of balance

had higher mean clinical severity scores. They also had significantly higher

neurophysiological severity scores. Patients who complained of burning

sensations had significantly lower neurophysiological severity scores. No other

differences were significant. Most patients (65%) had two or three symptoms,

with a mean of 2.3. There was no significant correlation between the number of

symptoms and age, clinical severity score, or neurophysiological severity score.

The shortest delay from first symptom to diagnosis was 1.8 years for burning

sensation and 2.8 years for hypersensitivity to touch, whereas the longest was

68

4.1 years for pain. The mean number of abnormal clinical findings (decreased or

lost responses or hypersensitivity) was 3.6.

Of the 168 patients, 139 had neurographic examinations. Those who were not

examined were older and had a lower mean clinical severity score although not

significant. The median or ulnar nerves and the peroneal and sural nerves on

both sides were examined in 132 patients. In 127 of these patients, at least 2 of 6

nerves showed abnormal values. Twelve patients had abnormal findings in only

one nerve or had normal findings, and these patients had significantly lower

mean clinical severity scores. Most patients had a combination of sensory and

motor nerve involvement with a mean clinical severity score of 1.7. The 6

patients with motor nerve involvement alone had the same clinical severity score

(1.7). The 29 patients with sensory nerve involvement alone had a lower mean

clinical severity score (1.3), which was significantly lower than the score of

those with sensorimotor involvement.

In 131 patients it was possible to state whether the nerve involvement was

demyelinating, axonal, or combined. Axonal polyneuropathy was the most

common (n=85) and these patients had a mean clinical severity score of 1.5. The

46 patients with the axonal and demyelinating form had a significantly higher

clinical severity score (1.8). The most common neurographic finding was that of

a mixed sensory-motor nerve involvement with axonal degeneration (n=62).

EMG examinations had been performed in 117 of the 168 patients. In 24

patients EMG in the anterior tibial muscle was normal. These patients had

significantly lower clinical severity scores than patients with abnormal EMG

(p<0.001). The 22 patients with chronic neurogenic findings and denervation

activity had significantly higher clinical severity scores (2.0) than the 70 patients

69

with chronic neurogenic findings alone (1.6) (p<0.05). One patient had

denervation activity alone.

Of the 139 patients who underwent neurography, 4 had neurophysiological

severity grade 0, 46 patients grade 1, 48 patients grade 2, and 41 patients grade

3. There was no difference in neurophysiological severity between men and

women. The patients in the most severe group were significantly older than

those in group 1 and 2 (p<0.01); and had significantly higher clinical severity

scores. Patients in the moderate group (grade 2) also had a higher clinical

severity score than those in the mild group (grade 1) (p<0.001). However, there

was no significant correlation.  

Study  II:  Occupational  determinants  

Male sex increased the risk for cryptogenic polyneuropathy, COR (Crude Odds

Ratio) 2.33 (95% CI 1.61-3.38), and increasing age was a determinant for both

men and women showing significantly statistical trends. Fewer women reported

chemical or vibration exposure; 19% of female referents were exposed

compared to 64% of male referents. Exposure in men to Stoddard solvent, petrol

exhausts, herbicides, and hand and foot vibrations were significantly associated

with increased COR, respectively.

As individuals tended to have multiple exposures, logistic regression was

performed. In men the logistic regression showed particularly increased risks

(LOR, Logistic Odds Ratio>3.50) for occupational exposure to sulphur dioxide,

xylene, methyl ethyl ketone, and herbicides. Risks remained increased

(LOR>1.50) for occupational exposure to lead, hydrogen sulphide, Stoddard

solvent, petrol exhausts, fungicides, and vibration exposure to the feet,

respectively. For leisure time only exposure to gases/smoke and solvents

70

showed increased risks in the logistic regression, but only solvents was

significant, LOR 8.84 (95% CI 2.43-32.04). In women half of the CORs above

1.50 remained that high in LOR i.e., lead, mercury, nitrous oxide, and

insecticides. Comparing LORs in men and women, only the exposure to lead

showed increased risk in both sexes. However, our results do not contradict risks

in both sexes as the confidence intervals are overlapping, except for mercury

exposure.

In the second logistic model including exposure categories and without an

unexposed reference group, the results were identical with the former results

both for men and women.

Interaction between occupational and leisure time exposure could only be

analyzed in detail for men. Occupational pesticide exposure was the only

statistically significant determinant without a concomitant leisure time exposure,

COR 3.13 (95% CI 1.20-7.91). Comparing the results, interaction was

particularly strong for leisure time exposure to solvents especially in

combination, with occupational exposure to metal dust, gases/smoke, solvents,

engine exhausts and vibrations, respectively. However, even if the interactive

effect seems strong, the largest contribution to the risk estimates is from the

occupational exposures as sole leisure time exposure is rare.  

Study  III:  Health  related  quality  of  life    

This study comprised 62 patients with an average age of 64.9 years. The mean

time from diagnosis was 6.9 years (range 2-21 years). As reference, 1,429

women and 1,292 men from the general population were used, with a mean age

of 60.6 years, which was significantly lower than in the patients.

71

SF-­‐36    When comparing the group of patients with cryptogenic polyneuropathy as a

whole with the general population, patients had lower QOL in all scales except

for MH (Mental Health) and mcs (Mental Component Summary). In the general

population, women had lower QOL than men for all scales. Women with

polyneuropathy tended to have lower QOL than men in all scales but the

differences did not reach significance. When patients and referents were

grouped according to age and sex, the physical scales PF (Physical Functioning),

RP (Role Physical), BP (Bodily Pain) and GH (General Health); and mental

scales VT (Vitality) and RE (Role Emotional) were decreased in most groups of

patients except for older women where only GH and VT were significantly

affected. On the other hand, no significant differences were observed in any

group in MH and mcs.

In the general population, the scores in PF, RP, GH, RE and both sum scales

decreased with increasing age. In polyneuropathy patients, the only statistically

significant difference was that 50- to 64-year old women had lower BP scores

than those who were 65 to 74 years old.

72

PF   RP   BP   GH   VT   SF   RE   MH   pcs   mcs  50-­‐59  (n=8)   70,8   57,4   49,4   51,8   56,2   76,5   58,8   75,5   39,9   45,8  

60-­‐69  (n=22)   59,9   54,6   60,1   61,9   59,3   80,6   72,8   80,4   38,3   50,9  

0,0  

10,0  

20,0  

30,0  

40,0  

50,0  

60,0  

70,0  

80,0  

90,0  

SF-­‐36  versus  age  in  men  

PF   RP   BP   GH   VT   SF   RE   MH   pcs   mcs  50-­‐64  (n=10)   52,0   37,5   42,3   48,2   43,0   81,2   51,7   75,2   32,8   47,2  

65-­‐74  (n=7)   55,7   53,6   60,0   39,5   51,2   76,8   76,2   83,4   34,5   51,5  

0,0  

10,0  

20,0  

30,0  

40,0  

50,0  

60,0  

70,0  

80,0  

90,0  

SF-­‐36  versus  age  in  women  

73

To analyze patients with polyneuropathy by duration of the disease, patients

were grouped into three categories, based on the disease duration: 0 to 5, 6 to 10

and more than 10 years. None of the scales in SF-36 showed any significant

difference between these groups.

0

10

20

30

40

50

60

70

80

90

PF RP BP GH VT SF RE MH

Aver

age

scor

e

SF-36 vs duration (years from first symptom) of polyneuropathy

0-5 (n=20)

6-10 (n=41)

>11 (n=43)

74

EQ-­‐5D    Because of the small number of patients in each group, all patients reporting any

problem have been analyzed together. Patients with cryptogenic neuropathy

reported significantly more problems in walking (mobility) (42%) than reference

subjects (14%). Problems with usual activities were reported by 31% of patients,

which was significantly more common than in the general population (8%). Six

percent of the patients reported problems with self-care (washing and dressing)

compared to 2% of the reference subjects. Pain was common in both patients

(85%) and the general population (56%). Anxiety or depression was reported by

35% of patients and 29% of reference subjects, which was the only not

significant difference. No significant differences were seen between men and

women. The results were not affected by disease duration for any of the five

questions.

EQ  barometer    Health state measured by the Visual Analogue Scale (VAS) was significantly

lower in male polyneuropathy patients older than 60 years and in women

younger than 70 years compared to the general population. The VAS scores

tended to decrease with increasing age, but there were no significant differences

between groups except between 50- to 59-year-old males and 60- to 69-year-old

males. Women with polyneuropathy tended to have lower VAS scores than men

in all age groups, but the difference was only significant for 50- to 59-year-old

patients. No relationship was seen between the QOL measured by the EQ

barometer and disease duration. However, patients reporting many symptoms

had lower EQ barometer values.        

75

Study  IV:  Genetic  polymorphisms    In total, 79 cases with cryptogenic polyneuropathy and 398 controls were tested

for genetic polymorphisms in the GSTM1, GSTT1, and mEPHX genes. The OR

for the null genotype of GSTM1 and GSTT1 was 0.99 (0.61-1.61) and 1.86

(0.82-4.24), respectively and for EPHX*3 YY versus YH/HH the OR was 1.06

(0.65-1.71). Among the controls there were significantly more women with

GSTT1 null than in men, (p=0.04), and the homozygous HH variant in mEPHX

was more common in men (p<0.01). The other variants did not differ between

men and women. There were no statistically significant differences between

cases and controls in any group.

Regarding clinical findings, 24 patients were considered to have mild findings

and 39 patients had severe findings. No significant differences were found

between the groups in clinical or neurophysiological severity at diagnosis except

a tendency for GSTM1 null to have more severe clinical findings than GSTM1

positive cases (mean 1.55 vs. 1.31, p=0.064). Axonal neuropathy was observed

in 41 patients and combined axonal and demyelinating neuropathy in 19

patients. Regarding neurophysiological findings, 2 patients had pure motor

neuropathy, 13, pure sensory neuropathy, and 64, a mixed sensorimotor

neuropathy. Genetic polymorphisms were not significantly related to these

neurographic findings.

We also investigated the effects of different exposures. The frequencies are

presented in the table below.

 

76

Exposure Referents Cryptogenic

polyneuropathy

Smokers or previous

smokers

189 (47%) 43 (54%)

Solvents 132 (33%) 24 (30%)

Pesticides 29 (7%) 8 (10%)

Generalized anesthesia 312 (78%) 59 (74%)

Private water supply 29 (71%) 51 (65%)

The odds ratios for cryptogenic polyneuropathy among exposed individuals

were calculated. GSTT1 null among smokers reached the highest odds ratio

(3.72, p=0.08), and EPHX*3 HH vs. YY among solvent exposed had the lowest

odds ratio (0.30, p=0.14). A logistic regression analysis for the different

polymorphisms, sex, age, and exposures did not show any confounding effects

except that increasing age and male sex increased the risk of cryptogenic

polyneuropathy. Interactions between genes were analyzed and showed an

increased odds ratio for GSTT1, which was strongest if the patients had the HH

form of EPHX*3 (OR 2.37, p=0.234).

Additional  results      

Evaluation  of  symptoms      In 2000 and again in2002, a questionnaire was sent to the patients, and 105

patients (77 men and 32 women) replied to both of the questionnaires. Of those

who responded, 87 fulfilled the criteria for cryptogenic polyneuropathy (61 men,

77

26 women). They were asked if they were experiencing any of 9 different listed

symptoms in either hands or feet. At the time of the first questionnaire 1.4 (0.88-

1.9; mean and 95% confidence intervals) symptoms from the hands, and 3.3

(2.7-3.9) symptoms from the feet were reported. At the time of the second

questionnaire 1.7 (1.2-2.2) and 3.8 (3.3-4.4) symptoms were reported

respectively. The total number of symptoms increased from 4.7 (3.8-5.6) to 5.5

(4.7-6.4). The differences were not statistically significant. In hands 18 patients

reported fewer symptoms and 29 reporting more symptoms (n.s). In feet the

difference was statistically significant (Wilcoxon p=0.016), with 21 patients

reporting fewer symptoms and 39 reporting more symptoms. A total of 43

patients experienced an increase in the total number of symptoms, and 19 had a

lower total number of symptoms (p=0.007).  

Number  of  symptoms   Hands  2000   Hands  2002   Feet  2000   Feet  2002     Total  2000   Total  2002  

0   46   32   20   8   66   40  1   14   17   8   7   22   24  2   10   14   12   14   22   28  3   0   10   4   14   4   24  4   6   4   10   13   16   17  5   1   1   13   10   14   11  6   4   2   8   5   12   7  7   2   6   6   6   8   12  8   3   1   4   5   7   6  9   1   0   2   5   3   5  

    87   87   87   87   174   174    

Number  of  reported  symptoms  in  2000  and  2002.  

The number of the respective symptoms was also analyzed. Numbness, impaired

sensation, pain, paresthesias, and distal weakness in the feet were the most

common symptoms reported. Pain in hands and feet, distal weakness in hands,

numbness and muscle cramps in feet were increasing most in frequency.

78

Burning sensation in hands and impaired sensation in hands and feet were

decreasing in frequency.         Hands  2000   Hands  2002   Feet  2000   Feet  2002  Numbness   24   25   45   56  Pain   14   22   34   45  Paresthesias   20   23   43   49  Distal  weakness   20   31   36   39  Burning  sensation   8   5   21   21  Muscle  cramps   17   20   23   31  Icing  sensation   7   7   17   23  Hypersensitivity  to  touch   7   10   15   20  Impaired  sensation   17   16   55   52        Frequency  of  different  symptoms  of  polyneuropathy  with  a  2-­‐year  interval.        

79

 

Quality  of  life  

       SF-­‐36  in  all  patients  that  responded  (n=104),  in  the  published  material  aged  50-­‐74  (n=62)  and  in  the  general  population.  

To evaluate the impact of cryptogenic polyneuropathy on QOL, 158 patients

fulfilling the criteria of cryptogenic polyneuropathy were sent validated

instruments (SF-36 and EQ-5D). Responses were received from 104 patients (70

men, 34 women [66% response rate]). Their average age was 70.3 years (range

43-88 years), and the mean time from diagnosis was 7.2 years (range 2-23

years). No significant differences were observed between responders and non-

responders in age at diagnosis, age at questionnaire, number of symptoms at

diagnosis, clinical or neurophysiological severity. However, the patients who

were no longer alive any longer would have been significantly older at the time

PF RP BP GH VT SF RE MH pcs mcs Cryptogenic polyneuropathy (n=104) 54,6 42,0 53,1 51,0 50,6 75,4 62,9 75,2 34,8 48,3 Cryptogenic polyneuropathy (n=62) 61,6 51,6 54,9 54,8 54,6 79,0 64,8 78,1 37,4 49,0 General population (n=2,721) 81,3 78,6 69,9 68,6 67,1 86,3 85,2 79,4 47,3 50,4

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

90,0

100,0

Aver

age

scor

e

SF-36

Cryptogenic polyneuropathy (n=104)

Cryptogenic polyneuropathy (n=62)

General population (n=2,721)

80

the questionnaire was sent out and were older at first symptom and diagnosis,

but did not differ in number of symptoms or clinical or neurophysiological

severity. As the control population had an upper age limit at 74 years and as

only two of the patients were younger than 50 years, the age limit in the final

study was changed to 50-74 years. The data of both the complete and published

materials are shown above. The older excluded patients had a lower HR-QoL in

most of the scales.

Diabetes  risk  evaluation  

According to the information in the medical records as described in Study I, 168

patients were considered as cryptogenic. All of these patients were sent the

questionnaire described in Study II. This questionnaire also included questions

about the medical history. A total of 110 patients replied (76 men, 34 women),

58 did not reply (37 men, 21 women) and 604 controls replied (274 men, 330

women).

It has been described in the literature that patients with cryptogenic

polyneuropathy have an increased frequency of impaired glucose tolerance [75,

122, 152, 165] and probably are at risk of developing diabetes, though others

have found contradicting results [82, 117]. As the patients’ data were collected

during a 7-year period, one important question was if they still were

cryptogenic. We, therefore, asked specifically about diabetes. The patients had a

mean age of 68.2 years (66.2-70.1; 95% confidence interval) and the controls

were 62.2 (61.3-63.1) years old (p<0.001) at the time of the questionnaire. Three

patients, who initially were not diagnosed with diabetes, reported that they had

developed diabetes (2.7%) and 30 controls (5.0%) reported that they had

diabetes. The incidence of diabetes type 1 and 2 in Sweden for 60- to 69-years-

olds is 732 cases per 100,000 and year [172], therefore, the incidence in our

material is at the same level.

81

Discussions  and  Conclusions    

Clinical  picture    Polyneuropathy is one of the most common neurological disorders and patients

are seen by physicians with many different specialties. The clinical diagnosis is

based on the finding of a distal, fairly symmetrical impairment of sensation,

muscle strength, or muscular atrophy, and progression over a period of months

or years. Reflexes are decreased or lost in the affected parts, but particularly in

the ankles. Symptoms usually occur in the feet before the hands [179].

Neurophysiological investigations with nerve conduction studies and EMG can

support the diagnosis.

The 182 cases of polyneuropathy in our first study were diagnosed as

cryptogenic by the treating neurologist. To make certain that there was no

known cause of neuropathy, the medical records were reviewed according to our

protocol. In many cases the patients had been followed up after the initial visit.

The questionnaire that was sent to the patients also included questions about

disorders known to cause polyneuropathy. As the patients were diagnosed up to

7 years before the first questionnaire, it is likely that tumors presenting with

polyneuropathy, as the first symptom would have been diagnosed. 8 patients

actually were excluded due to tumors. The risk of developing diabetes was also

low, confirming that the cases were correctly diagnosed. The major problem

with the diagnosis is that it is always possible to do a more thorough

investigation. Unfortunately, neurophysiological examinations were performed

in only 139 of the patients. It is, however, unlikely that any of these patients

would have an inflammatory neuropathy such as CIDP, as patients who were

deteriorating would have been followed up or referred back to our clinics. There

are no other clinics in the study area treating progressive neuropathies. In fact,

82

the patients who were not examined neurophysiologically had a lower clinical

severity at diagnosis supporting that they were cryptogenic. The most common

reasons for not performing neurophysiological tests were old age and low

clinical severity. Our definition of cryptogenic polyneuropathy is relatively

broad, but has the advantage of reflecting the clinical picture that is seen by a

neurologist at a secondary or tertiary center, which was the aim of our study.

The study has the drawback of being retrospective.

Polyneuropathy was more common in elderly patients and about twice as many

men as women were affected. This difference is in agreement with most

previous studies [37, 66, 107, 119] except one [190]. A male predominance may

support our hypothesis that polyneuropathy could be caused by a chronic toxic

effect of occupational or environmental factors.

In our series two thirds of the patients complained of numbness and about one

third complained of paresthesias, pain, impairment of balance, or distal

weakness. In a smaller study of 29 cases of unclassified polyneuropathy, 28

patients had hypoesthesia or hyperalgesia, 26 paresthesias, and 10 pain [66].

Vrancken reported higher prevalences of symptoms in CIAP, this is, however,

probably due to study design [180]. In a study of chronic cryptogenic sensory

polyneuropathy, distal numbness was reported in 86% and pain in 72% of the

patients [190]. In our series impairment of balance and muscle weakness was as

common as pain, probably reflecting the fact that we also included patients with

motor or sensorimotor polyneuropathy.

Two symptoms brought patients more rapidly to the neurologist: a burning

sensation and hypersensitivity to touch. These symptoms are very disturbing to

patients and make them seek medical attention early. In contrast, patients with

pain and muscle cramps had the longest delay from first symptom to diagnosis.

83

Wolfe also found that patients with pain had their symptoms significantly longer

than those without pain, for which they had no clear explanation [190]. Wolfe

and colleagues also found that only 10% of their patients complained of pain

alone [190].

When patients were asked about symptoms with a 2-year interval, the number of

symptoms increased. All symptoms except burning sensation and impaired

sensation in hands or feet became more common. Unfortunately, we do not have

any data about the development of severity of the symptoms.

The most sensitive signs of polyneuropathy are decreased or lost distal

proprioception or sense of vibration, and ankle jerks, both with a sensitivity of

75-80%.

Our scale for clinical severity focused on functional deficits (particularly ataxia

and need for assistance), so it was not surprising to find that the symptoms

impairment of balance and distal weakness had the highest clinical severity

scores. However, other symptoms such as pain and burning or icing sensations

probably affect the QOL as much. We classified 93% of the patients in this

series as having mild or moderate disease; but they probably had a more severe

disease than patients in other studies. Some of the previous epidemiological

studies were based on people in primary care [14, 103] and there might be

important differences between those studies and ours. Because of the large

number of patients in primary care with mild symptoms, some patients might be

diagnosed as having cryptogenic polyneuropathy, but later turn out to have other

diseases or simply normal aging of the peripheral nerves.

Of the 84% of patients who had neurographic examinations performed, more

than half had a mixed motor and sensory nerve involvement and only 4% had

84

motor nerve involvement alone, which is in accordance with the results of

Notermans et al. [119], who found only 3% with motor involvement alone.

Several of their patients who initially had sensory neuropathy later developed

sensorimotor involvement [121].

The EMG studies showed chronic neurogenic signs with denervation in 23 of

123 patients, compatible with a mainly axonal polyneuropathy, which is in

agreement with others [119]. The EMG findings also suggest that even if most

cryptogenic polyneuropathies are mainly sensory or sensorimotor, there is also

an involvement of motor nerves, which is important when judging the relevance

of neurophysiological findings and their correlation with somatic neurological

findings [66, 119, 190].

We found a weak correlation between clinical and neurophysiological severity.

A larger prospective study with a better classification of neurophysiological

severity would probably find a stronger correlation. In some cases the

neurophysiological severity is greater than expected from the neurological

examination. Another reason for neurophysiological examination is that axonal

and demyelinating polyneuropathies can be distinguished. The latter includes

hereditary neuropathies and the treatable chronic inflammatory demyelinating

polyneuropathy (CIDP) [144].

Health  related  quality  of  life    Cryptogenic polyneuropathy has usually been regarded as a relatively mild

neurological condition, which commonly does not severely affect the patient’s

ability to walk or perform activities of daily living (ADL). However, we found

that 42% of patients reported problems with walking and 31% had problems

with usual activities such as work, study, household work, family or leisure

activities. These problems were not affected by age. In another study focusing

85

on QOL in patients with CIAP, fatigue and walking disability were found to

interfere markedly with patients’ functioning in daily life [44].

Disease duration did not affect SF-36 or EQ-5D barometer scores in our study.

That finding might, in part, be explained by the study design as patients were

recruited over a 7-year period and some patients had short time of follow-up

from diagnosis to participation in our study. However, the results of a

prospective follow-up study of 40 patients with chronic polyneuropathy of

undetermined cause support that the disease is a stable or only slowly

progressive disorder in most cases [88].

Teunissen and co-workers showed that patients with CIAP have lower scores

than expected in all areas of the SF-36 except for ‘role limitations due to

emotional problems’. The differences in ‘social functioning’, ‘pain’, and

‘physical functioning’ were most marked [168]. Their patients and the reference

population were not sex and age matched. These results are in line with our

results, although we did not find any difference in ‘mental health’. Hughes

reports that QOL in CIAP was worse than norms from Australian Bureau of

Statistics in all SF-36 scales except ‘role emotional’. In the scale ‘mental

health’, they only found a difference among patients with pain [83]. The patients

reported by Hughes had lower scores in almost all scales most likely because

these patients were older or due to selection of the patient material. All three

studies support that chronic idiopathic or cryptogenic polyneuropathy impairs

physical functions and that the disease limits the ability to perform usual

activities in daily life.

In our study, 85% of the patients reported pain in EQ-5D. However, EQ-5D is a

very sensitive instrument for assessment of pain, which was reported by 56% of

females in the general population older than 50 years of age and at a slightly

86

lower frequency in men. In a study of Italian patients with chronic

polyneuropathy, the QOL was affected not only by the presence of neuropathy,

but also by the presence and intensity of pain. Moreover, the mental domains of

the SF-36 were only correlated with pain. Pain per se worsens the QOL of

neuropathic patients, regardless of disease severity [27]. Abresch and co-

workers have investigated the QOL in patients with different slowly progressive

neuromuscular diseases (myotonic muscular dystrophies, limb-girdle

syndromes, CMT disease, fascioscapulohumeral dystrophy, spinal muscular

atrophy and post-polio syndrome). Their results indicated that, except for adult

spinal muscular atrophy, the prevalence and severity of pain reported in slowly

progressive neuromuscular diseases were significantly greater than levels of

pain reported by the general US population. There was a significant correlation

between increased pain and lower levels of general health, vitality, social

function, and physical role, which confirms that pain is an essential symptom

affecting QOL in patients with diseases in the peripheral nervous system and

muscles [2]. They found the same results in patients with diabetic neuropathy,

which indicates that patients who have moderate or severe levels of pain may

benefit from a pain management program, rather than focusing on only physical

impairment [1]. These results were confirmed in patients with different kinds of

polyneuropathy by Liedberg and Vrethem [100].

In a study focusing on pain in CIAP it was found that non-neuropathic pain was

as common as neuropathic pain and that pain was strongly associated with the

physical functioning domain of the SF-36 in patients with mixed neuropathic

and non-neuropathic pain [45].

HR-QoL has been described in several studies of diabetic neuropathy showing

lower HR-QoL in patients with diabetes than in our group of patients with

cryptogenic polyneuropathy [8, 28, 74].

87

Exposures  in  work  and  leisure  time    Considering the magnitude of risk, the confidence intervals and the confounding

effect from other exposures, in our study, the independent determinants for

polyneuropathy in men seemed to be occupational exposure to lead, sulphur

dioxide, hydrogen sulphide, xylene, methyl ethyl ketone, herbicides, fungicides

and foot vibrations. Among leisure time exposures only solvents could be

regarded as a strong independent determinant. All other leisure time exposures,

except perhaps gases/smoke, seemed to be of minor importance for

polyneuropathy since the increased risk could be explained by concomitant

occupational exposures. In women the corresponding occupational determinants

were lead, mercury, nitrous oxide and insecticides, however no leisure time

determinant could be identified. Our study was limited by small numbers of

cases and by low frequency of exposure, especially in women, which was

reflected in broad confidence intervals, not always including unity.

Some individuals, especially in the older ages, might have found it difficult to

remember their life time exposures, but as cases were older than referents,

memory bias should work in the direction of lowering the risk estimates. None

of the referents answered that they had polyneuropathy. Evaluation of the

validity of information from subjects in case-referent studies has also failed to

find any recall bias of importance [90, 134]. In a study of 188 metal-exposed

subjects, exposure assessment performed by an industrial hygienist was

compared with self-reported exposures, showing an agreement in the

assessments from 83 to 94% for different metals. Interestingly, the hygienist

classified more workers to be exposed than the workers themselves [149].

88

Our study was too small to allow any further analyses of the exposure i.e.,

length or intensity, thus including only ever exposed. As a majority of the male

cases and referents were exposed to several potential determinants, a reference

category free of such exposures was used. Although Swedish women have a

relatively high employment rate, only a minority were exposed to occupational

chemicals or vibrations. This is the reason why the study was analyzed with men

and women separated.

Out of the initial list of well-established, but often rarely occurring, substances

that cause polyneuropathy, only lead, n-hexane and nitrous oxide showed an

increased risk in our study [158]. We also showed some synergistic effects with

increased risk estimates in various occupational and leisure time exposures

combined.

Occupational mercury exposure occurs in workers associated with glass cutting

and in the manufacture of scientific instruments, in dental personnel, and

following release of mercury vapor from amalgam tooth fillings. Methyl

mercury is used in the manufacture of paper, in the chloralkali industry, and in

other chemical production. General human exposure usually results from

ingestion of fish obtained from water contaminated with industrial effluents

[178]. Mercury was a determinant for cryptogenic polyneuropathy in women

according to our study. Organic mercury is clearly associated with

polyneuropathy [178]. However, there are case reports that elemental mercury

can also cause polyneuropathy in humans [4, 5, 26, 76, 79, 87, 151, 178]. Only

one study of workers exposed to mercury has failed to find any relationship with

polyneuropathy [176]. Unfortunately, our questionnaire did not distinguish

between organic and inorganic mercury.

89

Sulphur dioxide and hydrogen sulphide appeared to be strong determinants for

cryptogenic polyneuropathy in our study, and these associations have not been

previously published. A well-known mechanism of hydrogen sulphide is

respiratory paralysis and subsequent hypoxia to the central nervous system, but

there could also be a direct toxic effect on the brain [110]. Several enzymes in

the brain are inhibited by hydrogen sulphide i.e., carbonic anhydrase, an enzyme

involved in the neuronal lipid synthesis and/or re-organization of myelin

membranes [147]. Whether these mechanisms also are applicable to the

peripheral nervous system is less clear.

In our study toluene did not show an increased risk in the logistic regression

analysis although polyneuropathy has been described after abuse of toluene-

containing products [162]. Polyneuropathy has also occurred in different

occupational settings where toluene has been present [57, 104]. In contrast to

toluene, xylene was a relatively strong determinant in our study; a finding

supported by case reports on intoxication with products containing 5-10%

xylene [57]. Xylene (dimethylbenzene) is also chemically closely related to

toluene (methylbenzene) and can, therefore, be suggested as a potential agent to

cause polyneuropathy despite less documentation.

Methyl ethyl ketone was a relatively strong determinant in our study. In the

literature only case reports have been found, but the neurotoxic potential of

methyl ethyl ketone is difficult to evaluate as these cases have been exposed to a

mixture of solvents [6, 39, 63]. It has also been reported that methyl ethyl ketone

can act indirectly as an inducer of n-hexane-metabolizing enzymes [84].

7 male cases and 4 referents added exposure to jet fuel and jet engine exhausts

in the questionnaire, COR 6.73 (95% CI 1.54-33.21). There are only two

previous reports on this relationship in the literature [93, 94]. As both civilian

90

and military airports as well as an aircraft industry are located in southeast

Sweden, where our investigation was performed, this result seems reasonable.

In our study herbicide, and to some extent also fungicide, exposure in men and

insecticide exposure in women were determinants. Herbicides are not commonly

reported to cause peripheral polyneuropathy in the literature. In fact, only three

case reports describe polyneuropathy after occupational exposure to the

herbicide 2,4-D with predominant dermal uptake [16, 59, 174]. A case report

describes intoxication with weed killers containing phenoxyacetic acid that

resulted in a delayed peripheral neuropathy [123]. On the other hand, an

evaluation of soldiers exposed to Agent Orange (50:50 mixture of 2,4-D and

2,4,5-T) has concluded that there is inadequate or insufficient evidence for an

association with peripheral neuropathy [58]. Therefore, our results contribute to

the evidence that herbicides might cause polyneuropathy.

In contrast, exposure to organophosphates is a recognized cause of

polyneuropathy [7], but these compounds are no longer extensively used in

Sweden. Organophosphates are used mainly as pesticides and herbicides but are

also used as petroleum additives, lubricants, antioxidants, flame-retardants, and

plastic modifiers. Certain organophosphates cause a delayed polyneuropathy

that occurs approximately 2 to 3 weeks after acute exposure even in the absence

of the otherwise typical acute cholinergic toxicity [7]. Another insecticide,

dichlorodiphenyltrichloroethylene (DDT), was widely used in Sweden until the

ban in 1970. DDT belongs to the organochlorine pesticides known to cause

symptoms of the central nervous system at high doses, but the effects of chronic

low-level exposure are uncertain [7]. Lindane, another widely used insecticide,

has also been reported to cause polyneuropathy [175]. However, there were too

few exposed in our study to obtain a risk estimate. Pyrethroids are synthetic

insecticides that affect voltage-sensitive sodium channels and possibly also

91

voltage-sensitive calcium and chloride channels. Occupational exposure has led

to paresthesias that have been attributed to repetitive activity in sensory fibers as

a result of abnormal prolongation of the sodium current during membrane

excitation [156]. Convulsions may occur if substantial amounts are ingested

[137]. Fungicide exposure has not been suggested to be a determinant for

polyneuropathy, but in our study, the risk was a doubled in men.

Exposure to vibrating tools may cause a variety of symptoms depicted as the

hand–arm vibration syndrome. The symptoms may be of vascular, neural, and

muscular origin and may appear as digital vasospasm (vibration white fingers;

VWF), sensorineural disturbances, and/or as muscular weakness and fatigue

[53]. A negative relationship has been observed between nerve conduction

velocities in motor and sensory nerves in the arms, on the one hand, and age at

the time of the study or total number of working years with vibrating tools, on

the other [53]. Until now, there have been no reports that vibration of the feet

can cause a more generalized polyneuropathy, and therefore, in that respect our

finding should be interpreted with caution.

Genetic  polymorphisms  and  risk  of  cryptogenic  polyneuropathy    The frequency of GSTM1 null is 42-60% in Caucasians [51]. The frequency of

homozygous null GSTT1 varies greatly with ethnicity and is 10-20% in

Caucasians [141]. The EPHX*3 gene can be found in three different forms, the

wild type/normal activity variant (YY), heterozygous (YH), or homozygous/low

activity (HH) genotypes. In a Caucasian population, approximately about 40%

of subjects are heterozygous and 12% are homozygous for the HH genotype

[51]. The frequency of these polymorphisms in our study population was

similar. No differences in allele frequencies by age or sex were seen in large

studies [51]. Unfortunately, we had an imbalance in our control group with 19%

92

of the women and 12% of the men having the GSTT1 null polymorphism and

9% of the women and 18% of the men having the EPHX*3 HH polymorphism.

Thus, it is not possible to draw any conclusions about differences in risks of

cryptogenic polyneuropathy among men and women separately.  In Study IV of patients with cryptogenic polyneuropathy, we examined the

association of GSTM1 and GSTT1 null polymorphisms and EPHX1 exon 3 HH

polymorphism in relation to several environmental and chemical exposures.

Although we did not find any statistically significant increased risk, the GSTT1

null genotype was associated with an almost two-fold increased risk of

polyneuropathy. Our hypothesis is that the GSTT1 null polymorphism may be

related to an impaired metabolism of toxic substances and reactive oxygen that

could lead to nerve damage, involving multiple sites along motor and sensory

axons in the peripheral nervous system. This may result in axonal atrophy or

axonal swelling, leading to progressive distal axonal degeneration. The myelin

sheath may break down concomitantly with the axon. This could contribute to,

or directly result in, an axonal or combined axonal-demyelinating neuropathy.

Components of cigarette smoke are examples of exogenous substrates that are

toxic and, furthermore, are subject to bioactivation and may both directly and

indirectly be neurotoxic. We found a nearly four-fold increased risk of

polyneuropathy in GSTT1 null smokers that almost achieved statistical

significance. Teunissen and co-authors reported an odds ratio of 2.1 for current

smoking in patients with CIAP [169], and it has also been found that tobacco

use may predispose to earlier development and more severe symptoms of

diabetic neuropathy [167]. Our data indicate that this risk might be explained by

smokers carrying certain genetic polymorphisms leading to impaired

detoxification of the toxic compounds in cigarette smoke. The mechanism for

the toxicity of cigarette smoke on nerves is not known, but it has been

93

speculated that chemicals in the smoke mediate it, where PAHs are regarded as

the most important component. Impaired breakdown of PAHs in persons with

the null genotype of GSTs may lead to an increased exposure on nerves and

thereby increased loss of nerves. n-Hexane is another toxic substance that is

present in cigarette smoke and is a well-known cause of polyneuropathy [194].

We did not find a significant correlation between clinical or neurophysiological

severity and genotype except a small increase in the severity of clinical findings

in GSTM1 null patients that almost reached statistical significance. It is possible

that a correlation will be found if a more sensitive scale for clinical or

neurophysiological severity was used in a larger material.

There are several possible reasons why we did not find any significant

differences. The main reason is probably the small number of patients in our

study. However, in a Chinese study of 22 cases of polyneuropathy working in a

printing factory and 163 controls, an association was found with CYP2E1 Dra,

but not GSTM1 and GSTT1, indicating that either a more pronounced exposure

to a toxic agent is necessary or that other genes may have greater importance for

the development of polyneuropathy [194]. It is also possible that the referring

general practitioner or the diagnosing neurologist identified most cases of toxic

neuropathies.

Conclusions    Cryptogenic polyneuropathy is a slowly progressive sensorimotor nerve lesion

with minor or moderate severity. Men are affected almost twice as often as

women. The typical patient is at least 60 years old and complains of numbness

in the feet. Neurological investigation reveals impaired proprioception and/or

sense of vibration and decreased or lost ankle tendon reflexes.

94

Neurophysiological examination shows sensorimotor polyneuropathy with

mainly axonal involvement.

We have found that patients with cryptogenic polyneuropathy have poorer HR-

QOL, except for mental health scores, than the general population. Pain seems

to be one of the main contributors to the poor HR-QoL. More than 3 out of 10

patients reported problems performing activities of daily living, and it was even

more common to have problems walking, which was more common than

expected. Age and disease duration did not seem to affect QOL, but this is

contradicted by the fact that patients reported more symptoms when the

questionnaires were repeated 2 years later. However, our data support that

cryptogenic polyneuropathy is a slowly progressive disorder.

Our study is the first case-referent study focusing on occupational and

environmental determinants for cryptogenic polyneuropathy. The study has

limitations in size and exposure assessment as we had to rely on self-reported

exposure. Our results suggested that not only known determinants could be

confirmed, but also some new ones appeared i.e., sulphur dioxide, hydrogen

sulphide, fungicides, and vibrations in the feet. Moreover, our results point to a

synergistic effect of various exposures. Men were more often exposed to

neurotoxic chemicals and vibrations than women, probably explaining most of

the increased risk for polyneuropathy in men.

No significant correlation was found between GSTM1, GSTT1, and EPHX1

polymorphisms in patients with cryptogenic polyneuropathy compared with

controls. A strong tendency, however, was seen for the GSTT1 null phenotype,

which was enhanced among smokers compared to controls (OR 3.7). The

GSTT1 null polymorphism may be related to an impaired metabolism of toxic

substances and reactive oxygen that could lead to nerve damage in the peripheral

95

nervous system. This could contribute to, or directly result in an axonal or

combined axonal-demyelinating neuropathy. A larger study of unselected

polyneuropathy cases and controls is warranted to confirm these data.

Future work should also include a larger community-based prospective study of

slowly progressive symmetric polyneuropathy in which all patients have a

thorough neurological examination, and laboratory tests including blood

glucose, complete blood count, ESR, serum electrophoresis, renal and liver

function, vitamin B12/folic acid, TSH, and chest X-ray. In addition, nerve

conduction velocities and amplitudes should be performed before diagnosis. It

would also be of value to assess QOL using both generic and neuropathy-

specific QOL scales and perform clinical evaluation of patients with repeated

functional assessment and neurophysiological evaluations to describe the

implications in patients with cryptogenic polyneuropathy and the prognosis over

a longer period.

 

 

   

96

Acknowledgements  

This work was carried out as a collaboration project between the Departments of

Neurology, Neurophysiology and Occupational and Environmental Medicine at

the University Hospital in Linköping; the Department of Public Health and

Community Medicine, Institute of Medicine, University of Gothenburg;

Division of Cellular Biology, Department of Biomedicine and Surgery,

Linköping University; the Department of Internal Medicine, Division of

Neurology, Motala Hospital, and The Department of Internal Medicine at Ryhov

County Hospital, Jönköping.

I wish to express my sincere gratitude to:

Assistant Professor Magnus Vrethem, main supervisor, co-author

for his immense knowledge of neurology and neurophysiology in general and of

polyneuropathies in particular,

for his never-ending enthusiasm and encouraging support during the long

project and for constructive criticism during the preparation of manuscripts

and most of all for being a very good friend

Professor Eva Svanborg, co-supervisor

for her extensive knowledge about neurophysiology,

for her guidance in the scientific world and bureaucracy.

Med dr Martin Tondel, co-author

for deep knowledge in environmental medicine and public health,

for always asking questions and raising new possible hypotheses.

Med dr Bodil Persson, co-author

97

for her knowledge about the metabolism of toxic substances.

Professor Peter Söderkvist, co-author

for introducing me into the world of genetic polymorphisms and their

importance in the metabolism of solvents and other toxic substances.

Assistant Professor Mats Fredriksson, co-author

for his expertise in statistical methods,

for sorting everything out

Med dr Anders Österberg, co-author

for recruitment of patients

Dr Shahrzad Hosseininia, co-author

for laboratory work

Pia Jönsson, co-author

for epidemiological expertise

Research nurses Miriam Carlsson and Gun Johansson

for their outstanding assistance in collecting blood samples and questionnaires,

for bringing joy and laughter into the work.

Professor Jan-Edvin Olsson

for advice and help

Associate Professor Raymond Press

for advice and encouragement

98

Professor Anna-Christina Ek

for advice and for sharing her expertise in quality of life study methodology

Professor Bo-Erik Malmwall

for supporting me to take the step to work as a researcher

Dr Margareta Hultgren

for her endurance in clinical neurology and cooperative support during these

years

Co-workers at the Section of Neurology at the Department of Internal Medicine

at Ryhov County Hospital: Med Dr Anna Budzianowska, Dr Anna Eklund, Dr

Helena Bruhn, Dr Greta Gustafsson, Dr Owe Lannemyr, Dr Robert Bielis, Med

Dr Sven Pålhagen, nurses Gudrun Carlsson, Ingvor Lindh and Ulla Andersson

for cooperative support during years of studies.

The heads of Internal Medicine at Ryhov County Hospital: Dr Leif Ockander,

Dr Staffan Schöön and Dr Agneta Ståhl

The staff at the medical library at Ryhov Hospital

for always being nice and helpful in the search for literature

And finally to my wife Ulrika and our children Andrea and Philip

for supporting me during these years of too much work.

99

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