The onset and clinical picture of konzo are so distinct that the disease is recognizable by lay people within the affected regions. The disease has a sudden onset often preceded by physical exertion such as a long walk. During the initial phase, subjects affected by konzo experience trembling in their legs, a sensation of leg weakness, heaviness, or stiffness; and muscle cramping usually confined to calf musculature. Acutely reversible somatosensory symptoms are often reported and may include paresthesia, numbness, muscle aching, and a sensation of electrical discharge in the back and legs. Blurred vision and difficulties in swallowing have been occasionally reported. Clinical deficits are usually more severe at the onset of the disease confining the affected subjects to beds. Within a few days, the course of the disease stabilizes and the deficits are mostly confined to the motor system. However, a “second attack” remains possible. The most visible feature is the cross-legged (scissoring) gait of affected subjects who may able to walk and/or run. The observed scissoring gait is a good reflection of the Yaka designation of the disease, i.e. konzo (tied legs). Once stabilized, the most prominent sign is a symmetrical postural abnormality with a spastic (cross-legged or scissoring) gait during ambulation. In case of subjects mildly affected by the disease, the spasticity of legs is revealed only when the subject is asked to run (Howlett et al. 1990; Tshala-Katumbay et al. 2001a, b; Tylleskär et al. 1995a). The World Health Organization (WHO) has adopted the following definition and epidemiological criteria for the disease: (1) a heavy reliance on cassava as staple food, (2) abrupt onset (<1 week) of leg weakness and a non-progressive course of the disease in a formerly healthy person, (3) a symmetric spastic abnormality when walking and/or running, (4) bilaterally exaggerated knee and/or ankle jerks without signs of disease of the spine. Based on the ability to walk, the following WHO classification of severity has been proposed: (1) mild form = subject is able to walk without support, (2) moderate form = subject has to use one or two sticks, and (3) severe form = subject is unable to walk (WHO 1996).

On neurological examination, the main clinical picture of konzo consists of an isolated symmetric spastic paraparesis. Deep tendon reflexes of the lower limbs are exaggerated and extensor plantar responses can be elicited in most cases when patients are tested in the recumbent position. Ankle clonus is frequently found. Upper extremities also show pathological reflexes in severely affected subjects, with a clearly noticeable palmomental reflex. Severely affected subjects may show a tetraparesis associated with weakness in their trunk and pseudobulbar signs in the form of speech and swallowing difficulties (Cliff et al. 1999; Cliff and Nicala 1997; Howlett et al. 1990; Tshala-Katumbay et al. 2001a, b; Tylleskär et al. 1995a). A bilateral optic neuropathy may be seen in subjects affected by konzo. This condition encompasses visual impairment, temporal pallor of the optic discs, and defect of visual fields. A pendular nystagmus has also been reported in few cases. The presence of visual symptoms at disease onset and/or optic neuropathy on subsequent examination do not correlate with the severity of konzo (Mwanza et al. 2003a, b). Hearing and sensory function, as well as urinary, bowel and sexual functions, appear to be normal. Subclinical forms and cognitive deficits have been suggested but still need to be confirmed in their nature and origin (Tshala-Katumbay et al. 2001a, b). Physically, stunting and goitre are commonly found (Rosling and Tylleskär 2000).

Biochemical markers of disease susceptibility include low serum levels of prealbumin, albumin, and inorganic urinary sulphate. Markers of toxicant cyanogenic exposure include high blood levels of linamarin (α-hydroxyisobutyronitrile β-d-glucopyranoside), cyanide, thiocyanate, and urinary thiocyanate, the main cyanide detoxification metabolite (Banea-Mayambu et al. 1997; Mlingi et al. 1993; Tylleskär et al. 1991, 1995a, b). Peripheral and central nerve conduction studies show a prominent dysfunction of the pyramidal system with evidence of subclinical involvement of sensory pathways (Table 1). Non-epileptic electroencephalographic abnormalities are found, while magnetic resonance imaging from two subjects has remained unremarkable (Tylleskär et al. 1993; Tshala-Katumbay et al. 2000, 2002a, b). Levels of cyanate, carbamoylated proteins, and markers of oxidative damage may be elevated in subjects severely intoxicated by insufficiently processed cassava (Kassa et al. 2011; Lundquist et al. 1979, 1983, 1995; Rosling 1994; Spencer 1999; Tor-Agbidye et al. 1999).

The diagnosis of konzo is relatively straightforward when the disease occurs in its epidemic form as several families within a community are affected within a common timeframe. The association with poor nutrition and overconsumption of foodstuffs derived from insufficiently processed bitter cassava is needed for the diagnosis of konzo. The disease must be differentiated from lathyrism, another spastic paraparesis associated with poor nutrition and overconsumption of the grass pea Lathyrus sativus (Bradbury and Lambein 2011); and tropical spastic paraparesis (TSP), a neurological entity endemic to tropical Africa, Latin America, and the Seychelles and Japan islands (Gessain and Gout 1992; Proietti et al. 2005). In certain parts of the world, for example the Bandundu province of the DRC, clusters of TSP coexists with konzo (Carton et al. 1986; Kayembe et al. 1990). Whereas konzo appears to be a toxiconutritional disease, the etiology of TSP is linked to the infection by the human T-cell lymphotropic virus type I (HTLV-I) (Gessain and Gout 1992). Because of this association, TSP has been named HTLV-I Associated Myelopathy (HAM). The differential diagnosis of konzo, lathyrism and TSP/HAM may be difficult when (a) either konzo or lathyrism coexist with TSP/HAM or (b) a TSP/HAM subject tests negative to HTLV-I while residing in a konzo- or lathyrism-affected area. In these cases, the differential diagnosis is made by the history of the disease obtained after a carefully conducted structured interview, the dietary habits, and findings at physical examination. TSP/HAM is a slowly progressive spastic paraparesis whereas lathyrism and konzo are non-progressive conditions usually of acute or subacute onset. In addition, clinical signs of sensory and sphincter involvement may be evident in the extremities of TSP/HAM subjects. In the absence of co-morbidity, subjects affected by konzo or lathyrism usually test negative for HTLV-I antibodies or protein immunoblots (Carton et al. 1986; Kayembe et al. 1990; Tshala-Katumbay et al. 2001a; Tylleskär et al. 1996).

The process of identifying the cause of a spastic paraparesis under the tropics may be challenging when the physician is faced with an isolated case. In this situation, the differential diagnosis should be made against other causes of non-compressive myelopathy including but not limited to the subacute myelo-optic neuropathy (SMON) due to clioquinol (5-chloro-7-iodo-8-quinolinol; iodochlorhydroxyquin) intoxication (Benvenisti-Zarom et al. 2005; Konagaya et al. 2004), infections or liver failure (Berger and Sabet 2002; McArthur et al. 2005; Utku et al. 2005), hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), or amyotrophic lateral sclerosis (ALS) (Strong and Gordon 2005). In many cases, the history of the illness, the presence of signs indicating a systemic disease, the genetic and serum and/or cerebrospinal fluid laboratory analyses, the virological testing against other viruses such as the human immunodeficiency viruses type I (HIV-I) and II (HIV-I-II) as well as the neuroimaging findings may help refine the diagnosis. An earlier detection of treatable causes of myelopathy and spastic paraparesis such as tuberculosis remains of paramount importance (Table 2).

The molecular mechanisms of konzo remain unknown, and the absence of an animal model of konzo is a major drawback to study this question. Since many subjects affected by konzo report intense physical activity prior to onset of the disease, failure in cellular energy production, in light of the putative role of cyanide toxicity, has been suggested but not proven. Nevertheless, epidemiological studies have consistently shown an association between the occurrence of konzo, a diet dominated by insufficiently processed bitter (toxic) cyanogenic cassava, and a low protein intake (Rosling and Tylleskär 2000). Bitter (poisonous) varieties of cassava contain large amounts of cyanogenic glucosides namely linamarin (~90 %) and lotaustralin (~10 %). Levels of cyanogenic glucosides in cassava—the plant’s chemical defence system against predators—depend on environmental conditions, including season, soil fertility and moisture (Dixon et al. 1994; Mahungu 1994; Sundaresan et al. 1987). The above-mentioned glucosides are stored in the plant cell vacuoles, while a cyanogen-cleavage enzyme (β-glucosidase, syn. linamarase) is present in the cell wall. Once the physical integrity of the cassava root tissue is disrupted, as in cassava processing for food preparation, the cyanogenic glucosides come into contact with linamarase and are hydrolysed. This leads to the formation of glucose and cyanohydrins (Du et al. 1995; Joachim and Pandittesekere 1991; Mkpong et al. 1990). At pH > 5, the cyanohydrins spontaneously breakdown into ketones and hydrogen cyanide (HCN) gas escapes (O’Brien et al. 1992). Lower pH would lead to persistence of cyanohydrins in the finished food product, with the result that HCN may be released by bacterial enzymatic cleavage in the human gut (O’Brien et al. 1992; Rosling 1994).