CNS Whipple Disease Clinical Presentation

Updated: Dec 11, 2014
  • Author: George C Bobustuc, MD; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Presentation

History

Whipple disease commonly starts with GI complaints, but because of the multisystemic involvement, presentation can be quite variable. At any time in the course of the disease a constellation of symptoms relating to different organ systems may be present. The GI symptomatology is initially mild, and affected persons may go years before seeking medical attention, often for symptoms other than GI-related ones.

  • Symptoms at presentation (other than CNS related) include the following:

    • Weight loss (80-100% of patients) generally ranges from 20-40 pounds over several months to years.

    • Diarrhea, watery or fatty, occurs in 75% of patients. Occult blood loss was reported with almost all patients, but clinically relevant lower GI bleed (hematochezia or melena) is distinctly unusual.

    • Arthralgia (70% of patients) typically is the most common cause of initial concern for the patient. It is migratory in nature and involves large joints in an asymmetric fashion.

    • Abdominal (nonspecific) pain (50%) is usually more severe after eating.

    • Chest (ie, pleural and/or pericardial) pain with or without nonproductive cough occurs in 50% of patients.

    • Fever occurs in 45% of patients.

    • Leg swelling (25%) typically occurs after 1-2 years of progressive arthralgias and diarrhea.

    • Glossitis occurs in 20% of patients.

    • Abdominal fullness (ie, ascites and/or splenomegaly) occurs in 20% of patients.

  • Fewer than 10-15% of patients with Whipple disease eventually develop clinically significant CNS involvement. A review of patients with CNS-WD showed that by the time of CNS disease onset they often report previous systemic problems, including the following:

    • Chronic migratory arthralgias or polyarthralgias, sometimes for several years, preceding the onset of neurological symptoms (48% of patients)

    • Unexplained weight loss (46% of patients)

    • GI complaints (45% of patients), including chronic diarrhea in 39%, abdominal pain in 20%, steatorrhea in 13%, and abdominal distension in 8%

    • Fever of unknown origin (40%)

    • Malaise (29%)

    • Night sweats (4%)

    • Blurry vision (2%)

  • GI complaints usually precede CNS-WD symptoms by several years. A limited group of patients has manifestations other than GI at onset, and they seem to have a higher likelihood of developing CNS involvement. CNS symptoms are more frequent at the time of relapse (60-70% of relapse patients, most of whom do not have recurrence of intestinal symptoms).

  • CNS symptoms: Fewer than 100 cases of patients with confirmed CNS-WD have been reported. Most of these patients presented for a combination of neurological and psychiatric symptoms. Most commonly the symptoms included cognitive changes, movement disorders (eg, myoclonus), hypothalamus-related problems (eg, polydipsia, hyperphagia, decreased libido), and seizures.

  • Altered mentation was the most frequent presenting symptom, seen in almost 75% of patients with CNS-WD.

    • Almost 50% of these patients had a concomitant psychiatric illness (eg, depression, hypomania, anxiety, psychosis; mostly with delusional content, or change in personality).

    • Two thirds of patients with altered mentation (almost 50% of all patients with CNS-WD) had dementia.

    • Other mentation problems were limited loss of memory, change in reasoning, and change in attention span. [17]

  • Hypothalamus-related problems (eg, polydipsia, hyperphagia, decreased libido, amenorrhea, change in sleep-wake cycle with insomnia, but never with isolated somnolence), though clinically significant and largely disregarded by patients, represented initial manifestations of CNS involvement in 30% of patients.

  • Myoclonus, including brief, irregular, jerky movements, represented the presenting symptom in 10-15% of patients.

  • Seizures (ie, simple or complex partial seizures, generalized tonic-clonic seizures, either alone or complicating partial seizures) represented the presenting symptom in about 10-15% of patients.

  • A specific clinical triad noted in CNS-WD includes dementia, vertical ophthalmoplegia, and myoclonus.

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Physical

Exhaustive physical examination should be performed to assess the extent of extraneuraxial involvement; systems and/or organs usually known to be affected in Whipple disease (ie, GI, cardiovascular, pulmonary, CNS, liver, skin) should be targeted.

  • Signs (other than CNS) seen at presentation are as follows:

    • Hypotension (defined as systolic blood pressure < 110 mm Hg and diastolic blood pressure < 60 mm Hg): This is usually a very late finding and has been described in more than 70% of patients with long-standing GI complaints (usually for several years). In some patients, hypotension is part of their dysautonomia. Another dysautonomic feature described in the late stages of Whipple disease is hypothermia.

    • Peripheral lymphadenopathy (more than 50% of patients)

    • Nonspecific abdominal tenderness (50% of patients)

    • Hyperpigmentation and/or skin photosensitivity (40% of patients; does not represent adrenal failure)

    • Low-grade fever (40% of patients)

    • Cardiac murmurs (more than 30% of patients)

    • Peripheral edema (25% of patients)

    • Splenomegaly (25% of patients)

    • Glossitis (25% of patients)

    • Ill-defined abdominal mass (20% of patients)

    • Pleural and pericardial friction rubs (less than 10% of patients)

    • Ascites (very infrequently chylous): This is rare.

    • Uveitis (2% of patients)

  • In patients with a high likelihood of having Whipple disease (based on historical data and general examination), the comprehensive neurologic examination should target cognition and (eye) movement abnormalities, especially signs with high pathognomonic value (eg, vertical supranuclear ophthalmoplegia [SNO] with or without oculomasticatory myorhythmia [OMM] [18] and/or oculofacialskeletal myorhythmia [OFSM]).

  • Although dementia, ophthalmoplegia, and myoclonus represent a highly specific diagnostic triad, it is encountered in only approximately 10% of patients with CNS-WD.

    • Dementia - Present in more than 50% of patients with CNS-WD

    • Psychiatric illness (ie, depression; hypomania; anxiety; psychosis, mostly with delusional content; change in personality) - Present in almost 50% of patients

    • Ophthalmoplegia - Present in 50% of patients

    • Myoclonus - Present in 20% of patients

  • Eye findings in CNS-WD are as follows:

    • Supranuclear ophthalmoplegia

      • Both horizontal and vertical SNO are found in approximately two thirds of patients with SNO.

      • Pure vertical SNO is found in approximately one third of patients with SNO.

      • Pure horizontal SNO is never found in CNS-WD.

    • OMM and OFSM are synchronous movements combining pendular vergence oscillations (PVOs) with myorhythmia.

      • PVOs are characterized by 1-Hz, rhythmic, smooth, continuous, convergent eye movements (unilateral or bilateral), varying from 1-25 degrees of amplitude per eye. Return divergent movements never go beyond the primary position. The oscillations continue during sleep and may be subtle and asymmetric. Convergent and return divergent movements happen at the same speed (this does not represent nystagmus, as both phases are of the same speed) and are not accompanied by miosis or accommodation.

      • Myorhythmia represents regular, repetitive contractions (1-2 Hz) of the facial, masticatory, and pharyngeal muscles with or without limb involvement. It persists through sleep and should be distinguished from oculopalatal myoclonus, which most commonly is caused by brainstem strokes and demyelination with a similar average frequency, although it is slightly irregular.

      • PVOs are synchronous with myorhythmic movements of the masticatory muscles and in some patients may include facial and pharyngeal muscles (in the case of OMM) and more extensive myorhythmic movements involving facial and limb muscles (in the case of OFSM).

      • OMM and OFSM are very infrequent signs (< 20 cases have been reported in the literature), and they have been described only in CNS-WD. In all reported cases, OMM and OFSM always have been associated with vertical SNO. Although OMM and OFSM are highly specific for CNS-WD, they have a very low sensitivity of approximately 20%.

      • OMM/OFSM together with vertical SNO are highly pathognomonic for CNS-WD and should prompt timely diagnosis and treatment.

    • Isolated ptosis is found in 23% of patients.

    • Pupillary abnormalities (usually anisocoria or unreactive pupil) are found in only 18% of patients.

  • Other neurologic signs are as follows:

    • Hypothalamic manifestations (in 30% of patients) included polydipsia, hyperphagia, decreased libido, amenorrhea, changes in sleep-wake cycle, and disruptive insomnia. Somnolence as an isolated symptom has never been encountered. Hypothalamus-driven hypopituitarism as a presenting feature was reported in one patient with Whipple disease at relapse, with an MRI-proven rostral infundibular lesion and low levels of cortisol, free testosterone, and free thyroxine without an elevated thyroid-stimulating hormone. [19]

    • Ataxia (cerebellar) is found in 25% of patients.

    • Seizures are found in 25% of patients (ie, simple or complex partial seizures, generalized tonic-clonic seizures, either alone or complicating partial seizures).

    • Segmental myoclonus (which is irregular/nonrhythmic, to be distinguished from myorhythmic movements of OMM and OFSM) is found in 20% of patients.

    • Sensory deficits (usually in a central distribution) are found in 10% of patients.

    • Isolated cranial nerve (CN) palsy (CN III, IV, V, VI, or VII) is very rare (< 3% of patients).

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Causes

Whether the clinical manifestations of Whipple disease result from direct bacterial invasion or from the ensuing inflammatory response is not yet clear.

More effective (ie, sensitive) diagnostic techniques (eg, PCR) have continued to provide more and more evidence of direct bacterial invasion at the various symptomatic-target organ sites, suggesting a combined mechanism of bacterial invasion and ensuing inflammatory response.

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