The main findings in our study are the frequency of motor symptoms, the preponderance of the axonal form and the dominance of diabetes, APRN and ALS in etiological investigations. To the best of our knowledge, this is the first hospital-based study on peripheral neuropathy in southern Morocco.

One of the challenges in comparative studies on etiological profiles is that several studies are demographic- or type-specific in that they explore neuropathies in the elderly only or in diabetic patients only. There is also the problem of definition. Different studies tend to define or group diagnoses together. As an example, Hanewinckel and colleagues defined inflammatory neuropathies as including “Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and neuropathies associated with paraproteins, paraneoplastic antibodies, and infections (human immunodeficiency virus, Lyme disease, leprosy).” This led to a prevalence of 13% for inflammatory neuropathies and this was distinct from connective tissue disease/vasculitis-associated neuropathies which had a prevalence of 4% [8]. Verghese and colleagues, however, distinguished inflammatory-demyelinating, cancer, MGUS (monoclonal gammopathy of undetermined significance), vasculitis, and infection. Unlike Hanewinckel and colleagues, however, they restricted their study to the “young-old” and the “old-old” [9]. Much like Verghese and colleagues, Visser and colleagues clustered etiologies [5]. This was not the case in our study. These make it difficult to have a clear general picture of etiological profiles and the relativity that exists across geographical zones.

A finding in our study consistent with patterns in the literature is the quasi-constant preponderance of diabetes [5, 8, 9]. A population-based study conducted in Egypt placed diabetes atop the list of non-compressive neuropathies [10]. A similar trend was reported in a study in Nigeria [11]. In a Norwegian study, however, idiopathic neuropathies were the most frequent in their sample [12]. In our study, idiopathic polyneuropathies represented only 5% of the sample and occupied the fifth position together with medication-associated polyneuropathies. A general trend in the literature is the gradual dwindling of idiopathic-tagged neuropathies with the advent of better diagnostic tools and the greater recognition of hereditary and immune-mediated causes which were much more difficult to distinguish in the past [13, 14]. Indeed, it has been suggested that both cryptogenic neuropathies and diabetic neuropathy might share common risk factors and a common underlying pathology [15]. The steep difference between diabetic and idiopathic polyneuropathies in our sample attests to the extensiveness of investigations in a quest to label neuropathies. Interestingly, Rudolph and colleagues report the absence of a cause in 28% of their sample [12]. Table 4 summarizes our findings compared to other hospital-based populations.

Table 4 Comparison of etiologies of peripheral neuropathies with four other studies

It is crucial, when faced with a patient with peripheral neuropathy, to first exclude emergencies. Guillain–Barré syndrome (GBS) is the peripheral neuropathy emergency par excellence. It is the idiopathic form of the APRN. Clinically, it is an acute bilateral, symmetrical, synchronous, ascending motor and/or sensory impairment. The risk of cardiovascular dysautonomic symptoms and the involvement of chest and bulbar muscles lead to a high mortality of the condition [16]. The ten deaths recorded in the study were due to APRN alone, resulting in a mortality of 21.3% of APRN cases. This is much higher than other series in the literature [16, 17]. This might be due to delay in diagnosis and limited means for adequate management of patients in an intensive care setting. APRN was the second most frequent form of peripheral neuropathy after diabetes in the present study. Epidemiological studies place GBS much further below diabetic neuropathy in frequency, with an annual incidence of 1–2 and 23–54 per 100,000 persons, respectively [8]. There is a relatively high prevalence of APRN in our sample. This could be due to the fact that neuropathy in other diseases such diabetes and systemic illnesses tends to be managed by other specialists. APRN; however, being an emergency tends to always fall to the neurologist.

In APRN, it is understood that the peripheral nervous system is caught in the crossfire between the immune system and pathogens in the body by molecular mimicry. The role of Campylobacter jejuni in the pathogenesis of the aberrant immune response that leads to auto-attack by antibodies has been well documented [18]. In like manner, growing evidence points to the implication of several other pathogens as is the case in the present study [19]. Causes found included Helicobacter pylori, Treponema pallidum and Mycobaterium tuberculosis infections. More recently, COVID-19 infection and vaccines have also been implicated [2]. Typically, electrophysiological data point to a demyelinating process. However, geographical variations have been observed with Western countries reporting demyelinating disease, whereas Asian region reporting axonal forms [20, 21]. In addition, a chronic form of polyradiculoneuropathy (CPRN) was found to have a much lower prevalence in this study. It generally causes more morbidity than mortality as compared to APRN [22].

Peripheral neuropathy due to diabetes is the most encountered scenario in the clinical setting. However, it should be considered a diagnosis of exclusion. Its prevalence has been estimated to be between 200 and 600 cases per 100,000 [8]. The presentation could be multifaceted and require exploration of other etiologies rather than settling down for the obvious diagnosis. Typically, patients present with sensory symptoms ranging from hypoesthesia to dysesthesia. Autonomic findings are also frequent and might involve erectile issues in males along with gastroparesis or constipation and urinary difficulties. Diabetic neuropathy occurs in patients who have had a long history of diabetes and typically uncontrolled blood glucose levels. This glucose toxicity leads to axonal damage. The link between blood glucose and neuropathy seems much less straight forward in type 2 diabetes than it is in type 1 diabetes. Several risk factors such as hypertriglyceridemia, dyslipidemia, obesity and hypertension might be implicated in neuropathology, and modifying them might help keep impairment at bay [23]. Diabetic neuropathy is a risk factor for falls and amputations. In fact, diabetic neuropathy is associated with an increased risk of mortality in patients [24].

The algorithm for ordering paraclinical investigations is based on the rule of using a justifiable number of tests with the greatest diagnostic returns. It is helped by the trends in regional frequency of causes and the ease of obtaining tests to make diagnoses. This requires knowledge of regional profiles of neuropathies, and available means. In addition, it is important to take note of patient history and the clinical picture. Routine tests such as the complete blood count (CBC), erythrocyte sedimentation rate (ESR), fasting blood glucose (FBG), blood electrolytes, renal, liver and thyroid function are an initial step toward making an accurate diagnosis [25]. In addition, in our setting, it is routine practice to order syphilis serology and CSF routine tests. Vitamin B12 assay is routinely ordered according to series in the literature but this was only ordered in 10/180 cases in this series.

Also, it is important to perform electrophysiological evaluation to classify the neuropathy type. Nerve conduction studies (NCS) would define the axonal or myelinic type and the sensory or motor type. In our setting, these routine tests were the most frequently ordered in case of peripheral neuropathies.

These tests could give an idea about the underlying pathology to the neuropathy. Elevated ESR might signal an inflammatory disorder or a neoplastic origin. Diabetes could be suspected on FBG, and renal, liver or thyroid dysfunction could be diagnosed on routine tests. In case of macrocytic anemia, for example, vitamin assays should be ordered. In the present work, vitamins B12 and E were the two vitamin assays ordered. In our study, deficiency neuropathy was present in 1.1% of our patients which is far lower than a Nigerian study which reported a frequency of 10.1% [11]. Visser et al., however, did not find deficiency neuropathies in their study in a Dutch population [5]. The differences in prevalence of deficiency neuropathies might be due to differences in standards of living. Deficiency neuropathies in developed countries might be associated with alcohol abuse and the accompanying denutrition, rather than malnutrition. Vitamin deficiency neuropathies are typically sensory neuropathies [26]. The mechanisms by which this deficiency occurs are multiple and sometimes multifactorial. They are dominated by malnutrition, malabsorption syndrome, chronic pancreatitis, as well as alcohol and tobacco use because of the undernutrition they cause [27]. A related neuropathy is critical illness polyneuropathy (CIP). Denutrition has been suggested as possible cause. However, this and the implication of other factors remain speculative [28]. Deficiency neuropathies and CIP are relatively less frequent in our population sample.

An important cause of peripheral neuropathies in our patients is alcohol abuse. It is twice as frequent as deficiency neuropathies and nearly four times as common as other toxic causes put together. This is interesting given the religious context in Morocco, where alcohol is prohibited. Alcohol neuropathy is classically a sensory neuropathy due to direct toxicity of alcohol and the implication of nutritional deficiencies associated with alcohol abuse [29].

Vasculitic neuropathies are also an important etiological mechanism of peripheral neuropathies. These could be encountered in the context of systemic illnesses, infections, paraneoplastic and drug-induced disorders [30]. Extensive laboratory workup is required in such instances. It is important to test for anti-ganglioside antibodies, anti-myelin associated glycoprotein, angiotensin-converting enzyme titer, anti-nuclear antigen profile, anti-neutrophil cytoplasmic antigen antibody profile, cryoglobulins, anti-Ro, anti-La, rheumatoid factor, as well as anti-Caspr1/2, anti-LGi1 and anti-ganglionic acetylcholine receptor antibodies. In addition, infectious serologies (hepatitis B and C, HIV, syphilis) should be performed [1]. Patients in this study with systemic illness-associated neuropathy were found to have Sjogren, rheumatoid arthritis and polyarteritis nodosa. Vasculitic neuropathies are usually associated with extra-neurological symptoms and constitutional symptoms. The classic clinical presentation is painful mononeuritis multiplex [31]. Infections such hepatitis C, Human immunodeficiency virus (HIV), Borrelia burgdorferi and Hansen bacillus infections were incriminated in infectious neuropathies in our cohort. Drug-induced neuropathies could also be encountered in the process of treatment of these neuropathies. Anti-retrovirals and anti-tuberculosis drugs, such as isoniazid are known culprits [32]. In addition, paraneoplastic neuropathies are worth determining as this might lead to an early diagnosis of a tumor [33].

These cases require extensive workup to come up with an exact diagnosis for proper treatment. Immunological tests in CSF and serum are crucial. Radiological imaging is also necessary. For patients presenting with paraneoplastic neuropathy in the present cohort, two patients were diagnosed with kidney tumors using magnetic resonance imaging (MRI), while a third had unlabeled abdominal masses on ultrasound evaluation. In addition, nerve biopsy in challenging cases could make a difference. In our cohort, nerve biopsy was ordered only in 4 cases.

In amyloid neuropathy, nerve biopsy is essential. Salivary gland and skin biopsies could also be performed to search for abnormal beta-sheet fibrillar protein aggregates. In the present study, only one case of amyloid neuropathy was identified, a testament to the rarity of the condition in our population. This single case was the subject of a case report in 2009 [34]. Amyloid neuropathy typically involves the autonomic system. It occurs in a context of systemic involvement including cardiac hypertrophy, hepatomegaly, renal and hematological disorders [3].

ALS is an important cause of peripheral neuropathy coming third in frequency in the present study. However, it involves both the upper and lower motor neurons such that the condition is characterized clinically by an association of both central and peripheral motor impairment. No sensory involvement is associated. Patients typically present fasciculations suggestive of anterior horn cell involvement and confirmed on NCS [35]. It is important to point out the presence of primary and secondary forms. The majority of cases in this study were of primary origin with only 5 cases imputed to syphilis. HIV-associated ALS has also been reported in other series [36].

Like the above, Friedreich’s disease involves both the central and peripheral nervous systems. However, unlike ALS, its systemic involvement is far-reaching and responsible for a clinical picture including several neurological findings, such as motor and sensory neuropathies, cerebellar impairment, visual and auditory issues, as well as musculoskeletal deformities, cardiovascular problems and diabetes [4]. The condition is an autosomal recessive disorder and, given the high rate of consanguinity in several areas in the country, we suspect there might be a higher prevalence of the condition in Morocco than elsewhere [37]. Out of the 5 cases identified in our patients, 2 were a brother and a sister from a consanguineous marriage.

The main limitation of the study is that we used a hospital-based cohort which might in reality be nothing like what goes on in the general population. However, it is important to point out that such a study, especially this convenience cohort, is important in revealing hospital-relevant diagnoses. That is, we know better the etiological profile of patients whose neuropathy would tend to land them in the hospital, and more specifically, in the Neurology ward. This knowledge is more important to the hospital practitioner than a population profile per se. Despite exhaustive investigations, an etiology was not found in 5% of cases.

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